Pediatric intensive care [2 ed.] 9788184482720, 8184482728

Table of contents :
Prelims_2
Untitled
Untitled
©
Contributors
Message
Preface
Chapter-01_Recognition and Stabilization of Critically Ill Child
Chapter-02_Predictors of Outcome of Critical Illness in PICU
Chapter-03_Oxygen Therapy
Chapter-04_Upper Airway Diseases
Chapter-05_Pediatric Airway Management
Chapter-06_Resuscitation
Chapter-07_Pediatric Mechanical Ventilation
Chapter-08_Respiratory Monitoring in PICU
Chapter-09_Acute Severe Asthma
Chapter-10_Pulmonary Edema
Chapter-11_Acute Renal Failure in Pediatric Intensive Care Unit
Chapter-12_Acute Heart Failure
Chapter-13_Intensive Care and Emergency Room Management of Arrhythmia in Children
Chapter-14_Vasodilators and Antihypertensives
Chapter-15_Hypertensive Crisis
Chapter-16_Physiology of Fluids and Electrolytes
Chapter-17_Inotropes and Vasopressors
Chapter-18_Multiorgan Dysfunction Syndrome
Chapter-19_Noninvasive and Invasive Hemodynamic Monitoring in the PICU
Chapter-20_Septic Shock
Chapter-21_Choice of Empiric Antibiotics in Severe Sepsis and Septic Shock
Chapter-22_Blood Components in Intensive Care Practice
Chapter-23_Evaluation of a Comatose Child
Chapter-24_Pathophysiology of Intracranial Pressure
Chapter-25_Head Injury in Children
Chapter-26_The Neuromuscular Diseases in Critically Ill Children
Chapter-27_Trauma in Children
Chapter-28_Adrenal Insufficiency in Critical Illness
Chapter-29_Diabetic Emergencies
Chapter-30_Endocrine Emergencies in PICU
Chapter-31_Abdominal Surgical Catastrophy
Chapter-32_Severe Acute Pancreatitis
Chapter-33_Burn Inhalation and Electrical Injury
Chapter-34_Pain Management in the PICU
Chapter-35_Envenomation
Chapter-36_Management of Poisoning
Chapter-37_Nutritional Support in the Critically Ill Child
Chapter-38_Transport of Critically Ill Child
Chapter-39_Critically Sick Child with Human Immunodeficiency Virus Infection
Chapter-40_Doses of Drugs Used in Emergency Situations
Index_2

Citation preview

IAP SPECIALITY SERIES ON

Pediatric Intensive Care

IAP SPECIALITY SERIES ON

Pediatric Intensive Care Editors Soonu Udani MD Pediatric Intensivist PD Hinduja National Hospital and Medical Research Centre, Mumbai Hon. Asst. Professor of Pediatrics Grant Medical College Mumbai, India Deepak Ugra MD (Ped) Consultant Pediatrician Lilavati Hospital and Research Center Mumbai, India Krishan Chugh MD Incharge, Paediatric Intensive Care Unit Chairman, Department of Pediatrics Sir Ganga Ram Hospital, New Delhi, India Praveen Khilnani MD FAAP (USA) FCCM (USA) Head Pediatric Pulmonology and Critical Care MAX Superspeciality Hospital New Delhi, India

®

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First Edition: 2008 ISBN 978-81-8448-272-0

Typeset at JPBMP typesetting unit Printed at Rajkamal

Contributors Akaash Deep Senior Fellow PICU, Royal Brompton Hospital London, UK

Deepika Singhal MD Consultant Pediatrics Intensive Care Apollo Center for Advanced Pediatrics IP Apollo Hospitals, New Delhi

Anand Shandilya MD DCH Consultant Pediatrician National Coordinator PALS IAP Mumbai

Dhiren Gupta MBBS MD (Ped) Consultant Pediatric Intensive Care Unit Sir Ganga Ram Hospital New Delhi

Anant Bangar Registrar Lilavati Hospital and Research Centre, Bandra, Mumbai

Gautam Ghosh MD DCH DNB Head Department of Pediatrics Shree Jain Hospital and Research Center Howrah

Arun MK Mangalore, Karnataka Avinash Bansal MD (Ped) Head Department of Paediatrics Bharat Vikas Parishad Hospital and Research Centre, Kota Bidisha Banerjee MD Senior Resident Division of Child Neurology Department of Pediatrics All India Institute of Medical Sciences New Delhi BR Nammalwar MD DCH DM (Nephro) Chief Nephrologist Department of Nephrology Kanchi Kamakoti CHILDS Trust Hospital, Chennai

Geeta Bansal MD (Ped) Senior Consultant Pediatrician and Director Nishtha Shishu and Kishore Swasthya Kendra, Kota Gurinder Pal Singh Pediatric Intensivist Max Balaji Hospital New Delhi

MD (Ped) FPCC (ISCCM)

HK Aggarwal Associate Professor Department of Medicine and Nephrology BD Sharma PGIMS, Rohtak Indira Jayakumar Consultant, Pediatric ICU Apollo Hospitals Chennai

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PEDIATRIC INTENSIVE CARE

Joe Carcillo Pediatric Intensivist Pittsburgh Children Hospital Pittsburgh, USA Krishan Chugh MD (Ped) Chairman Department of Pediatrics Sir Ganga Ram Hospital New Delhi Kundan Mittal Reader and Coordinator PICU Department of Pediatrics BD Sharma PGIMS, Rohtak Lalitha Janakiraman MD DCH Senior Consultant Kanchi Kamakoti CHILDS Trust Hospital Chennai M Jayashree Additional Professor Department of Pediatrics PGIMER Chandigarh

Narendra R Nanivadekar MD DCH DNB Kolhapur Narendra Rathi MD DNB (Ped) Hon. Asst. Professor of Pediatrics Govt.Medical College Consultant Pediatrician Akola Nitin Shah MD DCH – Hon. Hematologist Oncologist BJ Wadia Hospital for Children Mumbai – Consultant Pediatrician PD Hinduja National Hospital Mumbai – President, Indian Academy of Pediatics 2006 – Fellow, Indian Society of Hematology and Transfusion Medicine – Editor, Indian Academy of Pediatrics Textbook of Hematology Oncology – Editor-in-Chief, IAP Speciality Series Books

Madhavi Thakur Registrar (DNB-Pediatric Surgery) Lilavati Hospital and Research Centre Mumbai

Parvathi U Iyer MD Pediatric Intensivist Division of Pediatric and Congenital Heart Surgery Escorts Heart Institute and Research Centre New Delhi

Mahesh A Mohite Consultant Pediatrician and Intensivist Sai Children’s Hospital, New Panvel Maharashtra

Praveen Khilnani MD FAAP (USA) FCCM (USA) Head Pediatric Pulmonology and Critical Care MAX Superspeciality Hospital New Delhi

Manvinder Singh Sachdev MD FNB (Ped. Cardio) Junior Consultant Pediatric Cardiology Indraprastha Apollo Hospitals New Delhi

Rajeev Redkar Consultant Pediatric Surgeon Lilavati Hospital and Research Centre Bandra, Mumbai

MVH Chandramouli Senior Resident in Pediatrics Sir Ganga Ram Hospital New Delhi

Rakesh Lodha Professor of Pediatrics Consultant in PICU AIIMS, Ansari Nagar New Delhi

CONTRIBUTORS

Rashmi Kapoor MD Pediatric Intensivist Regency Hospital, Kanpur

Suchitra Ranjit Senior Consultant, Pediatric ICU Apollo Hospitals, Chennai

Rekha Luthra MD (Ped) Fellow in Critical Care Paediatrics, PICU Sir Ganga Ram Hospital Rajender Nagar New Delhi

Sudhir Sane MD DCH Consultant Pediatrician Lok Hospital, Thane Mumbai

Rishikesh Thakre MD DCH Consultant Neonatologist and Pediatrician Aurangabad S Chidambarnathan MD (Ped) Consultant Pediatrician Nataraja Children’s Hospital Chidambaram S Krishnan MD Asst. Prof. of Pediatrics and Pulmonology Westchester Childrens Medical Centre Westchester, USA Sanjay B Prabhu MD DCH Consultant Pediatrician and Neonatologist Neoplus Criticare Centre, Mumbai Santosh Karmarkar MCH Lilavati Hospital and Research Centre Mumbai Santosh T Soans Consultant Pediatrician Mangalore, Karnataka Shakuntala S Prabhu MD DCH Professor and Head Department of Pediatrics and Pediatric Cardiology BJ Wadia Hospital for Children Mumbai Soonu Udani MD Pediatric Intensivist PD Hinduja Hospital and Medical Research Centre, Mumbai Hon. Asst. Professor of Pediatrics Grant Medical College, Mumbai

Sukhmeet Singh MD Senior Consultant Pediatrician Guru Teg Bahadur Sahib Hospital Dugri, Ludhiana Suresh Gupta Consultant Pediatric Emergency Medicine Department of Pediatrics Centre for Child Health Sir Ganga Ram Hospital New Delhi Surpreet Nagi DCH Consultant Pediatrician Mumbai Utkarsh Kohli Department of Pediatrics AIIMS, Ansari Nagar New Delhi Vaman Khadilkar MD(Ped) DNB (Ped) DCH (Lon) MRCP (UK)

Child and Adolescent Growth Specialist and Pediatric Endocrinologist Jehangir Hospital and DMH Pune and Bombay Hospital, Mumbai Associate Professor, Pediatric Endocrinology Bharati Vidyapeeth Deemed University Medical College Pune Veena Kalra MD Professor and Head Department of Pediatrics All India Institute of Medical Sciences New Delhi

vii

viii

PEDIATRIC INTENSIVE CARE

Vikas Kohli MD FAAP FACC Senior Consultant Pediatric Cardiology Indraprastha Apollo Hospitals New Delhi

Vishram B Buche Pediatrician Om Child Trust Hospital Nagpur

Vikas Taneja DNB (Ped) Fellowship IAP/ISCCM Junior Consultant Pediatric Cardiac Intensive Care Indraprastha Apollo Hospitals, New Delhi

Vivek Shetty Consultant Orthopedic Surgeon ATLS Trainer and Coordinator PD Hinduja National Hospital and MRC Mumbai

Message Dear Colleague, It gives me great pleasure to present this IAP Speciality Series book on Pediatric Intensive Care. Need to have IAP books in pediatric specialities was always felt by many. While we have many such speciality books written by individuals, we do not have these books under the fold of IAP. We can standardize the format, contents, style and size by having these books under the banner of IAP. Looking at the need of having IAP Speciality books and availability of experts within IAP to do this job, we had targeted to publish books on major pediatric specialities under IAP Speciality Series. IAP published four books under IAP Speciality Series, i.e. Pediatric Infectious Diseases, Rational Antimicrobial Practice in Pediatrics, Pediatric HIV and Pediatric Hematology and Oncology last year. These books were highly appreciated by one and all and this has encouraged us to bring out three more books under the IAP Speciality Series this year, i.e. Pediatric Cardiology, Pediatric Quiz for Undergraduates 1996-2006 and Pediatric Gastroenterology, besides this book of course! I am thankful to Editors Dr Soonu Udani, Dr Deepak Ugra, Dr Krishan Chugh and Dr Praveen Khilnani for their wonderful and painstaking work. I am thankful to the experts who have contributed articles in this book and the IAP office bearers 2006 and 2007 for helping us with concept and editorial work of the entire IAP Speciality Series. I am sure you will find this book useful and informative and hope that this book becomes a desk companion for all the practicing pediatricians and postgraduates in pediatrics. Yours sincerely Nitin Shah Editor-in-Chief, IAP Speciality Series

Preface No other sub-speciality in pediatrics in India has seen as much of a growth and interest in the last decade as has critical care. This is akin to the growth seen in neonatology in the 70s and 80s. Our speciality was seen as being technology dependant and out of the reach of the average practitioner and patient. Additionally, there was little exposure in most medical schools at both the undergraduate and postgraduate levels. Graduates who sought training abroad rarely returned as they perceived that our country would not afford them the opportunities, both professional and financial, in this field. As the gap between the new world and the developing world narrows, many of these young well trained individuals are now seeking careers at home. Corporate hospitals have well staffed and equipped units and several teaching hospitals have equally equipped, excellently staffed units that are fertile training grounds for new generations of intensivists. The origins of formal training in Pediatric Critical Care was born from the initiative of a group who recognized the need for standardized training across the country. A course was designed and offered; first for a few days, then for a few weeks and finally for one year at 5 institutions. Many fresh students and practitioners enrolled for these courses. Today, there are several parallel courses, catering to various needs. There is also National Board recognition for the speciality on a two years fellowship. No doubt there are many excellent textbooks on the subject. Many in much more detail and by much more eminent people who are internationally recognized as doyens in the field. Why then are we bringing out this book? Across the length and breadth of the country, pediatricians look after very sick children and all of them do not have the luxury of Critical Care Units at their disposal, neither can they all complete fellowships in the subject. Yet they cannot turn away the critically ill child in the remote areas where they practice. The majority of our critically ill children do not go to the PICUs of the metros, they go to pediatricians in their towns and villages. This book is aimed at giving the practicing pediatrician knowledge of the subject in as comprehensive a manner as he or she needs. It is a book by our own IAP for us, by us-many of us. It is the collective effort of many. Certain issues like infections that have been covered in other recent IAP series are omitted here. We thank all our contributors and hope that this book fulfills the needs of all our fellow IAP members. Feedback would help us improve the next edition. Editors

Contents 1. Recognition and Stabilization of Critically Ill Child ................................................................. 1 Anand Shandilya, Surpreet Nagi 2. Predictors of Outcome of Critical Illness in PICU .................................................................... 7 Santosh T Soans, Arun MK 3. Oxygen Therapy ..............................................................................................................................12 Mahesh A Mohite 4. Upper Airway Diseases .................................................................................................................22 Avinash Bansal, Geeta Bansal, Rekha Luthra 5. Pediatric Airway Management ....................................................................................................36 Dhiren Gupta 6. Resuscitation ....................................................................................................................................55 Anand Shandilya, Surpreet Nagi 7. Pediatric Mechanical Ventilation ............................................................................................. 63 Praveen Khilnani, Deepika Singhal 8. Respiratory Monitoring in PICU ..................................................................................................89 Vishram B Buche 9. Acute Severe Asthma .................................................................................................................. 107 Gurinder Pal Singh, Krishan Chugh 10. Pulmonary Edema ........................................................................................................................ 114 S Krishnan 11. Acute Renal Failure in Pediatric Intensive Care Unit ......................................................... 121 BR Nammalwar, S Chidambarnathan 12. Acute Heart Failure ..................................................................................................................... 133 Vikas Taneja, Manvinder Singh Sachdev, Vikas Kohli 13. Intensive Care and Emergency Room Management of Arrhythmia in Children ......... 151 Suresh Gupta 14. Vasodilators and Antihypertensives ........................................................................................ 172 Shakuntala S Prabhu, Sanjay B Prabhu

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15. Hypertensive Crisis ..................................................................................................................... 184 Shakuntala S Prabhu, Sanjay B Prabhu, Gautam Ghosh 16. Physiology of Fluids and Electrolytes ...................................................................................... 190 Kundan Mittal, HK Aggarwal 17. Inotropes and Vasopressors ...................................................................................................... 198 Praveen Khilnani, Deepika Singhal 18. Multiorgan Dysfunction Syndrome .......................................................................................... 221 Krishan Chugh, MVH Chandramouli 19. Noninvasive and Invasive Hemodynamic Monitoring in the PICU ................................ 229 M Jayashree 20. Septic Shock .................................................................................................................................. 234 Praveen Khilnani, Joe Carcillo 21. Choice of Empiric Antibiotics in Severe Sepsis and Septic Shock .................................. 250 Suchitra Ranjit 22. Blood Components in Intensive Care Practice ...................................................................... 254 Nitin Shah 23. Evaluation of a Comatose Child ............................................................................................... 265 Veena Kalra, Bidisha Banerjee 24. Pathophysiology of Intracranial Pressure ............................................................................... 272 Soonu Udani 25. Head Injury in Children ............................................................................................................ 277 Rishikesh Thakre, Soonu Udani 26. The Neuromuscular Diseases in Critically Ill Children ..................................................... 291 Lalitha Janakiraman 27. Trauma in Children ..................................................................................................................... 302 Vivek Shetty 28. Adrenal Insufficiency in Critical Illness ................................................................................. 316 Indira Jayakumar 29. Diabetic Emergencies .................................................................................................................. 328 Sukhmeet Singh 30. Endocrine Emergencies in PICU .............................................................................................. 338 Vaman Khadilkar 31. Abdominal Surgical Catastrophy .............................................................................................. 346 Anant Bangar, Rajeev Redkar

CONTENTS

32. Severe Acute Pancreatitis ......................................................................................................... 353 Rashmi Kapoor 33. Burn Inhalation and Electrical Injury ..................................................................................... 360 Santosh Karmarkar, Madhavi Thakur 34. Pain Management in the PICU ................................................................................................ 365 Soonu Udani 35. Envenomation ............................................................................................................................... 374 Narendra Rathi 36. Management of Poisoning ......................................................................................................... 387 Narendra R Nanivadekar 37. Nutritional Support in the Critically Ill Child ....................................................................... 408 Parvathi U Iyer 38. Transport of Critically Ill Child ................................................................................................ 416 Akaash Deep, Sudhir Sane 39. Critically Sick Child with Human Immunodeficiency Virus Infection ........................... 429 Rakesh Lodha, Utkarsh Kohli 40. Doses of Drugs Used in Emergency Situations .................................................................... 442 Praveen Khilnani Index ................................................................................................................................................ 447

xv

Shandilya, Surpreet Nagi 1 RECOGNITION Anand AND STABILIZATION OF CRITICALLY ILL CHILD

1

Recognition and Stabilization of Critically Ill Child

INTRODUCTION A “critically ill child” is a child who is in a clinical state, which may result in respiratory or cardiac arrest or severe neurological complications, if not recognized and treated promptly. Many diseases can lead to this “critically ill state”. Whether a child presents with a primary cardiovascular, respiratory, neurological, infectious or metabolic disorder, the goal should be early recognition of respiratory and circulatory insufficiency. An experienced clinician finds it easy to recognize a critically ill child. It is essential for the clinician to assess and classify the degree of sickness. It is also important to identify a child with physiological derangement in its early stages when signs are subtle. The “golden hour” concept applies to all children with illnesses presenting as emergency. Early recognition of a “critically ill child” requires a systematic and rapid clinical assessment, with background knowledge of age appropriate physical signs and level of development. The process of examining a child is known as Rapid Cardiopulmonary Assessment. It should take the clinician about 30 seconds to complete this assessment with practice. Selected conditions that require a rapid cardiopulmonary assessment: Respiratory rate > 60/min Heart rate > 180 or < 80/min (under 5 years) > 160 or < 60/min (over 5 years) Respiratory distress - increased work of breathing (retractions, nasal flaring, grunting) Trauma Burns totaling > 10 % of body surface area Cyanosis Failure to recognize parents Diminished level of consciousness - unusual irritability or lethargy Seizures Fever with petechiae or rash Admission to an ICU.

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A very simple and quick way of assessment of overall illness and injury severity is by the mnemonic ABC: 1. Appearance of the child/Airway 2. Breathing 3. Circulatory status. APPEARANCE OF THE CHILD Appearance basically denotes the neurological status. It is determined by the oxygen and blood supply to the brain, which is dependent on the cardiopulmonary status and the structural integrity of the brain. The parameters assessed in appearance are alertness, distractibility or consolability, response to stimuli, eye contact, speech or cry, motor activity and color of the skin. In addition, seizures, abnormal posture, muscle tone and pupillary reaction are noted. 1. Alertness: Normal children exhibit awareness and interest in surroundings. It is important to determine if the child is confused, irritable, lethargic or totally unaware of the environment. Changes in level of consciousness can also be rapidly assessed by using the mnemonic - AVPU. • Awake • Responsive to Voice • Responsive to Pain • Unresponsive. 2. Distractibility or consolability by parent is a normal phenomenon in infants and young children. Children who are not distracted or consoled by the caregiver should be carefully assessed. 3. Eye contact with parents or physician is noted normally after 2 months of age. Failure to do so is an early sign of cortical hypoperfusion and brain dysfunction. 4. Speech/cry: It should be noted whether the cry is normal, whimpering, moaning or high pitched. 5. Motor activity: A note should be made of the movement of the trunk and limbs. An assessment should be made of the muscle tone. A child who is limp and hypotonic is compromised. 6. Color of the skin reflects skin perfusion and indirectly – the respiratory and circulatory status. The skin of the palm and fingers may be pink (normal), pale, cyanosed, mottled or ashen grey depending on the degree of compromise. 7. Posturing: Intermittent flexor (decorticate) or extensor (decerebrate) posturing occur with prolonged cerebral hypoperfusion. 8. Pupil size: Pupils may be small but reactive in cerebral hypoperfusion. Unequal pupils are a medical emergency; may indicate raised intracranial pressure or an intracranial bleed. Airway One needs to assess whether the airway is open and clear or maintainable with adjuncts like oropharyngeal or nasopharyngeal airways, suction, positioning or requires tracheal intubation to be maintained. Breathing

Respiratory Rate Tachypnea is an early sign of respiratory distress. Tachypnea without increased work of breathing (quiet tachypnea) is seen in shock, heart disease and acidosis (a response of the body to wash out

RECOGNITION AND STABILIZATION OF CRITICALLY ILL CHILD

carbon dioxide and usually denotes acidosis). A slow or irregular respiratory rate in an acutely ill child is ominous. Normal newborn

Normal 1 year

Normal 18 years

< 40 – 60

24

18

> 60 always abnormal

Work of Breathing Increased work of breathing (IWB) indicates respiratory distress or respiratory failure. IWB is assessed by nasal flaring, grunting, intercostal, subcostal and suprasternal retractions. Head bobbing and see saw respirations (severe chest retraction with abdominal distension) are more advanced signs of respiratory distress and respiratory failure. As long as the patient can maintain oxygenation and ventilation with this increased work of breathing he is said to compensate and is in Respiratory distress. Once a state is reached where the status quo of oxygenation and ventilation is not maintained, the child is said to be in Respiratory Failure. These are clinical distinctions.

Air Entry Effective tidal volume is assessed by chest expansion and auscultation of breath sounds. Stridor indicates upper (extra thoracic) airway obstruction and may be because of the tongue, laryngomalacia, vocal cord paralysis, hemangioma, tumor, cysts, infection, edema, or aspiration of a foreign body. Wheezing indicates intrathoracic obstruction due to conditions such as bronchiolitis, asthma, pulmonary edema, or an intrathoracic foreign body.

Skin Color and Temperature This will be discussed with circulatory status. Circulatory Status Circulation is assessed to find out if the cardiac output meets the tissue demands. Shock is defined as circulatory dysfunction in which there is inadequate delivery of oxygen and substrates to meet the metabolic demands of tissues. Circulatory status is assessed by heart rate and blood pressure directly. Heart rate changes alone may be too early a sign of derangement and are often nonspecific. By the time hypotension develops it may be very late and the shock is classified as decompensated shock. Hence we evaluate the organs perfused to assess for effective circulation. These are skin, peripheral pulses, brain, and kidneys.

Heart Rate Tachycardia is a common response to a variety of stresses including shock. Hence its presence mandates further evaluation. Bradycardia in a critically ill child is ominous.

Normal:

Newborn - 3 months

3 mos. - 2 years

2 - 10 years

> 10 years

140

130

80

75

3

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PEDIATRIC INTENSIVE CARE

Pulse Comparison of central (femoral, carotid and brachial) and peripheral (radial, dorsalis pedis and posterior tibial) pulses should be done. The presence, strength and volume of the pulses need to be assessed. One must be aware that a bounding pulse does not necessarily denote good perfusion. The loss of central pulse is a premorbid sign and is to be treated as cardiac arrest.

Skin Perfusion a. Temperature: When the ambient temperature is warm, the extremities should be warm. The peripheries start cooling when the cardiac output falls. Assessment of the temperature of the trunk and the extremities should be done simultaneously as cooling occurs from the periphery to the center. b. Color: Color of the skin reflects skin perfusion and indirectly respiratory and circulatory status. Skin of palm and fingers may be pink (normal), pale, cyanosed, mottled or ashen grey depending on the degree of compromise. c. Capillary refill time (CRT): This is checked by applying pressure on the skin or nail so as to cause blanching and assessing the time taken for the color to come back to normal. The normal CRT is less than 2 seconds. Delayed CRT is a feature of early shock. The exceptions are a rising temperature and cool ambient temperature. The extremity being tested should be raised above the level of the heart to make sure that only venous refill is not being tested.

Organ Perfusion a. Brain: Brain perfusion can be assessed by features already described in appearance, i.e. changes in level of consciousness, pupil size, muscle tone and posturing. b. Renal: Urine output may not be useful in initial assessment in a critically ill child, but is useful in monitoring the child and in evaluation of renal perfusion. At least 1 ml/kg/hour of urine output is normal. c. Blood pressure: Shock can be present with normal, increased or decreased blood pressure. In early compensated shock, BP is normal. In late or decompensated shock there is hypotension. Progression to irreversible/refractory shock or multiple organ failure or death rapidly follows. Lower limit (5th percentile) of blood pressure is: Newborn Up to 1 year 2 to 10 years Beyond 10 years

60 70 70 90

mm Hg systolic mm Hg systolic + (2 × age in years) mm Hg mm Hg systolic

Pulse Oximetry Oxygen saturation assessment is an important adjunct to identify oxygenation state in an acutely ill child. This is also called the fifth vital sign. Based on the appearance, breathing and circulatory status, the physiologic status of a critically ill child is classified as: 1. Stable 2. Respiratory distress

RECOGNITION AND STABILIZATION OF CRITICALLY ILL CHILD

3. 4. 5. 6.

Respiratory failure Compensated shock Decompensated shock Cardiorespiratory failure is characterized by agonal respirations, bradycardia and cyanosis. Based on this physiologic status the severity of the compromise is classified and the child is managed further accordingly. Patients must be re-evaluated after every intervention. For example; if a fluid bolus has been given then assess the child for any improvement as indicated by improved capillary refill, stronger pulses, improved urine output and a lower heart rate. Stabilization Depending on the physiologic status of the child, the following stabilization measures can be undertaken. Airway It should be assessed whether the airway is maintainable or unmaintainable. If the airway is unmaintainable, nasopharyngeal or oropharyngeal airway or intubation is required. The patency of the airway is to be assessed and excessive secretions should be cleared. Airway should be opened by the appropriate maneuver. Breathing Hundred percent oxygen should be provided to any critically ill child irrespective of the physiologic status. If the child has Respiratory Distress the child is kept with the caregiver, is allowed to maintain a position of comfort, and oxygen is provided in a non-threatening manner. Turbulent airflow leads to increased airway resistance; hence the child should be kept calm. If the child has Respiratory Failure, the approach is more aggressive. In case of inadequate chest expansion or respiratory arrest, bag and mask ventilation should be given with 100 % oxygen. Tracheal intubation may be required. Tracheostomy or cricothyrotomy may be required in cases of complete upper airway obstruction caused by diphtheria, severe orofacial injuries or laryngeal fractures. Circulation Once airway and breathing have been stabilized, vascular access is to be secured. Intraosseous route may be used in case of collapsed veins. No child should die due to a lack of vascular access. Any drug can be infused using this route provided it is followed by a flush of fluid to get the drug in the central circulation. Fluid resuscitation should be given. The child needs to be monitored after administration of each fluid bolus. The rate of administration and the number of boluses depend on the type of shock. Blood products should be administered only when specifically indicated for replacement o f blood loss or for replacement of components. When the circulation does not improve with fluid boluses alone, inotropes are used. The goal of therapy is to improve the perfusion and correct the hypotension. Arrhythmias if present need to be corrected.

5

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PEDIATRIC INTENSIVE CARE

CNS Support Seizures should be controlled by anticonvulsants. Raised intracranial pressure is to be corrected by appropriate measures. SUMMARY A Rapid Cardiopulmonary Assessment helps a clinician to classify the degree of compromise of the physiologic status. Based on the degree of compromise the patient is managed appropriately. During stabilization the priority is to address the Airway first followed by Breathing and Circulation. BIBLIOGRAPHY 1. Cummins RO, Hazinski MF. The most important changes in the international EED and CPR Guidelines 2000. Circulation 2000;102:I371-76. 2. Eisenberg MS, Mengert TJ Cardiac resuscitation. N Engl J Med 2001;344:1304-13. 3. Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care. Part 9: Pediatric basic life support. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 2000;102:1253-90. 4. Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular Care: Part 10: Pediatric advanced life support. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 2000;102: 1291-342. 5. Kochanek MK, et al. Cerebral resuscitation after traumatic brain injury and cardiopulmonary arrest in infants and children in the new millennium. Pediatr Clin North Am 2001;48:661-81. 6. Mathers LH, et al. Anatomical considerations in obtaining venous access. Clin Anat 1992;5:89-106.

Santosh Soans, Arun MK 7 PREDICTORS OF OUTCOME OF T CRITICAL ILLNESS IN PICU

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Predictors of Outcome of Critical Illness in PICU

The development of critical illness and outcome depends on a number of factors including the patient’s age, medical or surgical status, emergency or elective status, concomitant disease, physiological reserve, nature and severity of acute illness and quality of care. Critical illness causes alteration of physiologic status and biochemical parameters. Severity and outcome of critical illness may be predicted depending on the degree of alteration of physiologic status and organ system involvement, degree and alteration of vital organ function, status and duration of CVS decompensation, promptness of intervention and the primary disease process. The long-term outcome may also depend on the degree and duration of insult to the CNS. Outcome can be objectively assessed using various scoring systems. Scoring systems to evaluate the prognosis of PICU cases are available. These scoring systems are useful for making triage decisions and assessing the performance of an ICU. Various studies have validated the predictive value of these tests in assessing probability of mortality and outcome in PICU cases. These scores may not be reliable for decision making in a single patient. The scores may be useful in transfer of a case or starting an intervention (e.g. OI in respiratory failure for starting ECMO).1 THE SCORING SYSTEMS The scoring systems used in the PICU can be; 1. Organ specific – like the Glasgow coma scale or Blantyre score (for CNS cases) croup score, pulmonary score, or oxygenation index (respiratory failure) 1. Mechanism of injury – Pediatric trauma score (PTS) or Injury severity score. 2. Pediatric ICU cases – Pediatric Index of Mortality (PIM). Physiologic Stability Index (PSI) Pediatric Risk of Mortality (PRISM).

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PRISM SCORE The prognosis and mortality of PICU cases depends on the physiologic status of the child. The relationship between physiologic status and mortality risk may change as new treatment protocols, therapeutic interventions and monitoring strategies are introduced. Therefore these scoring systems are re-evaluated periodically. PRISM is a second-generation physiologic based predictor, derived from the Physiologic Stability Index (PSI). The Prism III score is a recent re-evaluated and updated version of the original score.2,3 PRISM III consists of 17 physiologic variables subdivided into 26 ranges. The score when obtained within 12 hours of admission is denoted as PRISM III -2 and within 24 hours as PRISM III –24.2,3 This score is developed after considering multiple factors influencing mortality. Contribution of each variable and its ranges to mortality prediction were evaluated and the system was derived. The variables most predictive of mortality are systolic BP, abnormal pupillary reflexes and stupor/ coma.3 The development of PRISM III resulted in several improvements over the original PRISM. The physiologic variables and their ranges were re-evaluated, eliminating some ranges that did not contribute significantly to mortality risk. Some variable including temperatures, PH, PaO2, urea, creatinine, WBC count are added. While age was included as an explicit variable in the original, PRISM III included age – adjusted variables. A formal, operational method for assessing mental status is also included to account for frequent use of sedation and paralysis. Additional predictive terms are also tested and included.3 The relationship between PRISM score and outcome has been calibrated to contemporary large reference PICU samples. Thus PRISM score is sufficiently representative, enabling the score to be used in comparative assessment of ICU outcomes.3 The predictive value of the score under Indian circumstances was studied and showed good results.4 PRISM and PIM scores are also useful in newly founded intensive care units.5 The PIM may perform well in countries where mortality rate is high and pre-existent chronic disorders are more common.6 Various studies have evaluated various scoring systems. PRISM and PIM were found adequate indicators of mortality probability. PRISM was not well calibrated i.e. predicted mortality was greater than observed mortality at different levels of mortality risk. The likely reasons for this could be difference in patient profile and greater load of severity of illness managed with lesser resources, both physical and human and also difference in quality of care.2,6 As mortality rises with increase in PRISM score at the time of admission, PRISM score can be taken as an indicator of the initial severity of illness. As ICU facilities are limited in India, the score is a useful indicator of requirement of ICU care.2 PSI score and organ system failure (OSF) scores were also accurate when used within 24 hours after admission. PELOD scoring system (Pediatric Logistic organ dysfunction) is used to estimate severity of organ dysfunction. The score analyses cumulative influence of and interaction of organ dysfunction. PELOD score is validated for use in mortality prediction in patients with MODS. Mortality also increases with increasing severity of septic state.7 Pediatric trauma score was designed originally for triage purposes. It utilizes six measures resulting in score inversely related to severity. Score of < 8 suggests admission to pediatric trauma center.1

PREDICTORS OF OUTCOME OF CRITICAL ILLNESS IN PICU

Organ Specific Scoring System The usefulness and validity of Glasgow coma scale (GCS), pulmonary score, croup scores for assessing the severity of disease and prediction of outcome is well known. Oxygenation index (OI) is useful in prediction of outcome with acute hypoxemic respiratory failure. OI is calculated – Mean airway pressure × FiO2 ×100/Postductal PaO2 PRISM SCORE9

Variable

Value

Score

Systolic B.P. Infant

45-65 205

3 4

Heart rate(per min)

Temperature

40°C

3

Mental status

GCS < 8

5

Pupillary reflex

One fixed Both fixed

7 11

pH

7.0 -7.28 7.48 – 7.55 < 7.0 >7.55

2 2 6 3

Total CO2 (mmol/L)

.> 34.0

4

PaO2 (mmHg)

42-49.9 75

1 3

Glucose

> 200 mg/dl

2

Potassium(mmol/L)

>6.9

3

Creatinine

>0.9 mg/dl

2

Blood urea

> 14.9 mg/dl

3

WBC count

< 3000

4

Platelets

1-2 lakh 50000-99999 < 50000

2 4 5

PT/PTT (sec)

PT>22 or PTT>57

3

Total PRISM Score = ……………..

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Predictors of outcome in respiratory failure like worst PaCO2, worst ventilatory settings do not correlate well with outcome. Peak OI, younger age and need for renal replacement therapy are significantly associated with longer time to extubation. After controlling for OI and PRISM, no other factor is significantly associated with time related death. But there is no clear-cut threshold that directly predicts mortality and categorization of patients into different levels of risk is not possible. OI greater than 30 at 12 to 24 hours or later predicts > 50% mortality thus OI> 30, could merit consideration for transfer to an ECMO center. Thus of all predictive factors OI significantly predicts outcome, time dependence for extubation and time dependent mortality in respiratory failure.8 Other factors. • Non-operative CV disease or diabetes • Chromosomal anomaly or cancer • Pre- PICU conditions– Previous PICU admission – Pre PICU CPR – Postoperative condition – Admission from in patient unit. Score

Probability of death (%)

5

9

10

15

15

23

20

35

25

49

30

63

35

75

How to Use the Score? • • • • • •

Calculate PRISM score at 12 hours and 24 hours after admission. Exclude admissions routinely cared in other hospital locations and ICU stay< 2 hours. Do not assess heart rate during cry or agitation. Use rectal, oral or axillary temperature. Non-reactive pupil should be >3 mm. Mental status: Include patients with suspected CNS pathology. Do not assess within 2 hours of sedation, paralysis or anesthesia. • Use calculated bicarbonate values from blood gases only if total CO2 is not measured. • pH and PCO2 may be measured from arterial, capillary or venous sites. PaO2 – use arterial measurements only. (From Pollack MM et al9).

PREDICTORS OF OUTCOME OF CRITICAL ILLNESS IN PICU

The scoring systems are useful as indicators of severity of illness and need for intensive care. They can be used to evaluate prognosis and outcome. This information is useful for optimum interventions and treatment to improve the outcome of critical illness. REFERENCES 1. Dicarlo JV, Frankel LR. Scoring systems and predictors of mortality. In Nelson’s textbook of pediatrics, 17th ed. Philadelphia: Sounders.2004; 277-79. 2. Thukral A, Lodha R, Irshad M, et al. Performance of PRISM, PIM and PIM2 in PICI in a developing country. Pediatrs Crit Care Med 2006;7(4):356-61. 3. Prince HL, Mathew DJ. Evaluation of pediatric intensive care scoring systems. Am J Resp Crit Care Med 2004;168:25659. 4. Singhal D, Kumar N, Puliyel J M, et al. Prediction of mortality by application of PRISM score in ICU. Ind Pediatr 2001; 38:714-19. 5. Ozer EA, Kizilgunesler A, Berrak S. Comparison of PRISM and PIM scoring systems for mortality risk in infantile intensive care. J Trop Pediatr 2004;50(6):334-38. 6. Gemke R J, VanVught J. Scoring systems in pediatric intensive care: PRISM Vs PIM. Intensive Care Med 2002;28(2): 105-7. 7. Leteurtre S, Martinot A, Duhamel A, et al. Validation of the PELOD scores; Prospective, observational, multicentre study. Lancet 2003;19;362(9379):192-97. 8. Trachsel D, Mccrindle BW, Nakagawa S, et al. Oxygenation index predicts outcome in children with acute respiratory failure. Am J Resp Crit Care Med 2005; 172: 206-11. 9. Pollack MM, Patel KM, Ruttiman UE. PRISM3: An updated pediatric risk of mortality score. Crit Care med 1996;24: 743-52.

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Mahesh A Mohite

PEDIATRIC INTENSIVE CARE

Oxygen Therapy

3 Whenever body tissues face stress, the first physiological response is an increased metabolic demand, which increases oxygen demand. Oxygen is probably the maximally used drug in intensive care units (ICUs) all over. Tissue oxygenation is determined by the formula: O2 delivered = O2 carrying capacity of blood × cardiac output = ( Hb in gm × 1.34 × % O2 saturation of Hb) × (stroke vol × heart rate) As a primary response, the body tries to fulfill these demands by increasing the stroke volume and heart rate. In adults, the stroke volume can increase significantly while in the pediatric age group there are minimal stroke volume reserves and increased heart rate compensates maximally. If the demands increase beyond the compensatory mechanisms (decompensation), tissue oxygenation is jeopardized and anaerobic metabolism ensues with generation of lactate–the cascade of metabolic acidosis–negative inotropism–circulatory maldistribution is stimulated and ends up in multi-organ failure. In a stressful condition this failure cascade can be prevented or at least delayed, by timely oxygen supplementation. Oxygen is a life saving drug; and being a medication it carries a recommended dose. Overuse of oxygen can lead to serious longstanding side effects; so while using it, exact indications need to be defined and it should be used judiciously. Adequate tissue oxygen supply is the end result of adequate ventilation through the upper airways, lower airways and lung parenchyma; optimum perfusion across alveolar and capillary membrane, proper flow of blood across heart and pulmonary vasculature, uninterrupted systematic distribution of blood by cardiovascular system to all tissues and adequate oxygen carrying capacity of blood. Failure at any level will demand extra oxygen supplementation.

OXYGEN THERAPY

INDICATIONS FOR OXYGEN SUPPLEMENTATION In clinical practice oxygen is supplemented therapeutically or prophylactically in the following conditions: • Significant airway obstruction–upper airway and or lower airway due to various causes. • Inadequate alveolar perfusion of oxygen due to parenchymal (alveolar, interstitial, etc.) disease— e.g. pneumonia, ARDS. • Arterio-venous shunting of blood—either intracardiac or extracardiac. • Failed cardiac pump—not able to pump adequate blood into lungs or into body. • Circulatory failure leading to maldistribution or poor distribution of blood, e.g. in septic shock or neurogenic shock. • Decreased oxygen carrying capacity of blood, e.g. severe anemia or abnormal Hb as in methemoglobinemia. • Increased oxygen demands by body tissues, e.g. generalized inflammation (SIRS) in sepsis or burns. Indications for Intervention • • • • •

Dropping SpO2 Increasing FiO2 Fatigue, confusion, agitation, drowsiness (ABG to look for PaO2, PaCO2, acidosis) Poor respiratory effort Heart rate, BP fluctuations Oxygen is also supplemented prophylactically where a drop in oxygenation is expected while doing a procedure as in • Pre-intubation • Prior to general anesthesia. Commonly the terms hypoxia and hypoxemia are used interchangeably but there is a theoretical difference where hypoxia indicates tissue under-oxygenation, while hypoxemia indicates decreased oxygen content of blood. A patient may be hypoxic but not hypoxemic as in severe septic shock and vice versa as in hemodynamically stable cyanotic heart disease. Hypoxia is always the cause of concern and usually a medical emergency. HOW TO DETERMINE OXYGENATION Clinical Markers of Hypoxia Hypoxia in a child will manifest by virtue of the body’s compensatory efforts and by effects on tissues, which are under oxygenated. Compensatory efforts are usually the initial events with tachypnea, dyspnea, tachycardia, palpitations, usually proportional to severity of hypoxia; and the tissue effects will manifest once the compensatory mechanisms fail to fulfill the demands, as– CNS: Lethargy, confusion, delirium, seizures, coma. Cardiac: A progressive shock state igniting the cascade of progressive multisystem failure. Initially non-vital tissues suffer, like intestinal hypoperfusion leading to abdominal distension, gastrointestinal ischemia; skin hypoperfusion leading to cold clammy skin. Later vital tissues like renal, cardiac, CNS, etc. fail progressively.

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Central symmetrical cyanosis: Clinical cyanosis should be interpreted knowing the hemoglobin (Hb) level. More than five grams reduced Hb is required to cause clinical cyanosis. Severe anemia may not show cyanosis in a severely hypoxic child and a polycythemic child looks cyanosed with even mild hypoxia. Measuring Oxygenation Clinically mild hypoxia up to hemoglobin saturation of 75% is difficult to detect and various investigation are helpful in early identification and regular monitoring of Oxygenation status.

Arterial Blood Gases (ABG) It determines dissolved oxygen in plasma (PaO2), and Hb saturation usually correlates well except few conditions with abnormal hemoglobin. Advantages of ABG: Exact O2 content of blood is determined. Hyperoxia is detected; so related complications can be prevented. Disadvantages of ABG: Continuous monitoring is difficult and costly unless an indwelling catheter for sampling is used. Abnormal Hb like Methemoglobinemia , Carboxyhemoglobin can be missed unless correlated with pulse oxymetry (Here SpO2 is low and PaO2 is normal). Pulse Oxymeter It determines hemoglobin oxygen saturation (SpO2), which follows S shape curve (Fig. 3.1) on SpO2, PaO2 curve.

Fig. 3.1: Oxygen dissociation curve

Curve shifts to right (less affinity of oxygen to hemoglobin and more release to tissues) in following conditions: acidosis (increased H+ ions), increased 2-3 DPG, hyperthermia. Curve shifts to left (more affinity of oxygen to hemoglobin and less release to tissues) in following conditions: alkalosis (decreased H+ ions), decreased 2-3 DPG, hypothermia.

Drawbacks of SpO2 • Hyperoxia cannot be identified since 100 PaO2 and 500 PaO2 both will have same oxygen saturation (SpO2) of 99-100%.

OXYGEN THERAPY

• • • • • •

Shock states—due to low peripheral perfusion SpO2 is not detected. Phototherapy, UV light will give false readings. Skin, nail coats, e.g. nail paints will hinder the infrared rays and will give wrong readings. Motion artifacts. Proximity to electrocautery gives false reading. Hazard of local burns.

Advantages of SpO2 • Cheap, easy, simple way of detection of SpO2. • Continuous monitoring possible. • Associated plethysmography in pulse-oxymeter will give you good information about hemodynamic status of patient.

Precautions • Pulse oxymeter should be calibrated periodically so as to avoid mistakes while treating a critical patient. • Probe site should be changed periodically to avoid burns. TRANSCUTANEOUS OXYGEN MONITOR (TcO2) Continuous monitoring of plasma oxygen with transcutaneous leads. Useful and accurate for following the trend. Used extensively in units using High frequency ventilation because of the fear of rapid changes in PaCO2. TO DETERMINE TISSUE OXYGENATION ABG, SpO2 and TcO2 will indicate oxygen content of blood (Hypoxemia issue) but tissue oxygenation (Hypoxia) cannot be identified. To detect hypoxia–indirect parameters like plasma HCO3 levels, plasma lactate can be used. Hypoxia leads to anaerobic metabolism hence lactic acidosis and decrease plasma HCO3 levels. HUMIDIFICATION OF OXYGEN Supplementation of non-humidified, unwarmed oxygen can cause hypothermia, impaired mucociliary function, drying of secretions and airway obstruction, more so in small size pediatric respiratory tract. In the normal respiratory tract, inhaled gases are humidified to 100% relative humidity. Artificial airways like the endotracheal tube or tracheostomy tube may bypass 25% of the humidification area. So a simple humidifier without heating capacity can be used in patients without artificial airways. Heated humidifiers should be used for patients with artificial airways. Optimum requirement is 80-100% humidity with 32-37°C temperature. Monitoring temperature and humidity while oxygen delivery is desirable which can be optimally done by heating wires in the breathing tubes. Condensation of water poses a potential risk of infection. Nebulizers in their droplets of water increases the potential of infection, specially when given through artificial, devices so should best be avoided.

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HOW TO GIVE OXYGEN Various devices are used depending upon age of child, dose of oxygen needed, convenience of patient, any additional method required and disease you are treating. The patient’s own flow requirements depend on the minute ventilation (MV). The flow rate set is 3-4 times the calculated MV. MV=tidal vol(Vt) × respiratory rate (RR); If the average Vt is taken as 6 ml/Kg a 5 Kg child breathing at 60 /minute requires a flow rate of 6-7 L/minute. Since flow is high and may pass the humidifying surfaces quickly, humidification is required. Oxygen Sources and Flow Regulators Medical gas is provided from either a wall source or a cylinder. A wall source should provide at least 50 psi pressure at all times. Cylinders operate at pressures of 1800-2400 psi. This is too much for any patient or ventilator and hence a down regulating valve is needed before the flowmeter attachment. The flowmeter regulates and reads the flow.

Low Flow Devices Nasal cannula: 2 soft prongs that enter the nostrils, attached to an oxygen source by a fairly long tube. It will provide low FiO2 between 30–40% (fitting a nasal cannula in a neonate will provide almost 90% FiO2 at 1 lit/min). Since humidifying mucosa is not bypassed and flow is less, humidification is not required. Flow in this system is less than minute volume so air mixing continues and precise FiO2 can’t be adjusted. In very small preterm babies, some inadvertent PEEP may be generated. However, this device is not suitable to deliver PEEP, where the shortest, broadest cannulae and tubings with least resistance should be used. Simple mask: A mask has perforations which are exhalation ports. It fits the face without much discomfort and is often loose enough to allow entry of room air hence the FiO2 is not very high. Precise FiO2 is not the aim when using these masks and they are not to be used for conditions of hypoxemia. Partial rebreathing masks: These are simple masks with an additional reservoir that allows the accumulation of oxygen enriched gas for rebreathing. A portion of the exhaled volume from the anatomical dead space is rich in oxygen. This is what enters the reservoir. Upto 60% FiO2 can be delivered but the pitfalls are similar to those of a simple mask. Non-rebreathing masks: These look similar to the rebreathing mask but have a valve that allows only O2 from the source to enter the reservoir and exhaled air does not enter. Hence 80-100% O2 is provided.

High Flow Devices 6-10 lit/min –Venturi, non-rebreathing masks, under tent high flow, etc. these devices deliver higher FiO2 60–90%, and precise FiO2 can be delivered. Non-rebreathing masks: These are like the above masks, but have a valve at the exhalation port that allows only exhaled gases to enter the reservoir. It prevents room air from being entrained. A well–fitting mask can provide up to 100% oxygen. The oxygen percentages obtained with different systems are summarized in Table 3.1.

OXYGEN THERAPY Table 3.1: Oxygen percentages with different systems

Liters/min

Simple

5 6

< 40%

Partial rebreathing

Non-rebreathing masks

45-50% 55-60% 45-50% 60% 60% 60-80%

8 10 12 15

35% 60-80% 80-90% 90% 90-100%

Air-entrainment or venturi masks: These are dilutional masks that work on the Bernoulli principle (Fig. 3.2). Oxygen is delivered through a narrow orifice at a high flow. Negative lateral wall pressure is created in the tubing system. There are openings (entrainment ports) near the nozzle that allow room air to be sucked in, diluting the oxygen. Changing the size of the nozzle, the flow rates, as well as ports, allows control of the amount of oxygen. The advantages of a venturi system include: (i) A high flow device guarantees the delivery of a fixed FiO2; (ii) The high flow comes from the air therefore saving on oxygen costs; (iii) Can be used for low FiO2 also; (iv) Helps in deciding whether the oxygen requirement is really increasing or decreasing; (v) Humidification not needed; and (vi) Fairly cheap and reliable.

Fig. 3.2: Principle of the air-entrainment or venturi mask

The oxygen concentrations obtained with venturi devices are shown in Table 3.2. Table 3.2: Venturi devices and delivery of oxygen

Litres/min (Oxygen/Total)

Oxygen concentration (%)

Air : Oxygen ratio

2/53 4/45 6/47 8/45 10/33 12/32

24 28 31 35 40 50

25:1 10:1 7:1 5:1 3:1 5:3

Each device will have a table on the package insert as a guide to flow rates required by that particular device. This should be followed.

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In children, the problem of fit and comfort is a daily issue. Infants too large for oxyhoods and too small for masks are our usual population. The average infant or even toddler is usually intolerant of a mask and will keep pulling it off. In fact, the infant that remains quiet when the mask is first fitted, is one that may be obtunded from hypoxia or too tired too fight. The Oxyhood: This is the small baby’s friend. A clear transparent hood that has enough room for the baby’s head to fit comfortably and allows free neck and head movement without hurting the baby, is the correct hood size to use. At least 3–4 sizes are available and a unit should keep one of each size. Too big a hood will dilute the oxygen and too small a hood will cause discomfort and result in carbon dioxide accumulation. Adequate flow of humidified oxygen ensures mixing of delivered gases and flushing out of carbon dioxide. Oxygen gradients can vary as 20% from top to bottom. Continuous flow at 6 L/min avoids this problem. Cold air will cause heat stress and condense on the baby’s head, which will be mistaken for perspiration. Measurement of Delivered Oxygen: An oxymeter or FiO2 meter is used to measure the concentration of oxygen actually delivered to the patient. The important part of this system is the actual sensor it’s quality and accuracy is of paramount importance. It is connected to an instrument that digitally converts the sensed concentration into a reading that is displayed. The sensor has it’s own life of about 1000 sensing hours. It is the most expensive part of the machine. It also tells us how wrong our own rough estimates of delivered oxygen can often be. The oxyhood is the ideal place to use it but it can also be held at the mouth/nose within a mask for a quick reading. Calibration with every use is needed. Continuous Positive Airway Pressure (CPAP): This is indicated as a possible device for correcting hypoxemia when the oxygen requirement is > 60 percent with a PaO2 of < 60 mmHg. This is the classic criterion but it must be stressed that clinical parameters and the general conditions of the patient must also act as a guiding force. CPAP, like background PEEP, reduces the work of breathing, increases the FRC and helps maintain it, recruits alveoli, increases the static compliance and improves ventilation perfusion ratios. Whatever the method of delivery, it is a versatile tool in the child with early, incipient or even frank respiratory failure. An easy method is to use snug fitting nasal prongs with a closed mouth in small neonates < 1400 grams this method can also provide non-invasive PP ventilation. A pacifier may help in keeping the mouth closed. There are several comfortable prongs available and the cheapest are the plastic oxygen cannula. CPAP systems vary from the unit made underwater seals to those on ventilators systems. FiO2 will be inaccurate in the locally made systems in the standalone CPAP systems with good oxygen blenders may be as expensive as basic ventilators. CPAP can be successfully used in mild RDS of prematurity, asthma, early ARDS, pneumonia, etc. It should be tried prior to conventional ventilation in any spontaneously breathing patient who does not require emergency ventilation. Oxygen Concentrator: This device separates oxygen from nitrogen in the air by using adsorption and desorption over a material called zeolite, that adsorbs only the nitrogen. No ventilator or CPAP

OXYGEN THERAPY

machine can run as the outlet pressure is only 5 psi. The resultant FiO2 is about 0.4. This is useful in many situations and is often used in home oxygen therapy. The device costs between Rupees 40,000 to 50,000. Hyperbaric Oxygen (HBO): The goals are to deliver extremely high partial pressure of oxygen > 760 torr. This diseases the plasma, partial pressure and the dissociation occurs in the plasma rather than from that bound to hemoglobin. At room air, the PaO2 is 80–100 torr, at 1 ATA (atmospheric absolute) with 100% oxygen, it is 500 + torr. At 2ATA in 100% oxygen it is 1200 + torr. The indication for HBO are summarized in Table 3.3. Table 3.3: Indication approved for HBO Smoke inhalation

Clostridial myonecrosis

Carbon monoxide poisoning

Osteomyelitis (Refractory)

Cyanide poisoning

Acute traumatic ischemia

Thermal burns

Compromised skin grafts

Anemia due to severe blood loss

Radiation injury

Air embolism

Intracranial mucormycosis

The goal of therapy is to achieve the optimal level of oxygen in the blood at the least possible concentration. Clinical assessment of oxygenation includes the five vital signs namely, heart rate, respiratory rate (including level of distress), blood pressure, temperature and SpO2 measurement. Patient assessment for distress is more important than any other parameter in deciding further therapy. Algorithms help but only as guidelines. Weaning: This is based on clinical and laboratory parameters. The SpO2 levels are a boon in this phase and ABGs are usually not needed. Abrupt cessation may precipitate rises in pulmonary pressures in neonates. The flow/concentration should be gradually lowered while monitoring the child. Low flows and concentration can continue without ill effects for a long time. A high flow system can be replaced by low flow system, but this doubles the costs. DOSE OF OXYGEN Being a drug it has to be given in defined dose. And most accurate method is to give O2 in planned fraction of inhaled gases (FiO2). Room air contains 21% O2–mixing it with 100% O2 in various proportion gives various FiO2 — This can be done by calculation of air and oxygen flow or readily done by blenders in CPAP and ventilator machines. HOW TO START OXYGEN In a hypoxic child start with 100% oxygen, and once child is stabilized reduce the FiO2 to a level which will just avoid cyanosis clinically —determine the FiO2 level at which cyanotic tinge just appears and set FiO2 10% above that level. With pulse oxymeter monitor, in chronically hypoxic patient maintain SpO2 of 88%, and in acutely hypoxic patient maintain 92%.

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PRACTICAL GUIDELINES 1. If bag and mask ventilation is required, use same FiO2. Higher FiO2 may cause microatelectasis. 2. During physiotherapy increase FiO2 by 5%. If patient desaturates stop the procedure. 3. Oxygen requirement is reduced by: maintaining thermoneutral environment, minimal handling, correction of anemia and acidosis. 4. Oxygen requirement is increased by: any stress- hypothermia, sepsis, infection, post-trauma, congenital cardiac or lung malformations. 5. To improve oxygenation: • Increase FiO2 • Increase mean airway pressure (MAP): increases proportionately to PEEP, PIP, flow rate and inspiratory time on ventilator • Maintain optimum hemoglobin level. • Improve and maintain cardiac output. WHEN AND HOW TO WEAN AND STOP OXYGEN Wean gradually: In acute hypoxia with recovery of underlying condition oxygen can be weaned fast, but in chronically hypoxic child weaning should be slow. In documented hypoxemia oxygen is stopped once SpO2 and PaO2 is maintain for more than 40 min on room air. In hypoxic child plasma pH and HCO3 needs to be maintained on room air before oxygen can be stopped totally. HAZARDS OF OXYGEN Hypoxia is dangerous but equally dangerous is hyperoxia. Various hazards are: 1. Direct lung injury–If FiO2 more than 60% used for long time. 2. Collapse (Derecruitment) of alveoli. If higher FiO2 used for longer time (replaces Nitrogen from alveolar air). 3. Retinopathy of prematurity — Babies less than 32 weeks, less than 1500 gm are at higher risk. PaO2 desirable is less than 80 and SpO2 88–93%. Periodic retinal examination is mandatory after completion of 32 weeks to avoid irreversible retinal damage. 4. Oxygen promotes combustion. 5. Paul-Bert effect: Breathing hyperbaric oxygen can cause severe cerebral vasoconstriction and epileptic fits. FIELD FOR RESEARCH In spite of using oxygen so much in clinical practice we still don’t know everything of oxygen therapy. Certain aspects still form the gray zone and need further research, e.g. • What is acceptable cut off level to prevent ROP? • What is acceptable level to prevent lung damage? • Is there any permissive hypoxia? COST OF OXYGEN It is a costly medicine so should be used very judiciously. Small cylinder would cost between 50– 150 Rs. for refilling and a big cylinder costs 150–350 Rs for refilling.

OXYGEN THERAPY

Oxygen therapy saves lives. Yes, there are side effects but the advantages far out-weight the risks. Hypoxia kills more people than correctly delivered oxygen. Use but do not abuse. BIBLIOGRAPHY 1. Duc G. Assessment of hypoxia in the newborn, suggesting of practical approach. Pediatrics 1971;48:469-71. 2. Egan DF. Aerosol and humidity therapy. In: Fundamentals of Respiratory Therapy, 3rd edn. St.Louis, CV Mosby, 1977;213-21. 3. Greenough A. Chronic lung disease in newborn. In: Rennie JM, Roberton NRC(Eds): Textbook of Neonatology(3rd edn.) Edinburgh: Churchil Livingstone, 1999;608-22. 4. Gioid FR, Stephenson AC, Alterwitz SA. Principles of respiratory support and mechanical ventilation: In: Rogers M (Ed.): Textbook of Pediatric Intensive Care. Baltimore, Williams and Wilkins, 1987;113-69. 5. Guidelines for perinatal care, AAP ELK- Grove IL (3rd edn.) 1992:2001. 6. Gilbert R, Keighley JF. The arterial/alveolar oxygen tension ratio: An index of gas exchange applicable to varying inspired oxygen concentrations. Am Rev Respir Dis 1974;109:42. 7. Klein EFJ, Graves SA. “Hot pot” Tracheitis. Chest 1974;65:225. 8. Tobin MJ. Respiratory monitoring. JAMA 1990;264:244. 9. Wukitsch MW, Petterson MT, Tobler DR, et al. Pulse oxymetry: Analysis of theory, technology and practice. J Clinical Monitoring 1988;4:290.

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4

Avinash Bansal, Geeta Bansal, Rekha Luthra

Upper Airway Diseases

INTRODUCTION The upper airways extend from the nares to epiglottis. This includes nose, nasopharynx, eustachian tubes, mastoids, sinuses, oropharynx, tonsils, adenoids and vellopharynx. However, because of similar pathophysiology and signs and symptoms, some authors consider epiglottis, glottis, subglottis and extrathoracic trachea also under upper airways. Upper airway diseases remain the commonest cause for visits to a pediatrician. Most of the diseases like cold, rhinitis, sinusitis, pharyngitis and otitis media are benign whereas there are some potentially serious ones like sinusitis, otitis media, mastoiditis, epistaxis, spasmodic laryngitis. Some like choanal atresia, croup, retropharyngeal abscess, epiglottitis require intensive care also. The upper airway performs a number of functions, namely respiration, olfaction, speech and mucosal defense. Diseases leading to compromise of the airway are the most frequent cause of cardiac arrest in pediatric patients. Prompt recognition of these illnesses can lead to timely intervention and improve the outcome of these patients. The small size of the infant’s trachea makes airway obstruction more likely and particularly dangerous. The normal anteroposterior diameter of the infant’s glottis is 4.5 mm. One millimeter of circumferential tracheal edema reduces the glottis lumen to 30% of its normal size. Poiseuille’s law stipulates that laminar flow of gas through a tube is inversely proportional to the fourth power of the radius of the lumen. Unfortunately, airflow through a normal trachea is usually turbulent which worsens the situation because resistance to turbulent flow of gas past an obstruction is inversely proportional to the fifth power of the radius of the lumen. Gas exchange will be dramatically reduced by minor degrees of impingement on an infant’s trachea. This means that a child will not tolerate lesions that would not even produce symptoms in an adult.

UPPER AIRWAY DISEASES Table 4.1: Causes of upper airway diseases

Broad groups

Newborn and early infancy

Late infancy and childhood

Upper airway anomalies

Choanal atresia, Pierre-Robin syndrome, floppy epiglottis, laryngeal web, tracheal stenosis, vocal cord paralysis, tracheomalacia, vascular ring

Tracheal stenosis, vocal cord paralysis, vascular ring, laryngotracheomalacia.

Aspiration/ infection

Foreign body, vomitus, laryngotracheitis, diptheria epiglottis, peritonsillar or retropharyngeal abscess.

Tumors

Hemangioma, cystic hygroma, teratoma

Papilloma, hemangioma, lymphangioma, teratoma, hypertrophy of tonsils and adenoids.

Allergic or reflex

Laryngospasm from local irritation (intubation) or tetany

Laryngospasm from local irritation (aspiration, intubation,drowning) or tetany. Allergy, smoke inhalation.

PATHOPHYSIOLOGY The basic pathophysiology is obstruction culminating into respiratory failure. Obstruction may be anatomic, like choanal atresia, enlarged adenoids or functional like obstructive sleep apnea or vellopharyngeal incompetence. Common Causes of Upper Airway Diseases (Table 4.1) We should clinically assess, diagnose and manage a case of upper airway. Disease requiring intensive care. HISTORY The upper airway diseases classically present with snore, stertor and stridor: Snore is the sound of nasal and nasopharyngeal obstruction. Stertor is a low pitched sniffly inspiratory sound and is generated from the oropharynx and epiglottis. Stridor is a high pitched, musical sound due to partial airway obstruction of larynx (inspiratory). Hollinger’s laws help us to differentiate between stertor and stridor (Table 4.2). Besides these, the patients can present with: Drooling, e.g. in retropharyngeal abscess, parapharyngeal abscess, epiglottitis . Difficulty in swallowing, choking — foreign body Anxious/toxic look — infections Severe headache, epistaxis, foul smelling nasal discharge, foul breath, e.g. infections like diphtheria, foreign body. Signs and symptoms of respiratory failure like excessive sweating, altered sensorium, restlessness, irritability.

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PEDIATRIC INTENSIVE CARE Table 4.2: Hollinger’s laws of airway obstruction Awake versus asleep • Obstruction that is worse when the patient is awake and that is exacerbated by exertion suggests a laryngeal, tracheal, or bronchial cause. • Obstruction that is worse when the patient is asleep suggests a pharyngeal cause; it is especially likely to be due to a disorder of the tonsils or adenoids. Inspiratory versus expiratory • Inspiratory obstruction suggests that the origin of the stridor is extrathoracic; usually this means a laryngeal anomaly, such as laryngomalacia or bilateral vocal cord paralysis, but occasionally a nasal or pharyngeal lesion is responsible. • Expiratory obstruction suggests that the origin of the stridor is intrathoracic; it mimics asthma and is usually due to tracheal or bronchial anomaly, such as tracheomalacia, bronchomalacia, vascular rings, or extrinsic compression.

PHYSICAL EXAMINATION The child should be stabilized before undertaking a detailed physical examination. After upper airway obstruction has been diagnosed, a combination of physical and radiographic findings may help localize the lesion. With identification of the anatomic site of the lesion, the diagnostic possibilities are greatly narrowed. During the diagnostic evaluation, the child may sit in the parent’s lap if this reduces anxiety. If it is thought to be safe, examination of the patient’s head and neck may reveal the cause of illness. Depending on the patient’s condition, the degree of respiratory embarrassment may be quantified. DIFFERENTIAL DIAGNOSIS The differential diagnoses of upper airway diseases causing obstruction are detailed in Tables 4.3 to 4.5. INVESTIGATIONS It is essential to stabilize the patient before undertaking any investigations. A person trained in airway management should always accompany the patient to the laboratory or radiology department and should carry all the equipments required for resuscitation. The blood counts will be raised (TLC, DLC) with polymorphonuclear leukocytosis in cases of retropharyngeal, parapharyngeal and peritonsillar abscesses, epiglottitis, acute bacterial tracheitis and diphtheria. Cultures from the local site and blood may be helpful in defining the causative organism. The common causative organisms are Haemophilus influenzae, Staphylococci, Group B Streptococci, Streptococcus pneumoniae, Corynebacterium diphtheriae and anaerobes. RADIOLOGY X-rays A plain skiagram AP and lateral view of neck and chest helps in the diagnosis. High kilovoltage, short-exposure, endolateral view with head in slight extension in deep inspiration provides a

UPPER AIRWAY DISEASES Table 4.3: Differential diagnosis of stertor Eqiglottitis

Laryngeal foreign body

Retropharyngeal abscess

Choanal atresia, bony

Pathology

Bacterial,usually Haemophilus influenzae type-B.

Small foreign bodies like beans, nuts, small toys

Bacterial Staphylococcus aureus

Obstruction

Age

2-6 years

Any

1-4 yrs

Newborn

Rapid- less than 6 hours

Rapid

Slow-usually history of tonsillitis or upper respiratory tract infection +

Shortly after birth if B/L

Previous attacks

Not reported

-

-

-

Symptoms: Cough

Absent

Absent

Dysphagia Stridor

Severe Inspiratory

Paroxysms of coughing Occasional Inspiratory

Nil/excessive crying Yes Inspiratory Low pitched

Elevated Sitting, leaning forward Marked Large

Normal Variable Occassional None

Elevated Sitting with stiff neck Marked Large

Nil Nil

Quiet and Terrified Pale or grey Muffled Thumb sign Dangerous to perform Airway maintenance Antibiotics

Variable

Restless

Restless

Usual normal hoarse Foreign body is visible if opaque Airway maintenance Removal of foreign body

Flushed Hoarse Marked widening of retropharyngeal space Airway maintenance Antibiotics incision and drainage (I and D)

Greyish, cyanosis Hoarse Bony obstruction

History : Onset

Signs: Temperature Posture Drooling Cervical Glands Behavior Color Voice

X-ray Management

Severe Inspiratory

Normal Normal

Oral airway surgery

magnified view of the upper airway. Narrowing of the upper airway due to enlarged adenoids, increase in retropharyngeal space (greater than ½ the width of adjacent vertebral body in the upper cervical region up to C5 and almost exceeding the width of the adjacent vertebral body below C5) in retropharyngeal abscess/mass lesions in the cervical region, swollen epiglottis giving rise to the ‘thumb-sign’ and ‘steeple sign’ due to symmetrical narrowing of subglottic space secondary to acute laryngotracheobronchitis are classical pictures. A radiopaque foreign body may also be visualized. Acute supraglottitis (Fig. 4.1) characterized by airway obstruction caused by a swollen epiglottis can be seen in high kilovoltage, short-exposure, endolateral film of the upper respiratory tract.

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PEDIATRIC INTENSIVE CARE Table 4.4: Differential diagnosis of acute stridor Features

ALTB

Bacterial tracheitis

Diphtheria

Foreign body

Age

6 months - 3 years

1 months – 6 years

1–10 years

1–4 years

Etiology

Parainfluenza virus A, S. aureus, adenovirus and RSV H. influenzae are the most common

C. diphtherae

FB

Onset

Insidious

Insidious

Gradual

Abrupt

Fever

+/– , usually low

Moderate–severe

Moderate–severe

Variable

Cough

Barking

Brassy

Barking

+/–

Voice

Hoarse

Hoarse

Nasal twang

+/–

Others

Worsening at night

-

Pseudomembrane in the throat

–

Stridor

Moderate–severe, high pitched

Moderate–severe

Moderate–severe

Variable

Radiology

Steeple sign (subglottic narrowing)

Subglottic narrowing (subglottic air column diffusely hazy with multiple soft tissue irregularities)

Soft tissue swelling of neck

FB if radiopaque, hyperinflation on the side of foreign body if ball-valve effect present

Management

Airway management, inhaled steroids, inhaled epinephrine

Airway management, parenteral antibiotics

Airway management, Airway management, antitoxin, parenteral Bronchoscopic removal antibiotics of the foreign body

Fig. 4.1: Acute supraglottitis, characterized by airway obstruction caused by a swollen epiglottis (large arrow), can be seen in a high-kilovoltage, short-exposure, endolateral film of the upper respiratory tract. Also visible are the hypopharynx (curved arrow) and the laryngeal inlet (small arrow)

UPPER AIRWAY DISEASES Table 4.5: Comparative chart of retropharyngeal abscess, parapharyngeal abscess and peritonsillitis

Clinical features

Retropharyngeal abscess

Parapharyngeal abscess

Peritonsillitis

Age

< 4 years and adults

Older children, adolescents

Adolescents

Source

Pharyngitis, dental infection and trauma

Tonsillitis, otitis media, mastoiditis, parotitis and dental infection

Tonsillitis

On examination

Unilateral posterolateral pharyngeal wall bulging

Anterior compartment: Parotid area swelling Trismus Tonsil /tonsillar fossa pushed medially Uvula pushed to same side Posterior compartment: Pain trismus +/–

Unilateral tonsillar swelling

Hyperextension of neck Drooling of saliva Respiratory difficulty

Uvular displacement towards the opposite side Trismus Muffled voice

Complications

Spread to parapharyngeal space and posterior mediastinum

Carotoid blow-out Airway obstruction Metastatic abscess Lung aspiration Mediastinal extension Septic shock

Spread to parapharyngeal space

Treatment

Airway management Antibiotics I and D

Airway management Antibiotics, I and D

Antibiotics, I and D

CT/MRI Sometimes it may be necessary to do sophisticated imaging like computerized tomography (CT) and magnetic resonance imaging (MRI) for vascular anomalies compressing the trachea or oesophagus. These noninvasive methods are effective at showing complex three dimensional cardiovascular anatomy especially the extracardiac morphology. ENDOSCOPY Flexible nasopharyngoscopy, laryngoscopy, and bronchoscopy help in establishing diagnosis and also act as therapeutic modalities indications for diagnostic bronchoscopy are: 1. Severity of obstruction especially parental perception. 2. Progression of obstruction. 3. Cyanotic episodes. 4. Sleep obstructive apnea specially with cor pulmonale. 5. Radiological abnormalities detected by plain X-ray requiring further work up. They may be remembered by pnemonic SPECS-R.

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Precautions One should have both rigid and flexible bronchoscopes, esophagoscope and a laryngoscope. Child should be fasting for two to three hours prior to the procedure. All resuscitation and suction equipments should be ready. Adequate restraint facility to hold the child/sedation as required should be available. Flexible diagnostic endoscopy of upper airway may be performed on an awake child with topical 0.5% lidocaine anesthesia. OTHERS • Arterial blood gas analysis especially to detect and monitor respiratory failure. • Polysomnography is essential for quantifying sleep disturbance due to airway obstruction. • To confirm the site of obstruction and final diagnosis, a cross-table lateral fluoroscopy is indicated. MONITORING Continuous monitoring with pulse oximeter, transcutaneous carbon dioxide monitor or end tidal carbon dioxide monitor and arterial blood measurements are required to objectively measure respiratory function. MANAGEMENT Initial Management Once the diagnosis of upper airway obstruction has been made, efforts should be undertaken to minimize disturbing the patient unless the respiratory embarrassment is severe enough to be life threatening. Humidified oxygen should be administered through a nasal cannula or a face mask. If SpO2 is =/> 95 %, ABG may be unnecessary. An ABG is useful to identify the patient who may be hypercapnic, but this will usually be at the price of further upsetting the child. After the upper airway obstruction has been diagnosed, a combination of physical and radiographic findings may help localize the lesion. The initial evaluation should allow one to make important triage decisions about management and further evaluation of the patient with upper airway compromise. Depending on the severity of illness, a decision must be made about which diagnostic tests will be undertaken. In the case of severe respiratory compromise, it may be necessary to plan for invasive procedures. The aim of management is to prevent respiratory failure and treat the underlying pathology. A team comprising the pediatrician, otorhinolaryngologist, anesthetist and intensive care nursing staff is required. Rapid and systematic triage to maintain A (airways), B (breathing) and C (circulation) must be initiated based on clinical history and examination. Foreign body removal (in case of complete obstruction) should be attempted by back-blows and chest-thrust, (5 times in one go) in infants, and Heimlich’s maneuver in older children in case of complete obstruction. Blind finger sweeps should never be tried as it may push the foreign body deeper.

UPPER AIRWAY DISEASES Table 4.6: Various types of airways

Airway

Indications

Drawbacks

Nasopharyngeal

Pharyngeal and/or base of tongue collapse in alert or semi-conscious patients

Can cause epistaxis

Oral

Obstructed or injured nasal airway Unconscious patients

Dislodged easily Poorly tolerated by alert patients

Oral intubation

Need for controlled ventilation

Requires expertise and proper equipment Potential injury to larynx and pharynx

Blind nasal

Massive oral cavity injury Trismus

Epistaxis Requires expertise

Fiberoptic nasal

Suspected cervical spine injury

Difficult if excessive secretions or bleeding present Requires expertise and expensive equipments

Massive oral cavity injury Cricothyroidotomy

Failure of intubation No laryngeal injury Prior to definite tracheostomy

Surgical procedure can cause acute and chronic laryngeal injury

Tracheostomy

Laryngeal trauma Oropharyngeal obstruction not controlled by intubation After cricothyroidectomy preferrably within 48 hrs

Difficult than cricothyroidotomy Numerous potential early and late complications

Laryngeal mask airway

Failure of intubation

Can cause aspiration in full stomach patients

Airway Management Need for airway management depends on the site and severity of the obstruction . There are different ways of managing an airway depending on the indications (Table 4.6). Endotracheal intubation should be done as needed. Emergency tracheostomy under unfavorable conditions should be avoided because of complications of this setting. Indications for tracheostomy fall into three broad categories: 1. Airway obstruction 2. Assisted ventilation 3. Pulmonary toilet Pneumothorax or surgical emphysema may occur due to tracheostomy mishaps. Specific treatment of some congenital and acquired upper respiratory diseases: Choanal Atresia Surgical correction of choanal atresia if the infant has symptoms. Topical application of mitomycin to inhibit fibroblast proliferation has been shown to be an effective adjunct to surgical repair of choanal atresia.

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Laryngomalacia Infants tend to outgrow this problem during the first year of life. In most severe cases, surgical intervention with laser excision may be necessary (excision of the tissue that collapses into the glottis during inspiration). Laryngeal Webs, Stenosis or Tumors Surgical intervention is needed depending on the severity. Vascular Impingement on Trachea The innominate artery is the most common vessel causing tracheal compression. Vascular rings and enlarged pulmonary artery are also known to cause tracheal compression as are a variety of other respiratory abnormalities. These lesions cause recurrent respiratory infection but often do not cause stridor or swallowing problems. Barium swallow has been the historic method of diagnosing vascular impingement of the trachea. CT scanning and MRI have rapidly become the diagnostic modalities of choice. Treatment involves surgical correction of vascular anomaly in severe cases. Bronchomalacia and Intrathoracic Tracheomalacia Although these lesions may be congenital, many of the cases of tracheomalacia and bronchomalacia seen in the PICU are the result of infectious or mechanical insults to the trachea. Obstructive symptoms produced by these lesions may be relieved by: a. CPAP b. Tracheostomy or c. Surgical intervention with pericardial flap aortopexy or metallic airway stents. LTB Exposing the child to cold or misty air often improves the symptoms dramatically. When the illness is refractory to these measures, racemic epinephrine 2.25%, 0.5 ml, diluted in 2-3 ml of normal saline has been shown to produce dramatic reduction of airway obstruction (not available in India). L-Epinephrine in a dose of 5 ml of 1: 1,000 is as effective as racemic epinephrine. The onset of action is 10 to 30 minutes and duration of action is around 2 hours. There is a tendency to rebound and hence the patient should be reassessed after 2 hours. Rebound tracheal edema may occur several hours later when racemic epinephrine has been used as the effect of racemic epinephrine dissipates. Therefore, the child should be admitted to the hospital for observation when racemic epinephrine has been used. Oral, intramuscular and nebulized corticosteroids have been shown to be beneficial in randomized, blinded trials. Multiple meta-analyses in which the efficacy of corticosteroid was evaluated suggest that corticosteroids reduced the need for tracheal intubation or inhaled epinephrine, hasten improvement in the first 24 hours of illness, and reduce the frequency of readmission.

UPPER AIRWAY DISEASES

Goelhoed et al have demonstrated that a single oral dose of 0.15 mg/kg is as effective as 0.6 mg/kg. Inhaled budesnide 2 mg in Indian market 0.5 mg and 1 mg/2.5 ml respule is available) is equally effective as L-epinephrine. It is poorly bioavailable and a good part of the dose lies in the oral cavity where it is needed. Its effect can be seen within 1-2 hrs. Mixtures of helium and oxygen (heliox) have proven beneficial in settings with airway narrowing and turbulent airflow. Because this gas mixture is less dense than air, turbulent flow past the obstruction is facilitated, resulting in lower airway resistance and improved gas exchange gas mixtures containing less than 60% helium show little benefit. This mixture must be delivered through a face mask. A recent randomized study has shown that heliox will result in similar improvements in severe croup as compared with racemic epinephrine. Endotracheal intubation is occasionally necessary. The use of tracheostomy to treat life threatening LTB is much less common now than formerly. Unless merited by special circumstances such as severe subglottic stenosis in association with LTB, tracheostomy offers no advantages over endotracheal intubation. Epiglottitis Although most cases of epiglottitis are caused by the infectious pathogens, thermal injury from ingesting hot liquids can also cause epiglottitis. Patient should be minimally disturbed. Direct examination of oropharynx should not be attempted. Humidified oxygen through a plastic hose preferably held by the parent, should be given. Endotracheal intubation in severe cases, for 24-72 hours while epiglottis returns to normal size. Nasotracheal intubation is preferred to orotracheal intubation. As with LTB, endotracheal intubation is preferred to tracheostomy as it has been shown that complications are most common. The patient may breathe spontaneously through the ET tube or need mechanical ventilation. Bacterial Tracheitis Antibiotics are an important aspect of therapy. Because of the severity of airway compromise, endotracheal intubation is often necessary. The most common complication observed is pneumonia which is seen in 60% of cases. Peritonsillar Abscess Intraoral ultrasound examination has been suggested to be a useful test to differentiate abscess from cellulitis. Incision and drainage after intubation, is indicated if the abscess is fluctuant. Extubation is almost always possible after drainage of the abscess. Retropharyngeal Abscess A short trial of antibiotic therapy is often indicated before any decision is made to proceed with surgical drainage of the abscess.

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Surgical treatment of this lesion is drainage of the abscess after the patient has been anesthetised and an endotracheal tube has been inserted to protect the patient from pulmonary aspiration. Laryngeal Papillomatosis The laryngeal papilloma is the most common benign tumor of the larynx during childhood. The treatment for this illness is surgical excision of the polyps. Despite modern surgical treatments, recurrence is relatively common. Adjunctive treatment with alpha-interferon has been shown to reduce the relapse rate in both children and adults. Vocal Cord Paralysis May be either present at birth or acquired later. Patients with vocal cord paralysis may be able to phonate because the thyroid muscle may serve as a tensor of the vocal cords and is not affected in most cases of vocal cord paralysis. Most of the patients have inspiratory stridor. A neurological disorder such as brain stem compression by an Arnold Chiari malformation should be considered when acquired vocal cord paralysis is evaluated among pediatric patients. The treatment is primarily supportive. If a specific lesion may be addressed medically or surgically, such therapy should be undertaken. Occasionally, respiratory embarrassment is of sufficient magnitude to merit surgical intervention with an external arytenoidopexy or a tracheostomy. A recent meta analysis suggests that an external arytenoidopexy and an external arytenoidectomy are equally effective and that the two combined are significantly more effective than carbon dioxide ablative procedures. Intrathoracic Mass Lesions Causing Respiratory Obstruction Rapid evaluation and aggressive medical therapy is needed. Endotracheal intubation is indicated only if respiratory function becomes severely compromised. Trauma

Post-extubation Stridor Although most cases of postextubation stridor are caused by laryngeal edema, when this problem persists, other causes should be sought. The therapy of postextubation stridor is aimed at reducing edema. Racemic epinephrine and dexamethasone are most widely used agents. Racemic epinephrine, delivered by aerosol nebulizer, probably works by stimulation of alpha adrenergic receptors causing vasoconstriction, which in turn, reduces tracheal edema. Racemic epinephrine works rapidly, so improvement, when it occurs, should be observed within a few minutes of completion of therapy. Use of dexamethasone remains controversial. Although data from animal studies suggest that corticosteroid use at the time of extubation may reduce tracheal edema, inflammation and capillary dilatation, several human studies have failed to show reduction in postextubation stridor after corticosteroid use. In most cases postextubation stridor is self limited but occasionally reintubation may be necessary.

UPPER AIRWAY DISEASES

Acquired Laryngotracheal (subglottic) Stenosis Acquired laryngotracheal (subglottic) stenosis is a well-known complication following endotracheal intubation. It has been reported that subglottic stenosis occurs infrequently after nasotracheal intubation with a proper–sized endotracheal tube. It is thought that nasotracheal intubation may reduce the movement of tube within the trachea and diminish tracheal injury. Mild subglottic stenosis may be treated expectantly but more severe forms must be treated surgically.

Foreign Body Aspiration Foreign bodies are removed from the tracheobronchial tree with a bronchoscope. Occassionally bronchoscopic extraction is unsuccessful, and a pulmonary lobectomy is required.

Traumatic Injury to the Airway Most commonly these are blowout injuries that usually occur near the carina, and most involve mainstream bronchi. Small tracheobronchial disruptions may be managed conservatively, most of these lesions require surgical repair.

Angioedema If this should involve the soft tissues of upper respiratory tract, laryngeal obstruction may result. Administration of subcutaneous epinephrine may cause dramatic response. Occasionally endotracheal intubation is warranted in view of severe respiratory embarrassment. The evaluation of patient with this disorder should be directed at : 1. The identification of the causative agent. 2. The anatomical site of presentation to allow for stratification of airway risk and planning of appropriate triage for airway intervention. SUMMARY Upper airway diseases are life threatening and may sometimes require intensive care. The basic pathophysiology is partial obstruction of airways which may be congenital or acquired and may lead to respiratory failure. The classical clinical presentation is snore, stertor and stridor and symptoms and signs of respiratory failure. The history is diagnostic in 80-85% cases and a plain lateral film of neck is the most important diagnostic investigation to clinch the diagnosis. A team effort (pediatrician, otorhinolaryngologist, anesthetist, respiratory therapist, and intensive care nurse) with rapid and systematic approach to conduct an emergency triage (ABC), to prevent respiratory failure and to deliver specific therapy directed towards the cause gives gratifying results. KEYPOINTS 1. 2. 3. 4.

Upper airway disease present as stertor or stridor. History and high kv. X-ray neck (lateral view) is a key to diagnosis. Tachypnea is the first sign of respiratory distress or failure. First stabilize the patient and then perform detailed examination and investigations.

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5. Rapid and sequential management of airways, breathing, and circulation (ABC), is the key to enhanced survival. Things not to do 1. Do not use blind finger sweeps to remove a foreign body. 2. Do not examine the throat without resuscitation equipments at hand. 3. Do not send the patient for X-ray or other investigations without an accompanying competent person and resuscitation equipments. 4. Do not sedate the child until the airway is secured. BIBLIOGRAPHY 1. Acute respiratory tract infections in children. Doctors’ Manual. Government of India Ministry of Health and Family Welfare, New Delhi 1990;5. 2. Ausejo M, Saenz A, Pham B, et al. The effectiveness of glucocorticoids in treating croup: meta-analysis, BM 1999;319:595600. 3. Bernstein T, Brilli R, Jacobs B. Is bacterial tracheitis changing? a 14-month experience in a pediatric intensive care unit, Clin Infectious Dis 1998;27:458-62. 4. Brigger MT, Hartnick CJ. Surgery for pediatric vocal cord paralsis: A meta-analysis, Otolaryngol Head Neck Surg 2002;126:349-55. 5. Chaten FC, Lucking SE, Young ES, Mickell JJ. Stridor: intracranial thology, causing postextubation vocal cord paralysis, Pediatrics 1991;39-43. 6. Cinnamond MJ. Stridor. In: Scott Brown’s Otorhinology. Evans JNG (Ed). Butterworth-Oxford 1997;6.21/1-6.21/ 10. 7. Cotton RT, McMurray JS. Laryngotracheal stenosis. New perspectives, Pediatr Pulmonol 1999;18:64-6. 8. Darmon ]Y, Rauss A, Dreyfuss D, et al. Evaluation of risk factors for laryngeal edema after tracheal extubation in adults and its prevention by dexamethasone. A placebo-controlled, double-blind, ulticenter study [see comments], Anesthesiology 1992;77:245-51. 9. De la Sierra Antona M, Lopez HJ, Rupfrez M, et al. Estimation of length of nasotracheal tube to be introduced in children. J Pediatr 2002;140:772-74. 10. DeLorimier AA, Harrison MR, Hardy K, et al. Tracheobronchial obstructions in infants and children. Experience with 45 cases Ann Surg 1990;212:227-2S9. 11. Denneny JCI: Bronchomalacia in the neonate, Ann Otol Rhinol Laryngol 1985;94(5 Pt 1):466-69. 12. Donnelly BW, McMillan JA, Weiner LB. Bacterial tracheitis: Report of eight new cases and review, Rev Infect Dis 1990;12:729-35. 13. Dudin AA, Thalji A, Rambaud CA. Bacterial tracheitis among children hospitalized for severe obstructive dyspnea, Pediatr Infect Dis J 1990;9:293-95. 14. Duncan PG. Efficacy of helium-oxygen mixtures in the management of severe viral and post-intubation croup, Canadian Anaesth Soc J 1979;26:206-12. 15. Eckel HE, Widemann B, Damm M, Roth B. Airway endoscopy in the diagnosis and treatment of bacterial tracheitis in children, Int J Pediatr Otorhinolaryngo 1993;I27:147-57. 16. Ferrara TB, Georgieff MK, Ebert J, Fisher JB. Routine use of dexamethasone for the prevention of postextubation respiratory distress, J Perinatol 1989;9:287-90. 17. Friedman NR, Mitchell RB, Bailey CM, et al. Management and outcome of choanal atresia correction. Int Pediatr Otorhinolaryng 2000;52:45-51. 18. Furman RH, Backer CL, Dunham ME, et al. The use of balloon- expandable metallic stents in the treatment of pediatric tracheomalacia and bronchomalacia, Arch Otolaryngol Head Neck Surg 1999;125:203-07. 19. Garcia-Mllian R, Santos A, Perea SE, et al. Molecular analysis of resistance to interferon in patients with laryngeal papillomatosis, Cytokines Cell Mol Ther 1999;5:79-85. 20. Goelhoed GC. Croup, Pediatr Pulmonol 1997;23:370-74. 21. Goelhoed GC. MacDonald WB. Oral Dexamethasone in the treatment of croup. 0.15 mg/kg, versus 1.3 mg/kg versus 0.6 mg/kg. Pediatrics. Pulmon. 1995:20:363-68. 22. Greenholz S, Hall R, Lilly J, Shikes R. Surgical implications of bronchopulmonary dysplasia, Pediatr Surg 22:113219S7;1136. 23. Handler SD. The Larynx. In Pediatrics. Rudolph AM, Hoffman JLE (Eds). Appelton Century-Crofts. Norwalk 1982; 908-14.

UPPER AIRWAY DISEASES 24. Haramati LB, Glickstein JS, Issenberg HJ, et al. MR imaging and CT of vascular anomalies and connections in patients with, congenital heart disease: significance in surgical planning, Radiographics 2002;22:337-47. 25. Holinger LD. Etiology of Stridor in the neonate, infant and child. Ann Otol Rhinol Laryngol 1980;89;397-400. 26. Johnson DW, Jacobson S, Edney PC, et al. A comparison of nebulized budesonide, intramuscular dexamethasone, and placebo for moderately severe croup, N Engl Med 1998;339:498-503. 27. Jones KM. Molyneux E, Philips B, Wieteska S. Advanced Pediatric Life Support. The Practical Approach 2001. BMJ Books London 37-38. 28. Kadish H, Schunk, Woodward GA. Blunt pediatric laryngotracheal trauma: case reports and review of the literature, Am J Emerg Med 1994;12:207-11. 29. Kairys SW, Olmsteaq EM, O’Connor G’J. Steroid treatment of laryngotracheitis: a meta-analysis of the evidence from randomized trials, Pediatrics 1989;83:683-93. 30. Kapoor Rashmi. Acute stridor. Indian Journal Practical. Pediatrics 2006;6(1):27-34. 31. Klassen TP, Craig WR, Moher D, et al. Nebulized budesonide and oral dexamethasone for treatment of croup: A randomized controlled trial, JAMA 1998;279:1629-32. 32. Koyluoglu G, Gunay I , Ceran C, Berkan O. Pericardial fl”p,aor- topexy: an ea~and sate technique In the treatment of tracheomalacia. Cardiovascular Surgery 2002;43:295-97. 33. Lalakea ML, Messner AH. Retropharyngeal abscess management in children: current practices, Otolaryngol Head Neck Surg 1999;121:398-405. 34. McClurg FL, Evans DA. Laser laryngoplasty for laryngomalacia, Laryngoscope 1994;104(3 Pt 1):247-52. 35. Miller R, Pollack M, Murphy T, Fink R. Effectiveness of continuous positive airway pressure in the treatnent of bronchomalacia in infants: A bronchoscopic documentation, Crit Care Med 1986;14:125-27. 36. Miller R, Woo P, Kellman R, Slagle T. Tracheobronchial abnormalities in infants with bronchopulmonary dysplasia, Pediatr 111:779. 37. Molteni RA. Epiglottis: Incidence of extraepiglottis and pneumonia: Report of 72 cases and review of the literature, Pediatrics J 1976;58:526-31. 38. Pagtakhan RD, Pastekemp H. Intensive Care of Respiratory Disorders. In Kending’s. Disorders of the Respiratory Tract In Children. Chernick Y, Kendig Jr EL (Eds). WB Saunders Company. Philadelphia 1990;205-24. 39. Prasad M, Ward RF, April MM, et al. Topical mitomycin as an adjunct to choanal atresia repair, Arch Otolaryngol Head Neck Surg 2002;12S:39S-400. 40. Rosevelt GE. Acute Inflammatory Upper Airway Obstruction. In Nelson. Textbook of Pediatrics. Nelson WE, Behnnan RE, Kliegman RM, Jenson HB (Eds). Saunders. Philadelphia 2004;1404-9. 41. Ross DA, Ward PH. Central vocal cord paralysis and paresis presenting as laryngeal stridor in children, Laryngoscope 1990;100:10-13. 42. Ruddy RM. Smoke inhalation injury, Pediatr Clin North Am 1994;41:317-36. 43. Russell K, Wiebe N, Saenz A, et al. Glucocorticoids for croup, Cochrane Database of Systematic Reviews (1):CDOOI955, 2004. 44. Tann HKK. Holinger LD. How to Evaluate and Manage Stridor In Children. The J of Resp Dis 1994;15(3):245-60. 45. Tellez DW, Galvis AG, Storgion SA, et al. Dexamethasone in the prevention of postextubation stridor in children, J Pediatr 1991;118:289-94. 46. Thangavelu S. Management of URTI Pediatric. Pulmon. Update 2000; 12 (2):17-20 5. 47. Toynton SC, Saunders MW, Bailey CM. Aryepiglottoplasty for laryngomalacia: 100 consecutive cases, Laryngology Otology 2001;115:35-3S. 48. van Aalderen WM, Hoekstra MO, Hess J, et al. Respiratory infections and vascular rings, Acta Paediatr Scand 1990;79:477-80. 49. Waisennan Y, Klein BL, Boenning DA, et al. Prospective randomized double blind stuby comparing L-epinephrine and racenic epinephrine aerosols in treatment of Laryngotracheitis (croup). Pediatrics 1992;89-302-06. 50. Weber JE, Chudnofsky CR, Younger JG, et al. A randomized comparison of helium-oxygen mixture (Heliox) and racemic epineph rine for the treatment of moderate to severe croup, Pediatrics 2001;107:E96. 51. Yamashita M, Chin I, Horigome H, et al. Sudden fatal cardiac arrest in a child with an unrecognized anterior mediastinal mass, Resuscitation 1990;19:175-77. 52. Zbar RIS, Chen AH, Behrendt DM, et al. Incidence of vocal fold paralysis in infants undergoing ligation of patent ductus arteriosus, Ann Thorac Surg 1996;61:814-16.

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5

Pediatric Airway Management

Safe management of the critically ill child’s airway requires understanding the anatomic and physiologic changes that occur from birth through adolescence, recognition of congenital and acquired airway abnormalities, appreciation of the pathophysiologic consequences of the airway manipulation and preparation for potentially difficult airways. Laryngoscopy and intubation are potent physiologic stimuli that are associated with severe discomfort, profound cardiovascular and cerebrovascular changes and increased airway reactivity. The chapter focuses on basic physiology and anatomy of airway and describes the techniques and adjuncts used in airway management and treatment of respiratory failure. This chapter is divided into following sections 1. How pediatric airway is different from adult airway with their clinical consequences? 2. How to manage a patient with respiratory failure? 3. Alternative approaches to airway management. ANATOMIC AND PHYSIOLOGIC CONSIDERATIONS Basic understanding of pediatric airway is very important as minor alteration in technique of intubation (based on difference in anatomy) can avoid major problem. The pediatric airway differs from the adult airway in several important anatomic and physiologic ways.1 A. The infants nose is short, soft and flat with small, nearly circular nares. The nasal valve is small. By 6 months, dimensions of the nares have nearly doubled, but they are still easily occluded by edema, secretions or external pressure. B. The airway of the infant or child is much smaller in diameter and shorter in length than the airway of the adult. This reduction in diameter markedly increases resistance to airflow and therefore work of breathing. C. The infant’s tongue is relatively larger to the oropharynx. Posterior displacements of the tongue may cause severe airway obstruction. During tracheal intubation in a child, there is less room

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D.

E.

F. G.

H.

I.

to compress the tongue anteriorly, so that it may be difficult to control the position of the tongue with the laryngoscope blade The infant larynx is high in the neck at birth, with the epiglottis at the level of the first cervical vertebra. By 6 months the epiglottis has moved to about the level of the third cervical vertebra. It continues to descend to its adult position at about the fifth or sixth cervical vertebra. The high position of the larynx makes the angle between the base of the tongue and glottic opening more acute. As a result, straight laryngoscope blades are often more useful than curved blades for creating a direct visual plane from the mouth to the glottis. The epiglottis in infants and toddlers is long, floppy, narrow and angled away from the long axis of the trachea. Controlling the epiglottis with a laryngoscope blade is more difficult. This problem can be overcome by using a straight laryngoscope blade and by directly lifting the epiglottis. The vocal cords have a lower attachment anteriorly in the infant and child. While intubating a child the tracheal tube may become caught at the anterior commissure of the vocal cords. In children younger than 10 years, the narrowest portion of the airway is below the vocal cords at the level of the non distensible cricoid cartilage and the larynx is funnel shaped. In teenagers and adults the narrowest portion of the airway is at the glottic inlet and the larynx is cylinder shaped. Tracheal tube size must be based on the size of the cricoid ring rather than the size of the glottic opening. In the infant and young child, the subglottic airway is smaller and more compliant and the supporting cartilage less developed than in the adult. The subglottic airway tends to collapse or narrow if there is upper airway obstruction. The epiglottis is long floppy. Under normal conditions the glossopharyngeal muscles maintain the tone of pharyngeal airway. This approximation of structures in combination with large tongue, small mandible and inadequate glossopharyngeal muscle tone (especially in a child with altered level of consciousness) contributes to the vulnerability to airway obstruction in infants.

APPROACH TO AIRWAY MANAGEMENT Airway management (Flow chart 5.1) depends on a brisk assessment of the patient’s breathing and knowledge of the likely progression of the airway problem that is deterioration vs improving function. In virtually any settings where respiratory difficulty is suspected, oxygen should be administered. Any patient who is unable to maintain airway develop respiratory failure or require therapeutic hyperventilation (increased intracranial pressure) a functional airway should be established and ventilated. Steps for establishing a functional airway are: 1. Oxygen delivery 2. Bag mask ventilation 3. Intubation 4. Alternative airways Oxygen Administration Administer oxygen to all seriously ill or injured patients with respiratory insufficiency, shock, or trauma. In these patients inadequate pulmonary gas exchange and inadequate cardiac output

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PEDIATRIC INTENSIVE CARE Flow chart 5.1: Approach to airway management

resulting from conditions such as a low circulatory blood volume or disturbed cardiac function limit tissue oxygen delivery. During cardiac arrest a number of factors contribute to severe progressive tissue hypoxia and the need for supplemental oxygen administration. At best, mouth-to-mouth ventilation provides 16 to 17% oxygen with a maximal alveolar oxygen tension of 80 mm Hg. Even optimal external chest compressions provide only a fraction of the normal cardiac output, so that blood flow and therefore delivery of oxygen to tissues are markedly diminished. In addition, CPR is associated with right-to-left pulmonary shunting caused by ventilation-perfusion mismatch, and respiratory conditions may further compromise oxygenation of the blood. The combination of low blood flow and usually low oxygenation leads to metabolic acidosis and organ failure. Oxygen should be administered to children demonstrating cardiopulmonary arrest2 or compromise to maximize arterial oxygen content even if measured arterial oxygen tension is high, because oxygen delivery to tissues may still be compromised by a low cardiac output. Whenever possible, humidify administered oxygen to prevent drying and thickening of pulmonary secretions; dried secretions may contribute to obstruction of natural or artificial airways. Administer oxygen by nasal cannula, simple face masks, and nonrebreathing masks. The concentration of oxygen delivered depends on the oxygen flow rate and the patient’s minute ventilation. As long as the flow of oxygen exceeds the maximal inspiratory flow rate, the prescribed

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concentration of oxygen will be delivered. If the inspiratory flow rate exceeds the oxygen flow rate, air is entrained, reducing the oxygen concentration delivered.

Masks If the patient demonstrates effective spontaneous ventilation, use a simple face mask to provide oxygen at a concentration of 30 to 50%.2 If a higher concentration of oxygen is desired, it may be administered through a nonrebreathing mask; typically at a flow of 15 L/min. Masks should be available in a selection of sizes. To provide a consistent concentration of oxygen, the mask of appropriate size should provide an airtight seal without pressure on the eyes. A small under-mask volume is desirable to minimize rebreathing of exhaled gases. If the mask has an inflatable rim, the rim can mold to the contours of the child’s face to minimize air leak.3

Nasal Cannulae A nasal cannula is used to provide supplemental oxygen to a child who is breathing spontaneously. This low-flow device delivers varying inspired oxygen concentrations, depending on the child’s respiratory rate and effort and the size of the child.3 In young infants, nasal oxygen at 2 L/min can provide an inspired oxygen concentration >50%. Nasal cannulas are often better tolerated than a face mask and are suitable to use in children who require modest oxygen supplementation. Nasal cannula flow rates >4 L/min for prolonged periods are often poorly tolerated because of the drying effect on the nasal mucosa. 3

Oropharyngeal and Nasopharyngeal Airways An oropharyngeal airway is indicated for the unconscious infant or child if procedures to open the airway (eg, head tilt–chin lift or jaw thrust) fail to provide a clear, unobstructed airway. Do not use an oropharyngeal airway in the conscious child because it may induce vomiting. Oropharyngeal airways are available for pediatric patients of all ages.4 Appropriate selection of airway size requires training and experience. An improperly sized oropharyngeal airway may fail to keep the tongue separated from the back of the pharynx or may actually cause airway obstruction. To select the proper size (length) of oropharyngeal airway from flange to distal tip, choose one equal to the distance from the central incisors to the angle of the jaw. To evaluate the size, place the airway next to the face (Fig. 5.1). Nasopharyngeal airways (Fig. 5.2) are soft rubber or plastic tubes that may be used in conscious patients requiring relief of upper airway obstruction. They may be useful in children with a diminished level of consciousness or in neurologically impaired children who have poor pharyngeal tone leading to upper airway obstruction. They are available in a selection of pediatric sizes. In very young patients, airway secretions and debris readily obstruct small nasopharyngeal airways, making them unreliable. Moreover, children may have large adenoids, which can lead to difficulty in placing the airway; trauma and bleeding may occur during placement. Large adenoids also may compress the nasopharyngeal airway after placement, leading to increased airway resistance and an ineffective airway.

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Figs 5.1A and B: Oropharyngeal airway (OPA). Selection of an oral airway–The tip of the airway should end just cephalad to the angle of mandible. A curved piece of plastic inserted over the tongue that creates an air passage way between the mouth and the posterior pharyngeal wall

Figs 5.2A and B: The length of the nasal airway can be estimated as the distance from the nares to the meatus of the ears and is usually 2-4 cm longer than the oral airway

BAG MASK VENTILATION A patient who is apneic or in very severe respiratory distresses require ventilation assisted initially with bag and mask. A ventilation face mask allows the rescuer to ventilate and oxygenate a patient. Equipment Required • • • • • •

Face mask Bag Oxygen source Suction source Roll of sheet Oropharyngeal or nasopharyngeal airway

Face Mask: A ventilation mask consists of a rubber or plastic body, a standardized 15 mm/22 mm connectivity part and a rim or face seal. In infants and toddlers the undermask volume should be as low as possible to decrease dead space and minimize rebreathing of exhaled gases. Ideally

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Figs 5.3A and B: Bag and mask

the mask should be transparent permitting the rescuer to observe the color of the child’s lips and condensation on the mask (indicating exhalation) and to detect regurgitation. Face masks are available in a variety of sizes. The mask should extend from bridge of the nose to the cleft of the chin enveloping the nose and mouth but avoiding compression of the eyes. The mask should provide an airtight seal. If an airtight seal is not maintained, the inspired oxygen concentration is lowered during spontaneous respiration and controlled ventilation cannot be effectively provided (Fig. 5.3). Bag: Two types of bags are in general use: self-inflating resuscitation bags and standard anesthesia bags. A. Self inflating manual resuscitator devices (Fig. 5.3) An inflating bag valve device with a face mask provides a rapid means of ventilating a patient in an emergency and does not require an oxygen source.4-6 The bag recoil mechanism fills the self inflating bag from a gas source (if available) or form room air. During bag reinflation the gas intake valve opens and supplemental oxygen if available or room air is drawn into the bag. During bag compression the gas intake valve closes and a second valve opens to permit gas flow to the patient. During patient exhalation the bag outlet valve(non rebreathing valve) closes and the patient’s exhaled gases are vented to the atmosphere to prevent rebreathing of carbon dioxide. As noted, a selfinflating bag-mask device delivers room air unless supplemental oxygen is provided. At an oxygen inflow rate of 10 L/mm, pediatric self-inflating bag-mask devices without oxygen reservoirs deliver 30 to 80% oxygen to the patients depending on patient size and minute ventilation. An oxygen reservoir is used to deliver a consistently high oxygen concentration (60 to 95%). A minimum oxygen inflow rate of 10-15 L/min is required to maintain adequate oxygen volume in the reservoir. High oxygen flow rates may cause some soring - loaded ball or disk outlet valves4 to chatter or stick. Size of self inflating manual resuscitator bag • Neonatal size 250 ml4 –this may be inadequate to support effective tidal volume for full term infants • 450-500 ml appropriate for infants, child and full term infant • 750 ml–larger child 6,7

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Fig. 5.4: Flow-inflating (anesthesia) ventilation system

Regardless of the size of the manual resuscitator used, the rescuer should use only the force and tidal volume to cause the chest to rise visibly.5 Flow-inflating (Anesthesia) ventilation system (Fig. 5.4) Flow inflating ventilation systems8 consist of a reservoir bag, an overflow port, a fresh gas inflow port and a standard 15, 22 mm connector for mask or tracheal tube connection. The overflow port usually includes an adjustable clamp or valve. The volume of the reservoir bag for infants is 500 ml for children 600 to 1000 ml, and for adults 1500 to 2000 ml. Flow-inflating bags do not contain a non-breathing valve, so the composition of impaired gas is determined by fresh gas flow. If the pressure relief valve offers too much resistance to flow, the bag will become distended, producing huge airway pressure and the potential for barotrauma and its complications.9 If the gas flow is reduced while the pressure relief valve is too tight, insufficient washout of exhaled gases may result in rebreathing of exhaled air and resultant hypercapnia. In addition, the bag may refill slowly, limiting the rate of ventilation. During ventilation with a flow-inflating bag, fresh gas inflow should be adjusted to at least 250 ml/kg per minute. PEEP or CPAP may be provided through this bag by partially closing the adjustable pressure relief valve until the desired level of PEEP (5 to 10 cm H20) is achieved. PEEP or CPAP may be delivered only by using a tight- fitting mask or a tracheal or tracheostomy tube. Suction Devices A suction force of 80 to 120 mm Hg is generally necessary.4 A wall mounted suction unit should provide a vacuum of more than 300 mm Hg when the tube is clamped at full suction. Suction catheters can be flexible plastic catheters or rigid wide bore suction cannulas.10 Size of tracheal suction catheter (Fr) = 2 × tracheal tube Procedure of Bag and Mask Ventilation Positioning of the baby (Fig. 5.5): The head should be placed on a thin cushion to cause slight cervical spine flexion and gentle extension at the atlantooccipital joint. In infants, the large occipitofrontal diameter makes the cushion unnecessary, although a thin pad under the shoulders may useful(under 2 year of age ). Current recommendations are to avoid overextending the baby’s very flexible cervical spine, which may stretch and compress the trachea. Appropriate head tilt separates the tongue from the posterior pharyngeal wall. If airway obstruction persists, the chin can be pulled forward by encircling the mandible behind the lower incisors between thumb and

PEDIATRIC AIRWAY MANAGEMENT

Figs 5.5A and B: Bag and mask ventilation—EC technique

fingers. The most effective means of relieving functional obstruction is the so called triple airway maneuver: with the fingers behind the vertical ramus of the jaw, the mandible is displayed downward, forward and finally upward again until the mandible and lower incisors are anterior to the maxilla. This action effectively pulls the tongue forward and away from the pharyngeal wall. Mask placement : Place the appropriate size mask on the bridge of the nose and the bony prominence of the chin. It is important to avoid airway occlusion with the mask or hand or pressure on eyes, soft nasal structures. A nasal or oropharyngeal airway may help in maintaining an adequate airway. Once a good position and mask fit is ensured, ventilation may be assisted. Ventilation: To provide bag mask ventilation, open the airway seal the mask to the face and deliver a tidal volume that makes the chest rise. This technique of opening the airway and sealing the mask to the face is called the EC clamp technique More effective ventilation can be achieved with 2 persons4 than with 1 person and 2-rescuer ventilation may be necessary when there is significant airway obstruction or poor lung compliance.11 One rescuer uses both hands to open the airway and maintain a tight mask to face seal while the other rescuer compresses the ventilation bag. Both rescuers should observe the chest to ensure that the chest rises with each breath. Problems during Bag and Mask Ventilation (Table 5.1) If effective ventilation is not achieved (i.e. the chest does not rise) reposition the head ensure that the bag and gas source are functioning properly. Inflation of the stomach occurs especially in presence of partial airway obstruction or poor lung compliance. It may also occur if an excessive inspiratory flow rate or ventilation pressure is used. Gastric inflation after prolonged bag mask ventilation can limit effective ventilation12 but the inflation can be relieved by placing a nasogastric tube. It can further be minimized by increasing inspiratory time to 1 to 1½ seconds. A second rescuer can apply cricoid pressure also may prevent regurgitation and aspiration of gastric contents.13,14

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PEDIATRIC INTENSIVE CARE Table 5.1: Problems during bag and mask ventilation and their solution 1. Ineffective ventilation 2. Gastric inflation

Reposition the head ensure that the mask is sealed snugly Place nasogastric tube Increase inspiratory time Apply cricoid pressure (sellick maneuver)

3. Regurgitation of gastric Table 5.2: Indication for intubation a. b. c. d.

PaO2 < 60 mm with FiO2>0.6 (in absence of cyanotic congenital heart disease) PaCO2> 50 mm Hg (acute and unresponsive to other intervention) Upper airway obstruction, actual or impending Neuromuscular weakness • Maximum negative inspiratory pressure >-20 cm H2O • Vital capacity 1:3. 2. If pressure limited: Increase peak inspiratory pressure (PIP), decrease PEEP, increase frequency (rate) 3. Decrease dead space (increase cardiac output, decrease PEEP, vasodilator) 4. Decrease CO2 production: Cool, increase sedation, decrease carbohydrate load 5. Change endotracheal tube if blocked, kinked, malplaced or out, check proper placement 6. Fix leaks in the circuit, endotracheal tube cuff, humidifier. Measures to Reduce Barotrauma and Volutrauma: Folowing concepts are being increasingly followed in most pediatric intensive care units. 1. Permissive hypercapnia:9 Higher PaCO2s are acceptable in exchange for limiting peak airway pressures:as long as pH>7.2 2. Permissive hypoxemia: PaO2 of 55-65; SaO2 88-90% is acceptable in exchange for limiting FiO2 ( 30%. Patient ventilator dysynchrony:Incoordination between the patient and the ventilator: Patient fights the ventilator!! Common causes include, hypoventilation, hypoxemia, tube block/kink/malposition, bronchospasm, pneumothorax, silent aspiration, increased oxygen demand/increased CO2 production (in sepsis), inadequate sedation. If patient fighting the ventilator and desaturating: Immediate measures Use Pnemonic: D O P E D—displacement, O—obstruction, P—pneumothorax, E—equipment failure 1. Check tube placement: When in doubt take the endotracheal tube out, start manual ventilation with 100% oxygen. 2. Examine the patient: Is the chest rising? Breath sounds present and equal? Changes in exam? Atelectasis, treat bronchospasm/tube block/malposition/pneumothorax? (Consider needle thoracentesis) Examine circulation: Shock? Sepsis? 3. Check arterial blood gas and chest X-ray for worsening lung condition, and for confirming pneumothorax. 4. Examine the ventilator, ventilator circuit/humidifier/gas source. If no other reason for hypoxemia: increase sedation/muscle relaxation, put back on ventilator.

PEDIATRIC MECHANICAL VENTILATION

Sedation and Muscle Relaxation During Ventilation Most patients can be managed by titration of sedation without muscle relaxation. Midazolam (0.1-0.2 mg/kg/hr) and vecuronium drip (0.1-0.2 mg/kg/hr) is most commonly used. Morphine or fentanyl drip can also be used if painful procedures are anticipated. Routine Ventilator Management Protocol Following protocol is commonly followed: 1. Wean FiO2 for SpO2 above 93-94 2. ABG one hour after intubation, then am–pm schedule (12 hourly), and after major ventilator settings change, and 20 min after extubation 3. Pulse oximetry on all patients, End tidal carbondioxide (EtCO2) /graphics monitoring if available 4. Frequent clinical examination for respiratory rate, breath sounds, retractions, color 5. Chest X-ray every day/alternate day/as needed. Respiratory Care Protocol 1. Position change 2 hourly right chest tilt/left chest tilt/supine position . 2. Suction 4 hourly and as needed (In line suction to avoid de recruitement/loss of PEEP/ desaturation if available) 3. Physiotherapy 8 hourly Percussion, vibration and postural drainage. NO physiotherapy if labile oxygenation such as ARDS (Acute respiratory distress syndrome), PPHN (persistent pulmonary hypertension of neonate) 4. Nebulization: In line nebulization is preferred over manual bagging. Metered dose inhalers (MDIs) can also be used. 5. Disposable circuit change every 72 hours 6. Humidification/In line disposable humidifier. Respiratory Care during Ventilation10 Chest Physiotherapy (CPT) Despite the extensive use of chest physiotherapy in pediatric practice there is very scant information available on its use in mechanically ventilated children. There is very little evidence for the beneficial effect of chest physiotherapy (CPT). Its use is well established only in acute atlectasis and pediatric lung abscess in children greater than 7 years.11-13 Prolonged immobilization and supine positioning leads to atlectasis especially of the left lower lobe, due to the weight of the heart. This in turn leads to retention of secretions super added bacterial infection and nosocomial pneumonia. The physiological rationale behind CPT is to mobilize secretions, prevent pneumonia and reduce hospital stay. CPT consists of a series of maneuvers such as positioning, percussion, vibration and manual hyperinflation.11,12 Positioning: In order to increase drainage of secretion, improve ventilation/perfusion (V/Q) matching, improve oxygenation, decrease work of breathing and increase functional residual capacity (FRC)

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certain body positions are utilized in the ICU. These include the upright posture in a person who has obesity, ascites, abdominal surgery, or the 45o angle to decrease the risk of aspiration in a person being enterally fed. A person with unilateral lung disease is to be placed with the affected lung uppermost in order to improve drainage of secretion and also for a better V/Q matching14 (as both perfusion and ventilation will increase in the gravitationally assisted normal lung).11, 12, 15 One should however remember the risk of suppurative secretions draining into the normal lung and worsening the disease process. Prone positioning has been shown to improve oxygenation in up to 85% of patients in the early stages of ARDS by increasing FRC, increasing V/Q matching, enabling drainage of secretions and improving lymphatic drainage.16-19 Percussion and vibration: Percussion is performed by manually clapping the chest wall using cupped hands.13, 20 It is done to mobilize secretions from the nondependent areas of the chest to the central airways from where they may be suctioned. Vibration and percussion can be done mechanically as well. Vibration is generally used in neonates to avoid damage to their fragile chest walls. Manual hyperinflation: It is usually performed before and between suctioning to prevent hypoxemia while suctioning. The patient is disconnected from the ventilator and is bagged with a resuscitator bag using slow deep inspiration, inspiratory hold and quick release to enhance expiration. This causes the recruitment of atlectatic segments and also mobilizes secretions.11, 12 Continuous rotational therapy: This involves the use of specialized beds that continuously turn the patient along a longitudinal axis.11, 20 It is currently unavailable in India. Fiberoptic bronchoscopy (FOB): This is used for removal of retained secretions and for suctioning thick tenacious mucus plugs. Despite its widespread acceptance for removal of secretions, its superiority over chest physiotherapy has not been proven. Despite this, one should consider FOB in lobar or greater atlectasis in patients not responding to vigorous chest physiotherapy or in life threatening whole lung atlectasis.21 Complications: Chest physiotherapy is associated with increased incidence of hemodynamic disturbances, higher incidences of gastroesophageal reflux,11, 12 elevation of intracranial pressure22 and increase in oxygen consumption.23-25 To some extent the effect on intracranial pressure and hemodynamics can be decreased by prior sedation and paralyzation of the patient.26 The head down positioning while doing rigorous physiotherapy is likely to increase the risk of aspiration and worsening of intracranial pressure. Neonates and children with fragile bones such as in rickets and osteogenesis imperfecta can develop rib fractures. Currently, there is very little data supporting the using of CPT for any condition outside of atlectasis. Positioning is useful in ARDS and in individuals with unilateral lung disease. Studies however reveal that continuous rotational therapy and kinetic percussion20 decreases pulmonary complications. Studies done in adults show that chest physiotherapy fails to decrease the length of hospitalization, length of fever11 or duration of ventilation. Despite the rationale for its use CT has not been shown to hasten the recovery from pneumonia or decrease the duration of hospitalization.27

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Humidification Normally, the upper airway of a person heats and humidifies the atmospheric air to body temperature and 100% relative humidity. Medical gases have no humidity and bypassing the upper airway as in patients with artificial airway such as endotracheal tube or tracheostomy makes humidification a must.28, 29 Decrease in the humidity can lead to mucosal damage and tube occlusions, atlectasis, loss of FRC, hypoxia and increased incidence of pneumonia. Excessive humidification is also a problem and can decrease mucociliary clearance, cause hyper-hydration and loss of surfactant activity. Humidification can be achieved using heated water humidifier (HW),28,29 heated wire or by Heat and Moisture Exchange (HME) filters. The appropriate temperature and humidity to be used in ventilated patients has not yet been established. Heated water humidifier (HW): Heated humidifiers use heating elements to increase the temperature of water and humidity of the inspired gas.30 The degree of humidification of the inspired gas will depend on the temperature setting, flow rate, water level in the humidifier and the length of the circuit. These generally bubble the inspired gas through the column of water. These are to be used only with a high flow system such as that needed during mechanical ventilation. The temperature of the inspired gas has to be monitored in order to avoid over heating and tracheal burns. Heated wire circuit: In an attempt to decrease the rainout associated with heated water humidifier, heated wire circuit is available. This is available in both reusable and disposable form. The temperature of the gas is maintained at a select value. Heat and moisture exchangers (HME): HME filters combine humidifying properties31, 32 of plastic foam impregnated with hygroscopic substance, with bacterial filtering properties of filter membrane. HME filters are made of substances with low thermal conductivity such ceramic, polyurethane, polyethylene or cellulose sponge material.33 The hygroscopic substance can be Calcium Chloride, magnesium chloride, aluminium chloride or lithium chloride.31 It chemically absorbs water vapors in expired gas, which then saturates the inspired gas. HME has been found to provide safe and adequate humidification of inspired gases. Some of the filters available in the market claim to be 99.5% efficient in its filtration properties. A recently done study however casts doubts about this claim. Their use however is associated with lesser circuit contamination. There has not been any statistical difference in the incidence of ventilator associated pneumonia (VAP) with the use of HME filters. Its use can increase dead space and resistance, which may be overcome by increasing pressure support. It can be used safely up to a week32, 34 or until visible liquid contamination occurs. This gets converted to cost saving on disposables, fewer need for breaking the circuit and hence reduction in bacterial contamination. Aerosol Therapy Aerosol is a group of particles suspended in air for a relatively long time. Aerosol therapy is used in order to deliver the drug directly to the site of action, there by minimizing the systemic side effects and improving the efficacy. The size of the aerosol is expressed as mass median aerodynamic diameter (MMAD). The MMAD determines the rapidity with which the aerosol will settle in the airway. Aerosol gets deposited through the process of impaction, sedimentation and diffusion.35-36 In order to be maximally effective the aerosol particles should be 0.5–5 μm in size. Particles larger

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than 3 μm get impacted by its size on the tubing and endotracheal tube. Particles around 2 μm get sedimented due to gravity and still smaller particles undergo diffusion. Aerosol therapy may be provided using nebulizers or Meter dose inhalers (MDI). MDI‘s are as efficient and according to some studies more efficient than nebulizers. The latter however has a greater versatility and can be adapted to deliver various drugs. An array of drugs like bronchodilators, steroids, antibiotics, anticholinergics, mucolytics, prostacyclin, etc. gets delivered by the nebulizer route. The most common drug however is bronchodilator and steroids. The amount of the drug deposited in the lower airway will depend on several factors such as physiochemical properties of the drug,33, 35, 36 the nature of the device, position of the device in the circuit, the nature of the ventilator circuit, ventilatory parameters, humidity and density of the inspired air and on the airway anatomy. Characteristics of aerosol generating device: Greater respiratory tract deposition occurs when the MMAD of the aerosol is in the range of 1-3 mm. The larger size particle can get impacted in the endotracheal tube and in the ventilator circuit.35, 37 A nebulizer could have continuous or intermittent operation. Continuous operation requires the nebulizer to be driven by a pressurized gas source. Intermittent operation requires a separate line from the ventilator to drive the nebulizer during inspiration. Between the two, intermittent operation during inspiration is preferred as it lowers the wastage of drug. Ventilatory parameters: Adequate aerosol delivery is achieved in assisted modes of ventilation only if the patient is in synchrony with the ventilator. 20% more delivery can be achieved during CPAP mode than with volume cycled breaths.35, 38, 39 The tidal volume has to be higher than normal to compensate for the compressible volume of the tubing. Longer inspiratory time has to be used in order to increase the nebulizer generated aerosol to be inhaled with each breath. This is needed even in an MDI generated aerosol although the mechanism is not clearly known. Circuit characteristics: In general, smaller endotracheal tube, narrow internal diameter of the pediatric ventilatory circuit and humidification of gases35, 40 all reduce the aerosol deposition in the lung. Lower density gas such as heliox mixture enable better deposition of the aerosol by decreasing the turbulence of air flow. Position of the device: Aerosol delivery to the patient is improved by placement of a nebulizer at a distance of 30 cm from the endotracheal tube37,40 rather than between the patient wye and the endotracheal tube because the ventilator tubing acts as a spacer for the aerosol to accumulate between breaths. Suggested method for delivery of drug by nebulization (modified from recommendations by Hess:41 1. Clear secretions from endotracheal tube 2. Ensure a high tidal volume to eliminate the dead space of the tubing 3. Decrease the inspiratory flow rate such that the inspiratory time is prolonged 4. Ensure 4-6 ml of volume in nebulizer and place the nebulizer in the inspiratory limb 30 cm from wye connection 5. Ensure airflow of 6 lt/min to run nebulizer

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6. Nebulize solution only during inspiration 7. Tap nebulizer intermittently during operation 8. Disconnect nebulizer from the circuit after use. Meter dose inhaler (MDI): Only 1% of the content of MDI is the active drug. The rest is made up of propellants and preservatives. The amount of the drug delivered by MDI is much smaller than the nebulizer.35, 42 MDI may be used directly on ET tube or through a chamber. A variety of chambers are available for use of MDI during mechanical ventilation. As a rule it is better to use a chamber device than to use MDI directly on the ET tube. The chamber could be collapsible or noncollapsible and be attached to the inspiratory limb of the ventilator circuit.35 It is preferable to use a collapsible chamber that does not have to be disconnected from the circuit between uses. It is important that the actuation of the MDI is synchronized with the inspiratory time. An aerosol cloud enhancer spacer directs the fumes away from the patient into the spacer.43, 44 The drug then gets carried to the patient during the inspiratory flow and this method of delivery is the most efficient. Suggested method of aerosol delivery by MDI (modified from recommendations by Hess:41 Steps 1-3 are the same as that for the nebulizer treatment 4. Place the acturator-spacer device in the inspiratory limb of ventilator 5. Shake the MDI and place on the spacer 6. Discharge MDI at the onset of inspiration 7. Repeat 20 to 30 seconds later. Several studies have compared the efficacy of nebulizer and MDI.13, 33 When properly executed MDI may be better than nebulizer. The bio-availability is very poor when one uses the right angle MDI port and hence should not be used to deliver bronchodilator in mechanically ventilated patients. Of all the medicines used, bronchodilators are the ones that are most commonly delivered as an aerosol. Bronchodilators are used in an asthmatic. In order to reduce air trapping the ventilatory parameters one uses is almost exactly the opposite to the parameters that one has to use for optimization of aerosol delivery. Furthermore, humidification is not possible while using aerosol. All this makes it difficult, wasteful and even harmful to use continuous aerosol therapy while on ventilator. Mucolytics There are no randomized control trials in the usage of mucolytics in pediatric patients on the ventilator. However, there have been case reports in the use of N-acetylcystine and DNase in life threatening situations of mucous plugs. 21,35 N-acetylcystine works by breaking the disulphide bonds in the mucus and hence making it less viscid and easier to suction. N-acetylcystine installation has been associated with mucospasm, which can be overcome by using β2 agonist nebulization. Although DNase is used in patients with cystic fibrosis, it is not routinely used for removing secretions. Its use has been described in neonates and asthmatics with life threatening mucous plugs. It is expensive and not available in India. Endotracheal Suctioning Suctioning can be done using the closed or open suctioning system. In closed suction system the suction catheter is encased in a plastic sleeve and is a part of the ventilatory tubing. The advantage

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of the closed suctioning system is that cost of disposable is reduced; intuitively the risk of infection has to be less (although no published evidence). The peep effect is not lost while suctioning and hence the risk of hypoxemia in patients with reduced FRC is less.26 Its disadvantage is that resistance can be increased and it decreases the pulmonary bio-availability of β2 agonist when used in asthmatics. In order to decrease the viscidity of secretion when not contraindicated, we increase the fluid administration to the patient, i.e. hyper hydrate the patient. In some institutions normal saline installation into the ET tube is routinely practiced. We use it only when the secretions are viscid and copious. While suctioning it is important to remember that mucosal injury can occur. Hence, gentle suctioning taking care to not push the catheter up to the carina is a must. Personally in our ICU we use the open system except in ARDS. In patients with pulmonary hypertension and elevated intracranial pressure, sedation prior to suctioning is a must26 as significant elevations of pressures and deterioration of hemodynamic parameters can occur. Eye Care A ventilated patient is often heavily sedated and may be even paralyzed. This predisposes the individual to exposure keratitis, corneal ulceration and infection. Along with passive closure of the eyelid, using lubricants at scheduled intervals has been shown to provide protection from above mentioned problems. The exact lubricant and the number of times to use it have not been established. We use artificial tears every two hours and if we use an oily lubricant apply it four times a day. In conclusion except for a few practices that we use in day to day practice in the ICU, most methods are not proven to be effective. We should not let our practices be guided by hear say and should practice evidence based medicine as often as possible. Weaning from Mechanical Ventilation46 Process of weaning begins at the time of initiation of ventilation (i.e. minimal ventilatory settings to keep blood gases and clinical parameters within acceptable limits although these settings will be very high). If such procedure is followed then ventilatory settings would be reduced once the primary pathology/condition that led to ventilation is improving. How do we know if the condition is improving? Improving general condition, fever, etc. Decreasing FiO2 requirement Improving breath sounds Decreasing endotracheal secretions Improving chest X-rays Decreased chest tube drainage, bleeding/air bubbles (as the case may be) Improved fluid and electrolyte status (no overload or dyselectrolytemia) Improving hemodynamic status Improving neurological status, muscle power, airway reflexes/control. Described weaning criteria such as maximal negative inspiratory force, vital capacity measurement are usually impractical.In pediatrics and neonatal age group weaning criteria are generally clinical.

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Weaning Methodology There are no set protocols supported by any pediatric studies. Protocol followed at authors institution is as follows: When FiO2 requirement is down to 0.4, improvement in secretions, and chest X-rays, improving clinical condition, muscle relaxant drip is stopped and sedation can be slowly weaned. One should change control mode (or PRVC) to SIMV mode with pressure support. Pressure support can be set at 10-15 cm above PEEP so that the spontaneous breaths can be adequately supported. Trigger sensitivity should be 0-to negatve one. Following weaning guidelines can be followed 1. Decrease FiO2 to keep SpO2>94 2. Decrease the PEEP to 4-5 gradually by decrements of 1-2 cm H2O 3. Decrease the SIMV rate to 5 (by 3-4 breath/min) 4. Decrease the PIP (to 20 cm H2O, by reducing 2 cm H2O each time/Tidal volume, to no less than 5 ml/kg to prevent atelectasis (usually guided by blood gases) 5. Ventilator rate and PIP can be changed alternately. 6. If at any point patients oxygen requirement increases greater than 0.6, or spontaneous ventilation is fast or distressed with accessory muscle use (increased work of breathing), patient gets lethargic, hypercarbia on blood gas, weaning process should be paused and the support level increased patient may not be ready. 7. Goal is to decrease what the ventilator does and see if the patient can make up the difference without desaturations/hypercarbia/significant tachypnea and respiratory distress. (For example, If patients SIMV was reduced from 20/min to 15/min and the patients spontaneous rate is increased from 25 to 50, this patient may need more time on the ventilator) Extubation Most patients can be weaned to SIMV of 5 and extubated, some will need pressure support 510 above PEEP with CPAP, while others may need CPAP 5 cm H2O before extubation, with or without spontaneous breathing trials with T piece. Extubation can generally be performed when following criteria are met 1 Control of airway reflexes, minimal secretions 2. Patent upper airway (air leak around tube?) 3. Good breath sounds 4. Minimal oxygen requirement < 0.3 with SpO2 >94 5. Minimal rate 5/min 6. Minimal pressure support (5-10 above PEEP) 7. “Awake ” patient. Disease Specific Ventilation Status asthmaticus47 Main Indications are clinical deterioration despite maximal drug therapy. Rising PaCO2 (40 to 45 mm) from a low PaCO2 (25 to 30 mm)

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Fatigue, lethargy, deteriorating mental status Mixed respiratory and metabolic acidosis. Initiation of Ventilation Controlled intubation use sedation and muscle relaxation (short acting muscle relaxant such as succinyl choline. Use cuffed endotracheal tube if feasible Ketamine with midazolam are good sedatives for initiation and maintenance of mechanical ventilation Mechanical ventilation in asthma is Associated with high morbidity and mortality Risks involved include barotrauma (air leak) due to dynamic hyperinflation, impaired venous return (tamponade) and low cardiac output due to hyperinflation (pulsus paradoxus). Strategies that minimize end expiratory volume, intrinsic peep, and maximize expiratory time, using lower tidal volumes and respiratory rates with permissive hypercapnia have been shown to be associated with lower mortality. Ventilation Strategies Controlled hypoventilation using SIMV or assist control Volume or pressure limited mode Plateau pressure limit must be < 35 cm water Tidal volume 6-10 ml/kg f 8-14/min, PEEP 3-4 cm H2O Support modes: Volume or pressure support48 Patient determines (f) rate and (Ti) inspiratory time Plateau pressure limit set at 7.25 (permissive hypercapnia),50 and absence of metabolic (hypoxic)acidosis. Conventional ventilation is the most readily available modality.Earlier standard approach used to be: Volume ventilation with tidal volumes 10 to 15 ml/kg with positive end expiratory pressure. Adequate filling pressures with use of fluid and good cardiac contractility with inotropic support to prevent low cardiac output. Problems with conventional 10 to 15 ml/kg tidal volume and PEEP are as follows: Barotrauma, volutrauma, air leak (pneumothorax), chronic lung disease, delayed recovery, poor cardiac output, prolonged ventilation and nosocomial infections.

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In view of problems with conventional tidal volume ventilation: Low tidal volume strategy is recommended. (NIH ARDS Network study).49 This was a prospective randomized multicenter trial of 240 patients with two groups using 12ml/kg vs 6 ml/kg tidal volume, PEEP 5 to 18 cm of H2O, FiO2 0.3 to 1, showed 25 percent reduction in mortality in 6ml/kg group.In another study, use of higher positive end expiratory pressure with lower tidal volumes (Open lung approach)50, 51 has been used with improved results.Gattinoni et al in adults and Marraro in pediatrics ARDS patients, showed that chest CT (computerized tomography) may be useful to see the extent of pulmonary involvement .Gattinoni studied benefits of prone positioning52 in patients with ARDS with underventilated posterior zones.Prone positioning is being recommended although transient improvement in oxygenation occurs but no real effect on improving long-term outcomes has been shown.Problems associated with prone positioning include difficulty in nursing management and monitoring (chances of accidental extubation, especially during X-ray examination, and physiotherapy). Currently no good pediatric studies are available on use of prone positioning in ARDS patients and the effect on outcomes. Case Scenario 2 A 5 years old, premorbidly well child weighing 15 kg comes to emergency with 3 days of moderate to high grade fever and cough. He has been lethargic for the past 1 day and is not feeding well. Mother noticed that he is breathing fast since morning and has become dusky and unresponsive for the past 10 mins. On examination, he is unresponsive with a heart rate of 140/min, respiratory rate 60/min with retractions and head bobbing. He is peripherally cyanosed, saturating 80% in air and saturations slowly increasing to 88% in 100% oxygen. Auscultation reveals bilateral extensive crepitations. The chest X-ray is suggestive of ARDS with bilateral diffuse infiltrates in lungs. He was intubated and ventilated on PRVC mode. His initial settings were: • Tidal volume 90 ml (6 ml/kg) • FiO2 100% • Rate 25 • I:E ratio 1:2 • PEEP 6. His saturations improved to 85% on the above settings and an ABG done showed pH 7.30, PCO2 45, PO2 47, HCO3 20.4, BE–5 and saturation 85%. To improve his oxygenation, his PEEP was increased to 8 and I:E ratio to 1:1. Following the intervention, his saturations improved to 95%. Airleak Syndrome Pneumothorax, bronchopleural fistula Ventilation for airleak syndrome is challenging.Chest tubes are frequently required Ventilation strategies Using low mean airway pressures, low peak inspiratory pressures, low PEEP, lower tidal volumes, and lower inspiratory times are needed.

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Other modes useful in airleak syndrome High frequency oscillatory ventilator (HFOV) delivers small tidal volumes at high frequency with lower peak and mean airway pressures. Patient has to be muscle relaxed. Patient cannot be suctioned frequently as disconnecting the patient from the oscillator can result in volume loss in the lung. Likewise, patient cannot be turned frequently so decubitus ulcers can occur. Patient should be turned and suctioned 1-2times/day if he/she can tolerate it. Postoperative ventilation following open heart surgery General principles: One needs to understand the cardiac physiology associated with the lesion and corrective surgery as well as cardiopulmonary interactions in the postoperative period. Hypoxia and hypercarbia should be avoided to prevent pulmonary hypertension that increases right ventricular afterload/chances of Right ventricular failure. Excessive systemic vasoconstriction should be avoided to prevent increase in LV afterload. Volume/pressure limited ventilation : Mode of ventilation has not shown to make any real difference in outcomes. Excessive PEEP and excessive mean airway pressures should be avoided to prevent tamponade/ low cardiac output. Pulmonary and systemic vascular resistance can increase with pain causing increased after load on the heart. Consider nitric oxide in patients with severe preoperative pulmonary hypertension, in postoperative period. Chronic lung disease/neuromuscular weakness Tracheostomy is usually performed One needs to assess need for day/night/home ventilation Generally low ventilator settings are needed.LP60 (USA) pressure controlled ventilator can be used. Non-invasive positive pressure ventilation can also be tried to deliver PS and CPAP via tight fitting mask (BiPAP: bi-level positive airway pressure).One can set a “back up” rate in case of apnea. Case Scenario 3 A 13 years old immunized female child weighing 30 kg was admitted with complaints of sudden onset weakness of lower limbs with inability to stand and bear weight for 2 days. The next day she developed weakness of both upper limbs such that she could only move her arms in the bed. She started to have decreased volume of voice and complained of some tingling sensation in both legs. There was no history of fever, cough, loose stools, trauma, alteration in sensorium or seizures. She had an episode of fever with cough 2 weeks back which lasted for 3-4 days. On examination she was alert, conscious and oriented. Her heart rate was 110/min and respiratory rate 30/ min. She had shallow respiratory efforts with paradoxical respiration. CNS examination revealed quadriparesis with power in both lower limbs and upper limbs being 1/5 and 2/5 respectively. She had global areflexia. There was no objective sensory loss and no

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other focal deficits. She was diagnosed to have Guilain-Barre’ syndrome with respiratory muscle weakness supported by NCV findings. She was ventilated for neurogenic cause of respiratory failure on PRVC mode of ventilation with the following settings: Tidal volume 200 (6-7 ml/kg) Rate 15 FiO2 40% PEEP 3 I: E ratio 1: 2 His ABG on the above settings was within normal limits. Raised ICP (Intracranial pressure) Following points should be kept in mind. 1. Avoid ketamine, succinylcholine as theses agents raise ICP. 2. Midline head up position is ideal. 3. Adequate sedation and muscle relaxation is required to prevent coughing and bucking on the ventilator (leads to raised ICP) and adequate analgesia during painful procedures 4. Low PEEP (avoidance of excessive PEEP) to prevent ICP from going up. 5. Goal of ventilation to keep normal PaO2 and PaCO2 30-35 mm Hg; hyperventilation is no longer recommended53 Neonatal Ventilation54 Continuous positive airway pressure (CPAP):55 A continuous flow of heated humidified gas is circulated past the infants airway at a set pressure of 3-8 cm of H2O maintaining an elevated end expiratory lung volume while the infant breathes spontaneously.CPAP is usually delievered by means of nasal prongs or nasopharyngeal tube. It improves oxygenation by an increase in the functional residual capacity. However, over reliance on CPAP may be dangerous and it should only be used if infants show adequate respiratory effort, appear to be tolerating the procedure well and maintain adequate arterial blood (PCO2 7.25, PAO2 >50). With all CPAP devices some air may get into the gut and cause gastric distension. This can be prevented by using an open ended orogastric tube in situ. CPAP effectively splints the chest wall, keeps the airways patent thereby preventing obstructive apneas and atelectasis. Various studies have documented the efficacy of CPAP in respiratory distress (Hyaline membrane disease) of mild to moderate degree.2 Recently trials have been conducted on using nasal intermittent positive pressure (NIPPV) and it has been found to have similar results as CPAP. Conventional Neonatal Ventilation56, 57 Pressure limited time cycled ventilation The commonest type of ventilation used for neonates is pressure limited, time cycled ventilation where a peak inspiratory pressure is set and gas is delivered to achieve that target pressure. After the target is reached, the remainder of the gas volume is released into the atmosphere as a result the tidal volume delivery with each breath is variable despite the recoeded peak pressure being constant. Inspiration also ends after a preset time period.

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In contrast in volume limited modes, a preset volume is delivered with each breath regardless of the pressure that is needed.Some ventilators also use airway flow as the basis of cycling in which inspiration ends when flow has reached a critical low or preset level (flow cycled ventilation). In pressure limited, time cycled continuous flow ventilators following parameters are set at the outset: Peak inspiratory pressure (PIP) Peak end expiratory pressure (PEEP) Inspiratory time (ti) Rate This system is relatively simple and maintains good control over respiratory pressures. Disadvantages Poorly controlled tidal volume Does not respond to changes in respiratory compliance. Spontaneously breathing infants may receive inadequate ventilation and are at increased risk for airleaks. Case Scenario 4 A neonate is born to a 24 years old primigravida with pregnancy induced hypertension (PIH) through lower segment cessarean section due to uncontrolled hypertension at 34 weeks of gestation. He had a birth weight of 1.8 kg. He was tachypneic at birth with a rate of 68/ min and subcostal, intercostal and sternal retractions.He had grunting and had pulse oximeter saturations at 85% in room air which picked to 94% in oxygen. The chest X-ray revealed bilateral homogenous opacities suggestive of hyaline membrane disease (HMD). He was intubated and ventilated on pressure limited time cycled mode of ventilation with the following settings: PIP 22 PEEP 4 FiO2 100% Rate 50 Inspiratory time 0.4 sec. His ABG on the above settings showed a pH of 7.25, PCO2 60, PO2 68, HCO3 18, BE–5.0 and sats 95%. His ventilatory settings were revised to a PIP of 24 and rate was increased to 55 . Following this his PCO2 came down to 44 and pH normalized. Alternative Modes of Neonatal Ventilation Due to disadvantages associated with conventional ventilation, following alternative strategies are being used increasingly. Patient triggered ventilation (PTV): This is a form of ventilation where machine delivered breath is initiated in response to a signal derived from the patient’s own inspiratory effort thus synchronizing the onset of both spontaneous and mechanical breaths. The types of signals used to provide PTV to newborn vary and could be impedence, pressure or flow. The basic feature is shifting of control of breathing from clinician to patient and the newer generation of ventilators allow its application to the smallest of babies.56 PTV can be of following types.

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a. Assist/control ventilation- This is the best mode of ventilation in acute phase of illness as it requires least amount of patient effort and produces improved oxygenation at the same or lower mean airway pressure than conventional modes.In this type of ventilation a positive pressure breath is delivered in response to patient’s inspiratory effort (assist) provided it exceeds a preset threshold criteria. There is a back-up rate (control) in case patient stops breathing. The inspiratory flow is proportional to patient effort and ventilation is tolerated well. b. Synchronous intermittent mandatory ventilation (SIMV): In this mode of ventilation mechanically delivered breaths are cycled at a rate set by the clinician but are synchronized to the onset of the patient’s own breath.Patient breathes freely inbetween the mechanical breaths. This insures less risk of ‘fighting’ or airleaks and sedation is not required. SIMV is particularly helpful for weaning from ventilation.57 c. Pressure support ventilation (PSV): This is similar to assist/control ventilation except that it is flow cycled, thus patient has full control over how much to breathe and for how long (ti). Although PSV can be used for full ventilation (PSV max), in practice it is genarally used as a weaning mode. d. Proportional assist ventilation (PAV). e. Mandatory minute ventilation (MMV). These are other promosing ventilatory strategies currently under development for clinical use but no data is available relating to its use in neonates. Rescue strategies for management of neonatal ventilatory failure. Despite improved ventilatory techniques, conventional ventilation may fail in certain situations. A commonely used parameter to assess the efficacy of ventilation is oxygenation index (OI). OI = PAW = mean airway pressure FiO2 = concentration of inspired oxygen PaO2 = partial pressure of oxygen OI of 25-40 indicates insufficient ventilation with existing mode of support. OI of > 40 indicates respiratory failure. Various rescue therapies as given below are currently practiced. A. High frequency ventilation: This can be of two types: — High frequency oscillatory ventilation (HFOV) — High frequency jet ventilation (HFJV). In newborns high frequency oscillation has been found to be effective in certain situations. During this type of ventilation a continuous flow of fresh gas rushes past the source that generates the oscillation and a controlled leak or low pass filter allows the gas to exit the system.Both inspiration and expiration are active processes. Oscillations are generated at a frequency ranging from 3 Hz15 Hz (1 hurst (Hz) = 60 breaths) per minute. Pressure oscillations within the airway produce tiny tidal volume fluctuations around a constant distending pressure. The amplitude of the pressure, which varies from 15-50 cm H2O, determines the tidal volume. This ventilation causes uniform recruitment of alveoli and there is significantly lower risk of airleaks. Earlier studies on HFOV had raised some doubts about the risk of IVH, however, randomized controlled trials carried out

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with proper selection criteria have depicted a significantly better outcome with HFOV in certain conditions.58 This mode of ventilation has been found to be effective in respiratory distress complicated by PPHN.59 Only Sensorimedics 3100/3100A, a high frequency oscillator has been approved by FDA for early intervention (prophylactic HFOV) but it is not commonly preferred form of therapy. Case Scenario 5 A 29 years old 2nd gravida mother delivered at 38 weeks of gestation by lower segment cessarean section in view of meconium stained liquor (MSL). At birth the baby was crying vigorously. He developed respiratory distress soon after birth. He was breathing at a rate of 80/ min with severe retractions and was saturating 88% in 100% oxygen. His chest X-ray was suggestive of meconium aspiration syndrome (MAS). He was ventilated due to persistent hypoxia on the following settings: Mode: Pressure limited time cycled: PIP 26 PEEP 3 Rate 60 FiO2 100% I:E ratio 1:3 His post ventilation ABG was : pH 7.182, PCO2 56, PO2 40, HCO3 16.2, BE –7.5 and oxyhemoglobin saturation at 86%. An echocardiogram was done on suspicion of persistent pulmonary hypertension (PPHN) which showed pulmonary pressures of 90 mm Hg with systemic pressure being 82/40. He was started on dopamine to increase the systemic pressure and Milrinone for pulmonary vasodilation. Sodium bicarbonate was given to correct acidosis and PIP was increased to 28. I:E ratio was not increased due to a high risk of air leaks in MAS. After these interventions the ABG improved to pH 7.24, PCO2 45, HCO3 19.6, BE –2.6 but PO2 remained low on 45 mm Hg. He was given a trial of High frequency ventilation on which his hypoxia slowly improved. High Frequency jet ventilation: Is a variant of HFOV and the differences are tabulated below:

Rate (HZ) Expiration Special ETT (reintubation) Gas exchange PaCO2 reduction PaO2 increase Cardiac output Tracheal injury

HFJV

HFOV

1.5-3.00 Passive Yes ++ ++ ± ± ++

3.00-15 Active NO ++ ++ + _ ?

Inhaled Nitric Oxide (INO) Nitric oxide (NO)appears to be ubiquitously distributed within universe. Critical care physicians have been most interested in the profound regulatory effects of NO on vascular tone. Inhaled nitric

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oxide distributes only to aerated lung where it rapidly diffuses from endothelial cells into subjacent vascular smooth muscle cells and stimulates Guanylate Cyclase to increase the concentration of Cyclic Guanosine Monophosphate that in turn causes smooth muscle relaxation. This localized vasodilator effect improves V/Q mismatch. NO that diffuses into vascular space is quickly converted to methemoglobin thereby avoiding systemic vasodilator effect. Inhaled nitric oxide is particularly useful for treating persistent pulmonary hypertension complicating RDS. This can be used with both conventional and high frequency ventilation. Kinsella et al. have reported outcome in nine cases of PPHN treated with INO. Within 15 minutes of initiation, PaO2 increased from 55 to 136 mmHg and OI reduced from 60 to 26.60 The first three had to be shifted to ECMO but the remaining six recovered completely. Patients with pulmonary hypertension secondary to congenital heart disease may also benefit both diagnostically and therapeutically from NO. Sometimes NO may combine with O2 to form NO2 and peroxynitrite, which could be highly toxic to the body. Thus further studies are required to confirm the short-term and long-term safety of INO usage in very young infants. The dose range used (10-80 parts per million) also needs to be standardized. SUMMARY 1. Remember shock and post-resuscitation are important indications for ventilation, in addition to respiratory failure and neuromuscular disease. 2. Clinical monitoring of adequate chest rise and oxygen saturations is very important (Regardless of volume, pressure or time cycled mode). 3. If ventilator fails, or when in doubt, remove endotracheal tube and try bag-mask ventilation. 4. Think about pneumothorax in a patient on mechanical ventilation. 5. Pulse oximetry and ABG facility is necessary for ventilation. 6. Hypoxia should be ruled out/corrected before sedating an agitated child. 7. Do not muscle relax/sedate patient with upper airway obstruction unless very confident in endotracheal intubation. 8. Low tidal volume is permitted to prevent lung trauma (permissive hypercapnia) 9. End tidal CO2 monitoring and pulmonary graphics monitoring is desirable if available. REFERENCES 1. Todres ID, Khilnani P, Critical upper airway obstruction in Children. In Roberts J T (Ed): Clinical Management of the Airway WB Saunders (Philadelphia) 1993:383-97. 2. Khilnani P, Mechanical ventilation in pediatrics.Indian J Pediatr, 1993, 60 (1)109-17. 3. Nunn JF, Resistance of gas flow and airway closure, In Applied respiratory physiology, 3rd editon London butterworths (London) 1975;270-84. 4. Venkataraman ST, Orr RA. Mechanical ventilation and respiratory care In :Fuhrman BP, Zimmerman JJ (Eds): Pediatric critical care, Mosby year book (St.Louis), 1992:519-43. 5. Macintyre NR. Respiratory function during pressure support ventilation.Chest1986;89:677. 6. Toro-Figueroa LO, Barton RP, Luckett PM, et al. Respiratory care procedures, In Manual of pediatric intensive care, Toro-Figuera LO, Levin DL (Eds) Quality Med Pub 1997;1416-52. 7. Khilnani P. Mechanical Ventilation 1:Indian J Crit Care Med 2000;4(4): 158-70. 8. Khilnani P. Mechanical ventilation 2:Indian J Crit Care Med 2000;4(4): 171-180. 9. Tuxen D. Permissive hypercapnic ventilation. Am J Respir Crit Care Med 1994, 150:870. 10. Ramakrishnan M. Care of the ventilated patient, In Khilnani P (Ed): Practical approach to pediatric intensive care, Jaypee Brothers Medical Publishers (Delhi) 2004;279-84.

PEDIATRIC MECHANICAL VENTILATION 11. Kathy Stiller. Physiotherapy in intensive care: Chest 2000;(118) no.6. 12. Martin F Kause, Thomas Hoehn: Chest physiotherapy in mechanically ventilated children: a review. Critical Care Medicine 2000 Vol.28, No.5. 13. Stiller K, Geake T, Taylor J, et al: Acute lobar atelectasis. A comparison of two chest physiotherapy regimens. Chest 1990; 98:1336-40. 14. Ibanez J, Raurich JM, Abizanda R, et al. The effect of lateral positions on gas exchange in patients with unilateral lung disease during mechanical ventilation. Intensive Care Med 1981;7:231-34. 15. Gillespie DJ, Rehder K. Body position and ventilation-perfusion relationships in unilateral pulmonary disease. Chest 1987; 91:75-79. 16. Chatte G, Sab J-M, Dubois J-M, et al. Prone positioning in mechanically ventilated patients with severe acute respiratory failure. Am J Respir Crit Care Med 1997;155:473-78. 17. Jolliet P, Bulpa P, Chevrolet J-C. Effects of the prone position on gas exchange and hemodynamics in severe acute respiratory distress syndrome. Crit Care Med 1998;26:1977-85. 18. Mure M, Martling C-R, Lindahl SGE. Dramatic effect on oxygenation in patients with severe acute lung insufficiency treated in the prone position. Crit Care Med 1997;25:1539-44. 19. Trottier SJ. Prone position in acute respiratory distress syndrome: Turning over an old idea. Crit Care Med 1998 1935. 20. Suhail Raoof, Naseer Chowdhrey, Sabiha Raoof, Faroque A Khan. Effect of combined kinetic therapy and percussion therapy on the resolution of atlectasis in critically ill patient. Chest 1999;Vol.115, No.6. 21. Suhail Raoof, Sandeep Mehrishi, Udaya B. Prakash. Flexible bronchoscopy update. Clinics in Chest Medicine 2001;Vol.22, No.2. 22. Imle PC, Mars MP, Eppinghaus CE, et al. Effect of chest physiotherapy (CPT) positioning on intracranial (ICP) and cerebral perfusion pressure (CPP) [abstract]. Crit Care Med 1988;16:382. 23. Dean E. Oxygen transport: A physiologically-based conceptual framework for the practice of cardiopulmonary physiotherapy. Physiotherapy 1994; 80:347-55. 24. Dean E, Ross J. Discordance between cardiopulmonary physiology and physical therapy: Toward a rational basis for practice. Chest 1992; 101:1694-98. 25. Horiuchi K, Jordan D, Cohen D, et al: Insights into the increased oxygen demand during chest physiotherapy. Crit Care Med 1997;25:1347-51. 26. Klein P, Kemper M, Weissman C, et al. Attenuation of the hemodynamic responses to chest physical therapy. Chest 1988; 93:38-42. 27. Britton S, Bejstedt M, Vedin L. Chest physiotherapy in primary pneumonia. BMJ 1985;290:1703-04. 28. Chalon J, Loew D, Malebranche J. Effect of dry anesthetic gases on tracheobronchial ciliated epithelium. Anesthesiology 1972; 37:338-43. 29. Forbes AR. Temperature, humidity and mucus flow in the intubated trachea. Br J Anaesth 1974;46:29-34. 30. Marin H. Kollef, Steven D. Shapiro, Ellen Trovillion: A randomized control trial comparing an extended use hygroscopic condenser humidifier with heated water humidification in mechanically ventilated patients. Chest 1998 Vol.113, No.3. 31. Laurent Thomachot, Renaud Vialet, Sophie Arnaud, Claude Martin. Do the components of heat and moisture exchanger filters affect their humidifying efficacy and incidence of nosocomial pneumonia. Critical Care Medicine 1999;Vol.27, No.5. 32. Lee MG, Ford JL, Hunt PB, et al. Bacterial retention properties of heat and moisture exchange filters. Br J Anaesth 1992; 69:522-5. 33. Bethune DW, Shelley MP. Hydrophobic versus hygroscopic heat and moisture exchangers. Anaesthesia 1985;40:2101. 34. Richard JD, Dreyfus D. Efficacy and safety of mechanical ventilation with a heat and moisture exchanger changed only once a week. Am J Respir Crit Care Med 2000;16 (1):104-9. 35. Alexander G. Duarte, James B. Fink: Inhalation therapy during Mechanical Ventilation.Resp Care Cli of North America 2001;Vol.7, No.2. 36. Brain JD, Valberg PA. Deposition of aerosol in the respiratory tract. Am Rev Respir Dis 1979;120:1325. 37. Dhand R, Tobin MJ. Inhaled bronchodilator therapy in mechanically ventilated patients. Am J Respir Crit Care Me 3-10. 38. Hughes JM, Saez J. Effects of nebulizer mode and position in a mechanical ventilator circuit on dose efficiency. Respir Care 1987;32:1131. 39. O’Doherty MJ, Thomas SHL, Page CJ, et al. Delivery of a nebulized aerosol to a lung model during mechanical ventilation: Effect of ventilator settings and nebulizer type, position, and volume of fill. Am Rev Respir Dis 1992;146:383,. 40. Fink JB, Varshney R, Goode M, et al. Does placement of nebulizer before the humidifier improve aerosol delivery during mechanical ventilation. Am J Respir Crit Care Med 1999;159:86.

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PEDIATRIC INTENSIVE CARE 41. Gross NJ, Jenne JW, Hess D. Bronchodilator therapy. In Tobin MJ (Ed): Principles and Practice of Mechanical Ventilation. New York, McGraw Hill 1994;1077. 42. Crogan SJ, Bishop MJ. Delivery efficiency of metered dose aerosols given via endotracheal tubes. Anesthesiology 1989;70:1008. 43. Graham WGB, Bradley DA: Metered dose inhaler aerosol characteristics are affected by the endotracheal tube actuator/ adapter used. Anesthesiology 1990;73:1263: 987. 44. Waugh JB, Jones DF, Aranson R, et al. Bronchodilator response with use of Optivent versus Aerosol Cloud Enhancer metered-dose inhaler spacers in patients receiving mechanical ventilation. Heart Lung 1998;27:418. 45. Diot P, Morra L, Smaldone GC: Albuterol delivery in a model of mechanical ventilation: Comparison of metereddose inhaler and nebulizer efficiency. Am J Respir Crit Care Med 1995;152:1391. 46. Krishnan S, Weaning from mechanical ventilation, In Khilnani P (Ed): Practical approach to pediatric intensive care, Jaypee Medical Publishers (Delhi) 2004;285-92. 47. Tan IK Bhatt SB Tam YH .Use of PEEP for status asthmaticus during mechanical ventilation .Br J Anaesth 1993;71:3223. 48. Wetzel RC, Pressure support ventilation in children with severe asthma.Crit Care Med 1996;24:1603-5. 49. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342:1301-08. 50. Hickling KG, Henderson Sj, Jackson R. Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Medicine 1990;16:372-77. 51. Amato MBP, Barbas CSV, Medeiros DM, et al. Effect of protective ventilation strategy in the acute respiratory distress syndrome. N Engl J Med 1998; 338;347-54. 52. Gattinoni L, Togononi G, Pesenti A, et al. Effects of prone positioning on the survival of patients with acute respiratory failure.N Engl J Med 2001;345:568-73. 53. Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents.Crit Care Med 2003;31(suppl). 54. Goldsmith JP, Karotkin EH.In Assisted Ventilation of the Neonate. WB Saunders Company, Philadelphia 1996:1 55. Kattwinkel J, Nearman HS, Fnaroff AA, Katona PG, Klaus MH.Therapeutic effects of cutaneous stimulation and nasal continuous positive airway pressure. Pediatr 1975;86:588. 56. Do Boer RC, Jones A, Ward PS, Baumer JH. Long-term trigger ventilation in neonatal respiratory distress syndrome. Arch Dis Child 1993;68:308-11. 57. Bernstein G, Mannino FL, Heldtt GP, Gallahan JD, Bull DH, Sola A, et al. Randomized multicenter trial comparing synchronized and conventional intermittent mandatory ventilation in neonates. J Pediatr 1996;128:453-63. 58. Clark RH, Gerstmann DL, Null DM, et al. Prospective randomized comparison of high frequency oscillatory and conventional ventilation in respiratory distress syndrome, Pediatrics 1992; 89:5-12. 59. Bhuta T, Henderson-smart DJ. Rescue high frequency oscillatory ventilation for pulmonary dysfunction in preterm neonates Cocharane Database Sys. Rev 2000;(2)CD000438. 60. Kinsella JP, Neish SR, Shaffer E, et al. Low dose. Inhaled Nitric Oxide in Persistent Pulmonary Hypertension in the Newborn Lancet 1992;340:819.

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8

Respiratory Monitoring in PICU

Respiratory monitoring in Pediatric Intensive Care Unit (PICU) is an essence of critical care. Be it clinical, invasive or noninvasive, monitoring remains crucial in overall assessment of a critically ill child with cardiorespiratory problems. A functioning knowledge of the various tools of monitoring is essential in applying their use to patient care. This chapter discusses traditional methods of evaluation of respiratory system and newly established gold standard techniques as well. Attention is also given to newer modalities, including those that are investigational or currently limited to bench application, that give promise for future application in PICU clinical practice. Pulse oximetry and Capnography are the most commonly employed monitoring modalities, which have transformed the practice of critical care in last 10 years. Arterial blood gases and calculated oxygen indices have been most commonly used and form essential part of monitoring in PICU. However may be the excellent information provided by respiratory monitors it cannot replace careful bedside clinical examination. Essentially respiratory monitoring consists of: 1. Physical examination 2. Non-invasive monitoring 3. Invasive monitoring PHYSICAL EXAMINATION Measuring the respiratory rate (Table 8.1) is easy and has a got good accuracy in prediction of lower respiratory tract infection. Presence of increased work of breathing is suggested by flaring of alae nasi, suprasternal, intercostal and subcostal retractions, use of accessory muscles of respiration and paradoxical breathing. Cyanosis of tongue and oral mucosa indicate oxygen saturation (SaO2) of less than 80%. However, there is significant inter-observer variability and difficulty in SaO2 interpretation. Let’s take a moment to review the Silverman-Anderson Index related to the assessment of the neonates with suspected or diagnosed RDS. When a neonate is a premature, or has underlying

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PEDIATRIC INTENSIVE CARE Table 8.1: Normal respiratory rates

Age

Respiratory rate

Infant (birth–1 year) Toddler (1–3 years) Preschooler (3–6 years) School-age (6–12 years) Adolescent (12–18 years)

30-60 24-40 22-34 18-30 12-16

pathology, then expiratory grunting, retraction of the chest wall muscles and other signs of respiratory distress may be readily seen. The Silverman – Anderson Index, commonly referred to as the Silverman retraction score, was developed as a systematic means of assessing newborn respiratory status, particularly when respiratory distress is suspected. Table 8.2: Silverman-Anderson index

Feature

Score 0

Score 1

Score 2

Chest movement Intercostal retractions Xiphoid retraction Nasal Flaring Expiratory Grunt

Equal None None None None

Respiratory Lag Minimal Minimal Minimal Audible wheeze by stethoscope

See-saw respiration Marked Marked Marked Audible

The parameters assessed by inspection and auscultation of the upper and lower chest and nares on a scale of 0,1or 2. As it is observed in the Table 8.2, the higher the score, the more severe is the respiratory distress. NON-INVASIVE RESPIRATORY MONITORING History Oximetry measures the percentage of hemoglobin saturated with oxygen by passing specific wavelengths of light through the arterial blood. In 1875 a German physiologist named Karl von Vierofdt demonstrated that the oxygen in his hand was consumed when a tourniquet was applied. This was done utilizing transmitted light waves, but the development of the pulse oximeter was still a long way off. In 1936 Karl Matthes developed the first ear saturation meter that used two wavelengths of light. This compensated for the variations in tissue absorption. This idea was improved upon in 1940 when Glen Millikin developed a lightweight oximeter to help the military to solve their aviation hypoxia problem. The modern pulse oximeter was developed in 1972 by Takuo Aoyagi while he was working in Tokyo developing a noninvasive cardiac output measurement, using dye dilution and an ear densitometer. He noticed a correlation in the difference between unabsorbed infrared and red light and the oxygen saturation. This led to the clinical application of the pulse oximeter. It was not until 1980 that Nellcor produced the first commercial pulse oximeter that was reliable, robust, and affordable. In 1988 the use of a pulse oximeter during

RESPIRATORY MONITORING IN PICU

anesthesia and recovery room became mandatory in Australia. Since then, its use has become mandated in many areas from pre-hospital treatment to intensive care units. Pulse oximetry is now an integral part of PICU monitoring which helps in the assessment of the patient’s cardiorespiratory (oxygenation) status. It is a simple, non-invasive and continuous method of monitoring the oxygen saturation of arterial blood (SaO2) and now widely accepted as the fifth vital sign. The pulse oximeter is a convenient, cost-effective way to monitor the patient’s oxygenation status (and thereby O2 content) and determine the changes before they are clinically apparent. It is important to know how oximeters work in order to maximize their performance and avoid errors in the interpretation of results. Pulse oximetry is based on principles of spectrophotometry governed by Beer-Lambert law. The mandatory condition for interpretation of SaO2 is the presence of a pulsatile arteriolar blood flow.

How Pulse Oximeter Works? Interpretation of SaO2 is based on the fact that oxygenated hemoglobin (HbO2) and deoxygenated hemoglobin (Hb) have different absorption spectra. Currently available pulse oximeters use two light-emitting diodes (LEDs) that emit light at the 660 nm (red) and the 940 nm (infrared) wavelengths. These two wavelengths are used because HbO2 and Hb have different absorption spectra at these particular wavelengths. In the red region, HbO2 absorbs less light than Hb, while the reverse occurs in the infrared region. The ratio of absorbencies at these two wavelengths is calibrated empirically against direct measurements of SaO2 in volunteers, and the resulting calibration algorithm is stored in a digital microprocessor within the pulse oximeter. During subsequent use, the calibration curve is used to generate the pulse oximeter’s estimate of arterial saturation (SpO2). In addition to the digital readout of O2 saturation and pulse rate, most pulse oximeters display a plethysmographic waveform which can help clinicians to distinguish an artifactual signal from the true signal. There are two techniques of measuring SaO2: transmission and reflectance. In the transmission method the emitter and photodetector are opposite of each other with the measuring site in-between. The light can then pass through the site. In the reflectance method, the emitter and photodetector, is next to each other on top the measuring site. The light bounces from the emitter to the detector across the site. The transmission method is the most common type of method of choice in use. The normal SpO2 value for adolescents and elders is greater than 95%, and for children, a level greater than 90-92% is normal. SpO2 can be misleading as other factors must be considered when determining whether this SpO2 is normal for the particular patient. Critical discussion on Pulse oximetry (SpO2 = SaO2) SaO 2 gives fairly good idea of not only saturation but also of oxygen content (CaO 2 ) provided Carboxyhemoglobin (COHb) and methemoglobin (MetHb) are expected in normal amounts. Since 98% of CaO2 is contributed by saturated hemoglobin, hence it is a good idea that one should always calculate CaO2, every time, after observing SpO2 since CaO2 is the better indicator of oxygenation. CaO2 = SaO2 (98%) + PaO2 (2%).

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[CaO2 = 1.34×Hb×SaO2 + PaO2×0.003] Interpretation SpO2 should always be done in context of ODC. Since conditions causing Left shift can have normal saturation but patient may be hypoxic (low PaO2). Similarly conditions causing Right shift may have low SaO2 but patient may not be hypoxic. Left shift (Fig. 8.1A)

A

Right shift (Fig. 8.1B)

B Figs 8.1A and B: Oxygen dissociation curve

Limitations of Pulse Oximetry Oximeters have a number of limitations which may lead to inaccurate readings. Shape of oxygen dissociation curve, Carboxyhemoglobin, Methemoglobin Anemia, Dyes, Nail polish, Ambient light, motion artifact, Skin pigmentation and Low perfusion states are other causes as well. Pulse oximeters measure SpO2 that is physiologically related to arterial oxygen tension (PaO2) according to the oxyhemoglobin dissociation curve (ODC). Because the ODC has a sigmoid shape, oximetry is relatively insensitive in detecting the development of hypoxemia in patients with high baseline levels of PaO2 (upper flat portion of ODC curve). Since pulse oximeters use only two wavelengths of light and, thus, it can distinguish only two substances, Hb and HbO2. When COHb and MetHb are also present, four wavelengths are required to determine the ‘fractional SaO2’, i.e. (HbO2 × 100)/ (Hb + HbO2 + COHb + MetHb) and this can be measured by Co-oximetry. In the presence of elevated COHb levels, oximetry consistently over-estimates the true SaO2 6 by the amount of COHb present since it has got same absorption spectrum as of HbO2. Elevated MetHb levels also may cause inaccurate oximetry readings. Anemia does not appear to affect the accuracy of pulse oximetry even in non-hypoxemic patients with acute

RESPIRATORY MONITORING IN PICU

anemia; pulse oximetry was accurate in measuring O2 saturation. Severe hyperbilirubinemia (mean bilirubin, 30.6 mg/dl) does not affect the accuracy of pulse oximetry. Intravenous dyes such as methylene blue, indocyaninegreen, and indigocarmine can cause falsely low SpO2 readings. Nail polish, if blue, green or black, causes inaccurate SpO2 readings, whereas acrylic nails do not interfere with pulse oximetry readings. Falsely low and high SpO2 readings occur with fluorescent and xenon arc surgical lamps. Motion artifact continues to be a significant source of error and false alarms. In a recent, prospective study in an intensive care unit setting, SpO2 signals accounted for almost half of a total of 2525 false alarms. Inaccurate oximetry readings have been observed in pigmented patients, but not by all investigators. Low perfusion states, such as low cardiac output, vasoconstriction and hypothermia may impair peripheral perfusion and may make it difficult for a sensor to distinguish a true signal from background layers. An under-recognized and worrisome problem with pulse oximetry is that many users have a limited understanding of how it functions and the implications of its measurements. In a recent survey, 30% of physicians and 93% of nurses thought that the oximeter measured PaO2. Some clinicians also have a limited knowledge of the ODC, and they do not recognize that SpO2 values in the high 80s represent seriously low values of PaO2. In the above survey, some doctors and nurses were not especially worried about patients with SpO2 values as low as 80% (equivalent to PaO2 = 45 mm of Hg). Conventional pulse oximetry has problems during ambient light, abnormal hemoglobin, pulse rate and rhythm, vasoconstriction and cardiac function, physical motion and low perfusion and that has great impact on when making critical decisions. Arterial blood gas tests have been used to supplement or validate pulse oximeter readings. The advent of “Next Generation” pulse oximetry technology has demonstrated significant improvement in the ability to read through motion and low perfusion; thus making pulse oximetry more dependable to take decisions during critical period. It is important to remember that pulse oximeters assess oxygen saturation only and thereby Oxygenation status and gives no indication of the level of CO2 and thereby Ventilation status. For this reason they have a limited benefit in patients developing respiratory failure due to CO2 retention. The pulse oximeter may be used in a variety of situations that require monitoring of oxygen status and may be used either continuously or intermittently. It is not a substitute for an ABG, but can give clinicians an early warning of decreasing arterial oxyhemoglobin saturation prior to the patient exhibiting clinical signs of hypoxia. The pulse oximeter is a useful tool but the patient must be treated—not the numbers. As with all monitoring equipment, the reading should be interpreted in association with the patient’s clinical condition. If a patient is short of breath and bluish with a saturation reading of 100%, check for possible causes due to artifact. Never withhold therapeutic oxygen from a patient in distress while waiting to get a reading. If the patient appears to be in perfect health and the saturation is reading 70%, this should alert you to the possibility of interference. Never ignore a reading which suggests the patient is becoming hypoxic. The main disadvantage of pulse oximeter is its inability to use in cases of hyperoxia at saturations between 90-100%.

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Capnography End-tidal CO2 (EtCO2) monitoring is an exciting non-invasive technology that is more commonly used in the emergency department, intensive care units and in the pre-hospital settings. Its main use has been in verifying endotracheal tube position, during mechanical ventilation and cardiopulmonary resuscitation, but it is being studied and used for other purposes as well. The American Heart Association new guidelines states the secondary confirmation of proper endotracheal tube placement in all patients by exhaled CO2 immediately after intubation and during transport is essential. EtCO2 monitoring is an exciting new technology that measures CO2 in the exhaled breath continuously and noninvasively. CO2 is produced during cellular metabolism, transported to the heart and exhaled via the lung and so EtCO2 reflects ventilation, metabolism and circulation. If any two systems are kept constant then changes in the third system reflect changes in EtCO2. This was first studied clinically by Smallhout and Kalenda in the 1970’s, and in the late 1980’s – 1990’s this methodology has been studied extensively in various clinical settings. The most common use of EtCO2 is to verify endotracheal tube (ETT) position. It is being increasingly studied and used during cardiopulmonary resuscitation (CPR) and other clinical settings. What is Capnography? It is a graphical representation of noninvasive, continuous measurement of exhaled carbon dioxide (EtCO2) concentration over time accompanied by digital display that provides EtCO2 value and distinct waveform (tracing) for each respiratory cycle. Some definitions: Capnometry • Capnometer : Provides only a numerical measurement of carbon dioxide • Capnogram : Is a waveform display of carbon dioxide over time (Fig. 8.2) • Capnography: A numerical value of the EtCO2 and A waveform of the concentration of CO2 present in the airway. And Respiratory rate detected from the actual airflow

Fig. 8.2: Normal capnogram

RESPIRATORY MONITORING IN PICU

The Capnogram is divided into four distinct phases (Fig. 8.2): 1. Phase I (A-B) is the beginning of exhalation. It represents most of the anatomical dead space. CO2 is almost zero. 2. Phase II (B-C) is where the alveolar gas begins to mix with the dead space gas and the CO2 begins to rapidly rise. 3. Phase III (C-D) represents the alveolar gas, usually has a slight increase in the slope as “slow” alveoli empty. The “slow” alveoli have a lower V/Q ratio and therefore have higher CO2 concentrations. In addition, diffusion of CO2 into the alveoli is greater during expiration. This is more pronounced in infants. EtCO2 is measured at the maximal point of Phase III…… (D) 4. Phase IV (D-E) is the inspirational phase Note that the presence of the alveolar plateau confirms that the measurement is end-tidal. Without a Capnography you cannot be sure that a measured CO2 value is really end-tidal. A normal value for ETCO2 is approximately 38-40 mm Hg. Types of CO2 Monitors2 There are two types of CO2 monitors: 1. Mainstream and 2. Sidestream. Mainstream……salient features are…… • The infrared sensor is located in the airway adapter, between the ET tube and the breathing circuit tubing. • Response time is faster and may be as little as 40 msec • Water cannot be drawn-in to disrupt sensor function, and since no mixing of gases in the sample tube it is nearly a very accurate one. • Difficult to calibrate without disconnecting (makes it hard to detect rebreathing) • More prone to the reading being affected by moisture. • Sensor device is larger in size hence can kink the tube. • Adds dead space to the airway. • Bigger chance of being damaged by mishandling. Sidestream…… salient features are….. • Can be used with in intubated or non-intubated patients thus have wider applications. • The airway adapter is positioned at the airway (whether or not the patient is intubated) to allow aspiration of gas from the patient’s airway back to the sensor, which lies either within or close to the monitor, thus gas is sampled through a small tube • Analysis is performed in a separate chamber • Very reliable • Time delay of 1-60 seconds • Less accurate at higher respiratory rates • Prone to plugging by water and secretions • Ambient air leaks are common.

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PEDIATRIC INTENSIVE CARE Table 8.3: Differential diagnosis of abnormal capnogram

Symptom

Possible cause

Sudden drop of EtCO2 to zero

Esophageal intubation Ventilator disconnection or malfunction Defect in CO2 analyzer Dislodged OR obstructed endotracheal tube

Sudden fall of EtCO2 (not to 0)

Leak in ventilator system, obstruction Partial disconnect in ventilator circuit Partial airway obstruction (secretions)

Exponential fall of EtCO2

Cardiac arrest Hypotension (sudden) Severe hyperventilation Cardiopulmonary bypass Pulmonary embolism

Change in CO2 Baseline

CO2 absorber saturation (anesthesia) Calibration error Water droplet in analyzer Mechanical failure (ventilator)

Sudden increase of EtCO2

Accessing an area of lung previously obstructed Release of tourniquet Sudden increase in blood pressure

Gradual lowering of EtCO2

Hypovolemia Decreasing Cardiac Output Decreasing body temperature, hypothermia, drop in metabolism

Gradual increase in EtCO2

Rising body temperature Hypoventilation CO2 absorption Partial airway obstruction (foreign body), reactive airway disease

Constantly high EtCO2

Respiratory depression due to drugs Metabolic alkalosis (respiratory compensation) Insufficient minute ventilation

RESPIRATORY MONITORING IN PICU

CLINICAL APPLICATIONS OF CO2 MONITORING The EtCO2 level read on the display of the monitor depends upon the proper functioning of the following: • Lungs and airways • Patient ventilation system • Respiratory mechanism • Patient’s metabolism and circulation Malfunctions of the lungs and airway OR the patient’s ventilation system can be depicted as follows: • Upper airway obstruction — reflected by an increased EtCO2 • Apnea — reflected by a sudden cessation of EtCO2 readings • Improper ventilator operation — reflected by either high or low EtCO2 readings • Hyperventilation — reflected by a decreased EtCO2 • Hypoventilation — reflected by an increase in EtCO2 • A faulty one-way valve — reflected by an increased inspired CO2 and increased EtCO2 • Esophageal intubation — reflected by no EtCO2 reading • Respiratory depression (from anesthesia) — reflected by a decreased EtCO2 • Increased level of muscle relaxation — reflected by a decreased EtCO2 • Reversal of muscle relaxant and resulting improvement in muscle tone – reflected by an increased EtCO2 • Malignant hyperthermia — reflected by an increased EtCO2. PaCO2-EtCO2 Gradient • • • • • •

It is usually < 6 mm Hg EtCO2 is usually less Difference depends on the number of underperfused alveoli Tend to mirror each other if the slope of Phase III is horizontal or has a minimal slope Decreased cardiac output will increase the gradient The gradient can be negative when healthy lungs are ventilated with high tidal volume and low rate • Decreased functional residual capacity also gives a negative gradient by increasing the number of slow alveoli. Limitations 1. Critically ill patients often have rapidly changing dead space and V/Q mismatch 2. Higher rates and smaller tidal volumes can increase the amount of dead space ventilation 3. High mean airway pressures and PEEP restrict alveolar perfusion, leading to falsely decreased readings 4. Low cardiac output will decrease the reading.

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Indications for Capnography are: 1. 2. 3. 4. 5. 6. 7. 8.

Confirm and verify tracheal intubation placement. Evaluate ventilator settings and circuit integrity. Assess cardiopulmonary status and changes in pulmonary blood flow. Assess airway management and changes in airway resistance. Monitor effectiveness of CPR. Monitor ventilatory status of the respiratory impaired patient. Monitor ventilation of a nonintubated patient during sedation/analgesia. Monitor the effectiveness of ventilator weaning process, and response to changes in ventilator settings (i.e., respiratory rate, flow and/or volume). 9. Reduce the number and/or frequency of arterial blood gas drawings. 10. Aids in the treatment of neurological patients and the possibility of increasing intracranial pressures. Other uses……. • Metabolic – Assess energy expenditure • Cardiovascular – Monitor trend in cardiac output – Can use as an indirect Fick method, but actual numbers are hard to quantify – Measure of effectiveness in CPR – Diagnosis of pulmonary embolism by measuring measure gradient. Microstream Technology It is 3rd generation technology which can be used with intubated or non-intubated patients and requires low sample flow rate - 50 ml/min. It allows its use in neonate and pediatric patients. In this technology sampling lines not flooded with moisture. Microstream improves upon conventional Sidestream sampling based upon the principle that CO2 molecules absorb IR radiation at specific wavelengths.

Advantages 1. 2. 3. 4. 5. 6.

No sensor at airway. Intubated and non-intubated patients (neonatal through adult). No routine calibration. Automatic zeroing. Accurate at small tidal volumes and high respiratory rates. Superior moisture handling.

PULMONARY FUNCTION TESTS Few of the numerous pulmonary function tests currently available have an impact upon clinical management of the critically ill child, particularly if the patient has to be moved to a laboratory. A number of other tests require highly specialized equipment and fulfill a predominant research role.

RESPIRATORY MONITORING IN PICU

Clinical Relevant Tests Measurement

Tests

Common clinical use

PaO2,SaO2,PaCO2

Arterial blood gases

Oxygenation, Ventilation status

SpO2

Pulse oximetry

Oxygen saturation, content status

End-tidal PCO2

Capnography

Ventilation status

Vital capacity, tidal volume

Spirometry, electronic flowmetry.

Serial measurement of borderline function (VC < 10-15ml/kg) e.g. Guillain-Barré syndrome

Peak expiratory flow rate

Wright peak flow meter,

(Spontaneous ventilation) asthma

FEV1, FVC

Spirometry, electronic flowmetry.

(Spontaneous ventilation) asthma, obstructive / restrictive disease.

Lung/chest wall compliance

Pressure- volume curve

Ventilator adjustments, monitoring disease progression.

Flow volume loop, pressure volume loop

Pneumotachograph * manometry

Ventilator adjustment

*(Pneumotachograph: an apparatus for recording the rate of airflow to and from lungs)

Research Tests…(examples) Measurement

Tests

Research use

Diaphragmatic strength (transdiaphragmatic pressure)

Gastric and esophageal manometry

Respiratory muscle functions, weaning.

Pleural (intrathoracic) pressure Esophageal manometry

Ventilator trauma, work of breathing, weaning

Functional residual capacity

Closed circuit helium dilution (bag-in-box) open circuit N2 washout.

Lung volumes, compliance

Ventilation-perfusion relationship

Multiple inert gas elimination technique, isotope technique

Regional lung ventilation-perfusion, pulmonary gas exchange.

Pulmonary diffusing capacity

Carbon monoxide uptake

Pulmonary gas exchange.

Notes… • Compliance equals the change in pressure during a linear increase in volume above FRC. • The Bohr equation calculates physiological deadspace (VD); normally it is less than 30%. • The shunt equations estimates the proportion of blood shunted past poorly ventilated alveoli (Qs) compared to total lung blood flow (QT). These useful equations are supplement to assess pulmonary function, and ventilation/perfusion mismatch… • V/Q = 1, Ventilation and perfusion are well matched. • V/Q>1, increased deadspace (where alveoli are poorly perfused but well ventilated) • V/Q7.4 …Alkalosis, pH < 7.4 …………. Acidosis, pH = 7.4 …………. Normal or mixed disorder (Only Chronic Respiratory alkalosis can have normal value of pH) STEP 3: Who is responsible for this change in pH? Who is the CULPRIT? HCO3…… METABOLIC PCO2 …… Respiratory > 26 ….. Met. Alkalosis > 45 …… Resp. Acidosis < 22 ……Met. Acidosis < 35 …… Resp. Alkalosis It is essential to determine whether the disturbance affects primarily the arterial PaCO2 or the serum HCO3. • Respiratory disturbances alter the arterial PaCO2 (normal value 35-45) • Metabolic disturbances alter the serum HCO3 (normal value 22-26) If the pH is low (i.e., the primary and controlling disturbance is acidosis causing acidemia) either the PaCO2 is high or the HCO3 is low. (These are the only ways in which the pH can be low). A high PaCO2 defines a primary respiratory acidosis and a low HCO3 defines a primary metabolic acidosis. Conversely, if the pH is high (i.e., the primary and controlling disturbance is alkalosis causing alkalemia) either the PaCO2 is low or the HCO3 is high. (These are the only ways in which the pH can be high). A low PaCO2 defines a primary respiratory alkalosis and a high HCO3 defines a primary metabolic alkalosis. STEP 4 : If it is a primary respiratory disturbance, Is it acute? And/OR Chronic. For 10 mm change in pCO2 pH….changes….as Acidosis (↑CO2)..…pH ↓ … acute……by 0.08, chronic…by 0.03 Alkalosis (↓CO2).… pH ↑… acute…… by 0.08, chronic…by 0.03 HCO3…. Compensates as…. Acidosis (↑CO2)..…HCO3 ↓…….. Acute……by 1, Chronic…by 3 Alkalosis (↓CO2) … HCO3 ↑……Acute……by 2, Chronic…by 5 For example, In an acute respiratory acidosis, if the PCO2 rises from 40 to 50, you would expect the pH to decline from 7.40 to 7.32. In an acute respiratory alkalosis, if the PCO2 falls from 40 to 30, you would expect the pH to rise from 7.40 to 7.48. In chronic respiratory disturbances, there are renal mediated shifts of bicarbonate that alter and partially compensate for the pH shift for a change in the PaCO2. In a chronic respiratory acidosis, if the PCO2 rises from 40 to 50, you would expect the pH to decline from 7.40 to 7.37. In a chronic respiratory alkalosis, if the PCO2 falls from 40 to 30, you would expect the pH to rise from 7.40 to 7.43.

RESPIRATORY MONITORING IN PICU

Remember: to suspect if • Compensated HCO3 is > expected : additional metabolic alkalosis is there • Compensated HCO3 is < expected : additional metabolic acidosis is there STEP 5: If it is a primary metabolic disturbance, whether respiratory compensation appropriate? For metabolic acidosis: Expected PCO 2 = (1.5 x [HCO 3 ]) + 8 + 2 …….. Winter’s formula OR Expected CO2 is equal to Last two digits of pH (important and easy to remember). For metabolic alkalosis: Expected PCO2 = 6 mm for 10 mEq. rise in Bicarb. ………UNCERTAIN COMPENSATION Remember : to suspect if • Compensated PCO2 is > expected : additional respiratory acidosis is there . • Compensated PCO2 is < expected : additional respiratory alkalosis is there. Processes that lead to a metabolic acidosis can be divided into 1. Increased anion gap and 2) Normal anion gap. The anion gap is the difference between the measured serum cations (positive) and the measured serum anions (negative). (Of course, there is no real gap; in the body the numbers of positive and negative charges are balanced. The gap refers to the difference in positive and negative charges among cations and anions which are commonly measured.) The commonly measured cation is sodium. (Some people also use potassium to calculate the gap; that results in a different range of normal values). The measured anions include chloride and bicarbonate. Thus the anion gap can be summarized as: AG = [Na+] - ([Cl–] + [HCO3–]). The normal anion gap is 12. An anion gap of > than 12 is increased. Anion gap > 25 has got distinct value having significant ACIDOSIS. This is important, because it helps to significantly limit the differential diagnosis of a metabolic acidosis. The most common etiologies of a metabolic acidosis with an increased anion gap include: Commonest pediatric causes are Lactic acidosis, diabetic ketoacidosis and renal failure. Aspirin, Ketones (starvation, alcoholic and diabetic ketoacidosis) Uremia (renal failure), Lactic acidosis, Ethanol, Paraldehyde and other drugs Methanol other alcohols, and ethylene glycol intoxication Key point: The true anion gap is underestimated in hypoalbuminemia (fall in unmeasured anions); AG must be adjusted. Remember to adjust AG: For every 1.0 fall in albumin, increase the AG by 2.5 STEP 6 : Is more than one DISORDER present? — Proper Clinical history — pH normal, and PCO2 and HCO3 out of range — PCO2 and HCO3 moving in opposite directions — Degree of compensation for primary disorder is inappropriate.

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KEY MASSAGES Pulse oximetry and Capnography are the essential monitors in PICU which need clinical correlation. Arterial blood gas analysis is also an integral part of respiratory monitoring in PICU as well. SUMMARY Respiratory monitoring helps in the early diagnosis of change in a physiological parameter of oxygenation and ventilation, and provides guidelines towards institution of appropriate therapy. Basic knowledge of the principles of monitoring tools and correct interpretation of data is important since failure to do so can result in misdirected therapy. No amount of monitoring, though excellent information provided by monitors, however, can replace careful bedside clinical signs. BIBLIOGRAPHY 1. Amar D, Neidzwski J, Wald A, Finck AD. Fluorescent light interferes with pulse oximetry. J Clin Monit 1989;5: 135-6. 2. Barker SJ, Tremper KK, Hyatt J. Effects of methemoglobinemia on pulse oximetry and mixed-venous oximetry. Anesthesiology 1989;70:112-7. 3. Barker SJ, Tremper KK. The effect of carbon monoxide inhalation on pulse oximeter signal detection. Anesthesiology 1987;67:599-603. 4. Benjamin Abelow. In : Understanding acid-base 1998. 5. Bhende MS. Capnography in the paediatric emergency department. Peds Emerg Care 1999;15:64-9. 6. Chelluri L, Snyder JV, Bird JR. Accuracy of pulse oximetry in patients with hyperbilirubinemia. Respir Care 1991; 36:1383-6. 7. Comroe JH, Bothello S. The unreliability of cyanosis in the recognition of arterial anoxemia. Am J Med Sci 1947; 214:1-9. 8. Cote CJ, Goldstein EA, Fuchsman WH, Hoaglin DC. The effect of nail polish on pulse oximetry. Anesth Analg 1989; 67:683-6. 9. David B. Swedlow, Noninvasive respiratory monitoring. In: Jerry J. Zimmerman. Pediatric critical care, 1992; 99-109. 10. Edelist G. Acrylic nails and pulse oximetry. Anesth Analg 1995;81:882-91. 11. Gravenstein JS, Paulus DA, Hayes TJ. Clinical indications. In: Gravenstein JS, Paulus DA, Hayes TJ, editors. Capnography in clinical practice. Stoneham MA; Butterworth: 1989;43-9. 12. Ibanez J, Velasco J, Raurich JM. The accuracy of the Biox 3700 pulse oximeter in patients receiving vasoactive therapy. Intensive Care Med 1991;17:484-6. 13. Jay GD, Hughes L, Renzi FP. Pulse oximetry is accurate in acute anemia from hemorrhage. Ann Emerg Med 1994; 24:32-5. 14. Jubran A. Pulse oximetry. In: Tobin MJ (ed). Principles and Practice of Intensive Care Monitoring. New York: McGraw Hill, Inc.; 1998,261-87. 15. Lawrence Martin. In : All you really need to know to interpret arterial Blood gases 1992 16. Mervyn Singer, Andrew R. Webb. In : Oxford Hand Book of Critical Care 2005, 94-97 17. Runciman WB, Webb RK, Barker L, Curriie M. The pulse oximeter: applications and limitations: an analysis of 2000 incident reports. Anaesth Intens Care 1993;21:543-50. 18. Scheller MS, Unger RJ, Kelner MJ. Effects of intravenously administered dyes on pulse oximetry readings. Anesthesiology 1986;65:550-2. 19. Stoneham MD, Saville GM, Wilson IH. Knowledge about pulse oximetry among medical and nursing staff. Lancet 1994;344:1339-42. 20. Tsien CL, Fackler JC. Poor prognosis for existing monitors in the intensive care unit. Crit Care Med 1997;25: 614-9. 21. Tsien CL, Fackler JC. Poor prognosis for existing monitors in the intensive care unit. Crit Care Med 1997;25: 614-9. 22. Ward KR, Yealy D. End-tidal CO2 monitoring in emergency medicine. Part I: Basic principles. Acad Emerg Med 1998;5:628-36. 23. William R. Hayden. Respiratory monitoring. In Rogers Text book of Pediatric intensive care 1992;205-13.

Gurinder Pal Singh, Krishan Chugh 107 ACUTE SEVERE ASTHMA

Acute Severe Asthma

9 An acute attack of asthma is characterized clinically by progressively worsening of wheezing, shortness of breath, chest tightness or combination of the above symptoms. These events are characterized by reversible lower airway obstruction with air trapping due to inflammation, mucosal edema and bronchospasm, which are mediated by inflammatory mediators such as leukotriens, eicosanoids and platelet aggregating factors. Appropriate emergency room management of an acute attack includes assessment of the severity and appropriate interventions being carried out simultaneously, assessing response to the therapy and taking suitable actions in the face of unresponsiveness, so that the acute event does not result in loss of life. Evaluation of the severity of an acute episode of asthma (BTS guidelines for management of acute attack of asthma in children)1 Assessment of acute asthma in children aged over 2 years. Acute Severe: 1. Cannot complete sentences in one breath or too breathless to talk or feed. 2. Pulse > 120 (> 5 years) or > 130 (2-5 years). 3. Respirations > 30 breaths/min (> 5 years) or > 50 (2-5 years). Life-threatening: (Will require more aggressive options like ventilatory support) 1. Hypotension 5. Silent chest 2. Exhaustion 6. Cyanosis 3. Confusion 7. Poor respiratory effort 4. Coma Criteria for Admission 1. Transfer children with severe or life-threatening asthma urgently to hospital to receive frequent doses of nebulized β2 agonists (2.5-5 mg salbutamol or 5-10 mg terbutaline).

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2. Children with acute asthma in primary care who have not improved after receiving up to 10 puffs of β2 agonist should be referred to hospital. Further doses of bronchodilator should be given as necessary whilst awaiting transfer. 3. Treat children transported to hospital by ambulance with oxygen and nebulized β2 agonists/ MDI ± spacer, ± mask, during the journey. 4. Consider intensive inpatient treatment for children with SpO2 of < 92 % on air after initial bronchodilator therapy. The following signs should be periodically recorded: 1. Pulse rate: Increasing tachycardia generally denotes worsening asthma; bradycardia occurs in life-threatening in asthma as a pre-terminal event. 2. Respiratory rate and degree of breathlessness, i.e. too breathless to complete sentences in one breath or to feed 3. Use of accessory muscle of respiration–Best noted by palpation of neck muscles 4. Degree of agitation and conscious level. 5. NB: Clinical signs may correlate poorly with the severity of airways obstruction. Some children with acute asthma do not appear distressed. Home Management, i.e. Prior to Arrival in the Emergency Department2 All asthmatics should have a written action plan that can help guide them in recognizing and assessing their overall asthma control and the severity of acute asthma exacerbations. Recognizing symptoms early and intensifying treatment soon after symptoms worsen can often prevent further worsening and can keep exacerbations from becoming severe. The National Asthma Education and Prevention Program (NAEPP) guidelines recommend immediate treatment with rescue medication, i.e. inhaled short acting β agonist up to 3 treatments in 1 hour. A good response would be characterized by resolution of symptoms within an hour, no further symptoms over the next 4 hours, and improvement in PEF of 80% of the predicted or personal best. If the child has an incomplete response to initial treatment with rescue medication (i.e. persistent symptoms and/or a PEFR of 60-80 %of predicted or personal best), a short course of oral steroid therapy (Prednisolone 1-2 mg/kg/24 hr for 4 days), in addition to inhaled β agonist therapy should be instituted. If the child still does not respond, an early arrival at the emergency department would prevent the attack progressing to severe stage. Management Upon Arrival in the Emergency Department The key to managing acute episodes is to stabilize the patient as rapidly and as effectively as possible, ensure adequate oxygenation (children with life-threatening asthma or SpO2 of < 92% should receive high flow oxygen via a tight fitting face mask or nasal cannula at sufficient flow rates to achieve normal saturations), and reverse bronchial narrowing with a minimum of side effects. Freedom from wheezing and normal pulmonary mechanics take a long time to achieve and need not be the primary goal of acute therapy.3

ACUTE SEVERE ASTHMA

FIRST LINE THERAPY IN THE EMERGENCY DEPARTMENT Oxygen Profound hypoxemia is rare in uncomplicated acute asthma and few patients have oxygen saturations less than 90%. A child of acute asthma with SpO2 of < 92 % in the emergency department should be started on supplemental oxygen. Inhalation Therapy with β Agonists Moderately short-acting β2-adrenergic agonists such as salbutamol and terbutaline have rapid onset of action and provide three to four times more bronchodilatation than do methylxanthines and anticholinergics, making them the first-line treatment for acute illness.5 Long-acting agents such as salmeterol are not recommended in the acute setting. Dose–Response effects are found with the amounts commonly administered clinically (0.15 ug/ kg/dose). The degree of improvement is a function of how much medication is given, not of how it is delivered. There does not seem to be any advantage in giving larger quantities once pulmonary mechanics approach the lower limit of normal.4 Another β2 agonist Levoalbuterol has also been recently evaluated in few small studies. It appears to be an equally efficacious alternative. Continuous or Intermittent Nebulization Various studies have suggested that continuous nebulization therapy is safe, is at least as effective as intermittent nebulization, and may be superior to intermittent nebulization in patients with the most severely impaired pulmonary function.5 MDI V/S Nebulizers British Thoracic Society guidelines1 for management of acute asthma in children state that, a pMDI and spacer are the preferred option in mild to moderate asthma. It has been observed6 that use of MDI with spacer provided greater improvement in peak flow rates than use of nebulizers, had lower salbutamol dose, showed greater improvement in arterial blood gases, and also patients in the MDI group spent less time in the emergency department with less relapse rates at 14 and 21 days. Treatment for Incomplete Response

Key Points • Individualize drug dosing according to severity and the patient’s response. • The early addition of bolus dose of IV salbutamol (15 ug/kg) can be effective adjunct to treatment in severe cases. • Systemic (intravenous [IV], oral [PO]) corticosteroids should be used for all patients who do not favorably respond to the initial beta-agonist therapy. • Addition of anticholinergic may increase lung function and may decrease hospital admission rate.

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Corticosteroids Recommendations for use of steroids in case of acute asthma not responding to the initial inhalation therapy as per the British Thoracic Guidelines for acute asthma in children:1 Give Prednisolone early in the treatment of acute asthma attacks. Use a dose of 20 mg prednisolone for children aged 2-5 years and a dose of 30-40 mg for children > 5 years. Those already receiving maintenance steroid tablets should receive 2-mg/kg prednisolone up to a maximum of 60 mg. Repeat the dose of prednisolone in children who vomit and consider IV steroids Treatment up to three days is usually sufficient, but tailor length of course to the number of days necessary to bring about recovery.

Anticholinergics BTS guidelines for use of anticholinergics in childhood asthma1 If symptoms are refractory to initial β2 agonist treatment, add nebulized ipratropium bromide (250 ug/dose mixed with β2 agonist solution). Repeated doses of ipratropium bromide should be given early to treat children poorly responsive to β2 agonists. Ipratropium bromide or other anticholinergics may be used as an additional bronchodilator in conjunction with a beta2-agonist in cases of acute moderate to severe asthma. It’s most beneficial effects appear to be in multiple doses in more severe exacerbations. Literature has been inconsistent, but indicates that anticholinergic therapy may increase FEV1 or PEF, may decrease hospital admission rates slightly, may decrease the amount of beta-agonist needed, and may prolong bronchodilator effect. In view of this, it is recommended to consider anticholinergic use in moderate to severe asthma exacerbations.

High Dose IV Salbutamol in Bolus Form7 Statement from NHLBI: Although inhaled beta2 agonists and corticosteroids have been the cornerstones of acute asthma management, there remains a need to develop new strategies to treat these patients more effectively. This well-designed and executed study in a small group of children with acute, severe asthma is the first to show that an intravenous bolus of salbutamol (15 ug/kg), given early in conjunction with conventional therapy (oxygen, inhaled beta2 agonists, and intravenously administered corticosteroids) results in more rapid recovery, as measured by clinical assessment scores and the need for inhaled beta2 agonists and oxygen. The only side effect was tremor. Intravenously administered beta agonists have been traditionally reserved for the patients with the most severe exacerbations and given by continuous infusion in an intensive care unit setting. Similarly single dose of 15 ug /kg of IV salbutamol administered over 10 minutes in the initial treatment of children with acute severe asthma in the emergency department has been shown to shorten the duration of severe attacks and reduce overall requirements for inhaled salbutamol maintenance.8 Intravenous Terbutaline in Acute Severe Asthma Terbutaline is recommended as a useful adjunct in asthma in those patients who fail to respond to standard initial therapy.9 Terbutaline has been found to be effective and safe at doses of 1-5 ug/kg/min, especially in children who failed to respond to the initial standard therapy. Side effects

ACUTE SEVERE ASTHMA

of the drug reported include increase in heart rate and significant fall in diastolic blood pressure, and hypokalemia. Cardiac arrhythmias may occur very rarely.

Use of Ketamine in Acute Asthma10 One of off-label uses of ketamine includes adjunctive use in the management of refractory status asthmaticus. Ketamine promotes relaxation of smooth muscle fibers despite blockade of NO synthase by N-omega-nitro-L-arginine methyl ester (L-NAME), a potent NO synthase inhibitor and blockade of prostanoid production by the potent cyclo-oxygenase inhibitor, indomethacin. Probably ketamine relaxes airway smooth muscle via an epithelial-independent mechanism. Since the initial case reports appeared in the 1970’s, several additional case reports and investigations have demonstrated improved gas exchange, compliance, and overall lung function after infusion of ketamine in patients with status asthmaticus refractory to standard therapy.

BTS Guidelines for use of Aminophyllines in Patients with Acute Asthma1 Aminophylline is not recommended in children with mild to moderate acute asthma. Consider Aminophylline in an HDU or PICU with severe or life-threatening bronchospasm unresponsive to maximal doses of other bronchodilators and systemic steroids.

Heliox11 Heliox, a blend of helium and oxygen (70:30 Helium oxygen mixture), reduces airway resistance and may be a therapeutic option for severe refractory asthma in intubated patients, there is a decrease in peak inspiratory pressure and PaCO2. In nonintubated individuals, some studies have shown reduction in dyspnea, improved gas exchange, increased PEFR, and a diminution in pulsus paradoxus whereas others have not found any benefits. Patient stratification may be an issue. The effects of heliox are transitory and disappear when air is once again inhaled. Its temporary use, however, may lower respiratory resistive work long enough to forestall muscle fatigue and/or improve ineffective mechanical ventilation until bronchodilators and steroids can take effect. The mixture may improve the distribution of inhaled agents and lead to a faster rate of resolution of obstruction.

Magnesium Sulphate12 Magnesium is an important cofactor in many enzymatic reactions and hypo- and hypermagnesemia can cause contraction and relaxation of smooth muscles, respectively. Only three citations appeared in all of the meta- analyses and four trials appeared in three of them. Various meta-analysis done concluded that there was insufficient evidence to support the routine use of magnesium in acute asthma.

Antileukotriene Agents There are limited data on the effects of antileukotriene drugs in acute asthma. One abstract compared placebo with zafirlukast and found a small but significant difference in favor of the active agent. At present, these studies can be thought of only as preliminary and more data are required.

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Ventilation in Asthma13 Ventilatory assistance can be lifesaving. Both noninvasive and invasive techniques are available. Noninvasive facemask ventilation may offer short-term support for some subjects with hypercapnic respiratory failure who can cooperate with their care and are able to protect their airways. Its applicability, however, is limited by its poor patient acceptance. The generally accepted indications are progressive CO2 retention, obtundation, and impending cardiopulmonary collapse. The mere presence of hypercapnia is not sufficient. The goal of ventilatory support is to maintain adequate gas exchange until bronchodilators and corticosteroids relieve the airflow obstruction. This usually entails sedation, and possibly paralysis, as well as strategies to minimize dynamic hyperinflation. Ketamine may be necessary to supplement sedation with neuromuscular blockade with pancuronium, vecuronium, atracurium, or cisatracurium. All of the paralytics can be associated with myopathy, which is worsened by concomitant use of corticosteroids and aminoglycoside antibiotics. Major concern in ventilating children with acute asthma is dynamic hyperinflation (auto-PEEP), which can have profound physiological effects. It rises directly with minute ventilation and can compromise cardiac output by reducing venous return. The institution of positive-pressure ventilation in an already hyperinflated thorax can markedly worsen hemodynamics and cause abrupt falls in blood pressure including cardiac collapse. Because the airways are heterogeneously narrowed, the less involved parts of the lungs may undergo regional overextension when exposed to high inflation pressures and rupture. For these reasons, ventilatory strategies that provide the longest possible expiratory time are desired so that dynamic lung inflation is minimized. This goal is accomplished by combining the smallest tidal volume with the slowest inspiratory rate and fastest inspiratory time to keep a static end-expiratory pressure (plateau pressure) of less than 30 cm H2O. Approaches designed to reduce auto-PEEP often result in hypoventilation. The resulting hypercapnia is well tolerated as long as it develops slowly and the PaCO2 remains at 90 mm Hg or less. When necessary, the pH can be defended pharmacologically. Once the bronchospasm is relieved, the patient can be weaned off rapidly.

Supportive Treatment Overall care of the child should also be given due consideration, with maintenance of good hydration status, control of temperature and strict maintenance of the fluid and electrolytes balance. Routine use of antibiotics is asthma is not indicated. Prognosis Despite concerns about increasing mortality, most patients survive acute episodes. SUMMARY To summarize, appropriate interventions taken at the appropriate time will abort an acute attack of asthma, resulting in lesser morbidity and mortality. Short acting bronchodilators along with inhaled anticholinergics and systemic steroids constitute the mainstay of therapy. Other options include use of intravenous salbutamol, terbutaline infusion, ketamine, heliox and magnesium

ACUTE SEVERE ASTHMA

sulphate. Need for ventilatory support should be on an elective basis rather than letting the acute event reach life-threatening proportions. Measures should be taken during mechanical ventilation to avoid barotrauma and hemodynamic compromise. Prognosis in most cases is patient surviving the acute episode. KEY MESSAGES 1. Asthma is characterized by reversible lower airway obstruction with air trapping due to inflammation, mucosal edema and bronchospasm. 2. An acute attack of asthma is characterized clinically by progressively worsening of wheezing, shortness of breath, chest tightness. 3. Emergency management includes simultaneous assessment and institution of therapy, assessing response and taking appropriate action in the face of deterioration. 4. Normalization of the pulmonary mechanics should not be the aim. 5. Short acting bronchodilators along with inhaled anticholinergics and systemic steroids are the mainstay of therapy. 6. High dose IV salbutamol, terbutaline infusion, ketamine, heliox and magnesium sulphate are other available options. 7. Ventilatory support should be considered on an elective basis rather that letting the acute event become a life-threatening episode. 8. Prognosis in most cases is very good with recovery from the acute episode. REFERENCES 1. British Guideline on the management of Asthma, Thorax 2003;58(Suppl 1):1-94. 2. Andrew H Liu, Joseph D, Spahn Donald, YM Leung. Childhood Asthma. In: Behrman RE, Kleigman RM, Jenson HB, (Eds). Nelson Textbook of Pediatrics, 17th ed. Philadelphia: Saunders, 2004;760-4. 3. McFadden ER Jar, Elsanadi N, Dixon L, Takacs M, Deal EC, Boyd KK, et al. Protocol therapy for acute asthma: Therapeutic benefits and cost savings. Am J Med 1995;99:651-6. 4. Emerman CL, Cydulka RK, McFadden ER Jr. Comparison of 2.5 vs 7.5 mg of inhaled albuterol in the treatment of acute asthma. Chest 1999;115:92–6. 5. Reisner C, Kotch A, Dworkin G. Continuous versus frequent intermittent nebulization of albuterol in acute asthma: A randomized, prospective study. Ann Allergy Asthma Immunol 1995;75:41-7. 6. Newman KB, et al. A comparison of albuterol administered by metered-dose inhaler and spacer with albuterol by nebulizer in adults presenting to an urban emergency department with acute asthma. Chest 2002;121:1036-41. 7. Fan, Leland L. Randomized trial of intravenous salbutamol in early mangement of acute severe asthma in children, The Journal of Pediatrics, 1997;131(131):160-1. 8. Gary J Browne, Lawrence T Lam. Single dose Intravenous Salbutamol Bolus for managing children with Acute Severe Astham in the Emergency department, PCCM, 2002;3(2):117-23. 9. Kamabalapalli M, Nilchani S, Upadhyayula S, Safety of Intravenous Terbutaline in Acute Severe Asthma, A Retrospective study. Acta Paediatr 2005;94(9):1214-7. 10. David Galbis-Reig, Marc A. Rasansky. A Case Presentation and Literature Review of Successful Ketamine Administration in a Patient with Refractory Status Asthmaticus. The Internet Journal of Internal Medicine. 2004;5 Number 1. ISSN 1528-8382. Available at www.ispub.com/ostial/index.php. Accessed December 15th 2005. 11. Gluck EH, Onorato DJ, Castriotta R. Helium–oxygen mixtures in intubated patients with status asthmaticus and respiratory acidosis. Chest 1990;98:693–8. 12. Alter HJ, Koepsell TD, Hilty WM. Intravenous magensium as an adjuvant in acute bronchospasm: A meta-analysis. Ann Emerg Med 2000;36:191–7. 13. Slutsky AS. Mechanical ventilation: American College of Chest Physicians’ consensus conference. Chest 1993;104:1833– 59.

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Pulmonary Edema

10 INTRODUCTION Abnormal or excessive accumulation of water in the extravascular space of the lungs or pulmonary edema is almost always a manifestation of a serious underlying disease or disorder. Pulmonary edema is often life-threatening, but effective therapy can rescue patients from its deleterious consequences. It can be acute or long-standing with varying clinical manifestations. Broadly, it can be classified as cardiogenic, i.e. due to cardiac pump failure or non-cardiogenic. Frequently the latter term is used synonymously with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). This article will focus on management of the vascular issues. This article will discuss in brief the basic physiological principles that govern fluid filtration in the lungs, pathophysiology of pulmonary edema, diagnosis, treatment, and outcome of pulmonary edema and acute lung injury. PATHOPHYSIOLOGY OF PULMONARY EDEMA1-5 To understand pulmonary edema, it is useful to separate the lung into four distinct compartments through which lung water is distributed: The vascular compartment: This compartment consists of all blood vessels that participate in fluid exchange with the interstitium. The vascular compartment is separated from the interstitium by capillary endothelial cells. The interstitial compartment: The importance of this space lies in its interposition between the alveolar and vascular compartments. As fluid leaves the vascular compartment it collects in the interstitium before overflowing into the air spaces of the alveolar compartment. The alveolar compartment: This compartment is lined with type 1 and type 2 epithelial cells. There may be a role of these epithelial cells in active fluid transport.

PULMONARY EDEMA

The pulmonary lymphatic compartment: There is an extensive network of pulmonary lymphatics. Excess fluid present within the alveolar and interstitial compartments is drained via the lymphatic system. When the capacity for drainage of the lymphatics is surpassed, fluid accumulation occurs. Pulmonary edema occurs when fluid is filtered into the lungs faster than it can be removed. This in turn impedes efficient gas exchange which cannot occur in fluid-filled alveoli. The balance of driving forces normally causes filtration out of the bloodstream and there is usually a net outward flux of fluid and protein crossing from the vascular space into the interstitium. Because of the vast surface area of the lungs, most fluid and protein exchange in the lungs occurs across the interconnecting network of capillaries embedded in the alveolar walls. However, fluid exchange can also occur across capillaries located in the interstitium at alveolar wall junctions and also across small interstitial arteries and veins. Net movement of fluid across the alveolar-capillary membrane is expressed in the Starling equation: Q= k[ (Pc - Pi) - σ (Posmc – Posmi)] where Q is the net fluid-filtration rate (volume flow) across the microvascular barrier; k is the filtration coefficient (which is determined by permeability and surface area of the membrane), Pc and Pi are hydrostatic pressures in the capillary and interstitium respectively, σ is the osmotic reflection coefficient and Posmc and Posmi are the oncotic pressures in the capillary and interstitium. According to the Starling equation, the balance between the prevailing transmural hydrostatic pressures (Pc - Pi) and the colloid osmotic pressures (Posmc – Posmi) provides the “driving force” for filtration. Therefore the equation predicts the development of two fundamentally different kinds of pulmonary edema: increased pressure pulmonary edema, occurs when the driving forces increase, forcing fluid across the barrier at a rate that cannot be handled by lymphatic drainage; and the second, increased permeability pulmonary edema, which occurs in the presence of acute lung injury that damages the normal barriers to fluid filtration.3 There also is a third type of pulmonary edema caused by impaired lymphatic drainage of filtered fluid, but this is seen less commonly in the clinical setting. The first kind is often referred to as cardiogenic and the second kind non-cardiogenic. There are protective factors that prevent pulmonary edema in the normal lung noted below.6 Pulmonary edema occurs when these factors are overwhelmed. • Lung lymphatics • Fluid resorption by blood vessels • Drainage into the mediastinum and pleural spaces • Low permeability of the alveolar epithelial barrier • Surfactant (decreased alveolar surface tension) • Active transport at the alveolar epithelial cell surface. Increased Pressure Edema Also known as cardiogenic, high-pressure, hydrostatic, or secondary pulmonary edema. The flow of fluid and protein into the lungs increases when the sum of driving pressures is elevated. If the rate of fluid accumulation exceeds the rate at which it can be removed, increased pressure edema occurs.

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Mechanisms 1. Increased microvascular hydrostatic pressure: • Left ventricular dysfunction, e.g. arrhythmias, constrictive pericarditis, aortic stenosis or regurgitation, mitral regurgitation, coarctation of the aorta, systemic hypertension, acute myocardial infarction • Volume overload, e.g. iatrogenic increased administration of IV fluids • Mechanical obstruction of left atrial outflow, e.g. mitral stenosis • Pulmonary venous hypertension, e.g. veno-occlusive disease, pulmonary fibrosis • Overperfusion. Some unique situations where pulmonary edema occurs due to more than one mechanism include high altitude pulmonary edema (increased hydrostatic pressure–pulmonary hypertension and increased permeability)7 and neurogenic pulmonary edema (increased pulmonary blood flow and increased permeability).8 2. Decreased perimicrovascular hydrostatic pressure, e.g. postobstructive pulmonary edema.9 High negative intrathoracic pressure causes increases in cardiac preload and afterload and in pulmonary blood flow, all of which increase the microvascular pressure that drives fluid out into the interstitium, e.g. inspiratory airway obstruction as in croup, epiglottitis, pulmonary re-expansion.

Increased Permeability Edema (and Acute Lung Injury)10-12 Accumulation of fluid and protein increases when the lung endothelial and epithelial barriers are injured. If the rate of fluid accumulation exceeds the rate at which it can be removed, increased permeability edema occurs. Because the barriers limiting fluid and protein flow into the lungs do not function normally when the lungs are injured, the lungs are not protected against edema by the usual safety factors. This type of edema is more challenging to treat and requires a multisystem approach. The causes (mechanisms) of increased permeability pulmonary edema are summarized in Table 10.1.12 Multiple mechanisms may be at interplay in several of these conditions. Direct insult by bacterial/ other infectious organisms, inflammation, changes in mechanical properties, destruction of surfactant, influx of cytokines/chemokines, release toxic oxygen metabolites, disturbance of normal cardiopulmonary interactions, platelet/other microaggregation and other mechanisms have been proposed. DIAGNOSIS Clinical assessment: Symptoms and signs may vary with severity and the underlying disorder. Initial symptoms could be dyspnea, cough, and tachypnea. Wheezing may be heard and may present a problem in differential diagnosis (“cardiac asthma”).Older children, especially with insidious onset pulmonary edema, may complain only of vague fatigue, mild pedal edema during the day, or exertional or paroxysmal nocturnal dyspnea. Patients with alveolar edema usually have severe dyspnea, tachypnea, and a productive cough that is often frothy and sometimes blood-tinged. Crackles and rhonchi may be heard, though the classic “fine” crackles may be difficult to appreciate in a child. Cyanosis may be noted in severe cases.

PULMONARY EDEMA Table 10.1: Causes (mechanisms) of increased permeability pulmonary edema Infections Gram-negative or gram-positive sepsis Bacterial pneumonia Viral pneumonia Fungal, parasitic, mycobacterial disease Aspiration Gastric acid Food/other particulate matter Hydrocarbons Near-drowning Hemodynamic Shock Anaphylaxis High altitude Air embolism Trauma Lung contusion Fat embolism Burns Toxic fumes/gases Drugs – Barbiturates, salicylates, methadone, heroin, cocaine Hematologic DIC Blood group incompatibility Post-cardiac bypass Metabolic DKA Pancreatitis Neurologic Trauma Increased ICP Grandmal seizures

In patients with increased pressure pulmonary edema, the development of edema is often insidious because the alveoli are protected by the safety factors listed previously. However, in increased permeability edema, alveolar flooding can occur rapidly and the onset of symptoms may be sudden (“flash pulmonary edema”). Since pulmonary edema is usually due to an underlying pathology, signs of the primary condition should be identified so appropriate therapy can be instituted. Since increased pressure edema is usually caused by cardiac failure, there may be a history of heart disease. There may be signs and symptoms of any of the causes of chronic or acute congestive heart failure, such as hypertension, valvular heart disease, and severe volume expansion. Large tender liver, peripheral edema, heart murmur, gallop rhythm, arrhythmias, raised JVP and increased heart size may be present. History and physical examination may help differentiate increased permeability edema from increased pressure edema and identify a possible cause of acute lung injury. Signs or symptoms of underlying

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cardiac disease are usually not present. A cause of acute lung injury may be suggested by the clinical setting (e.g. sepsis, pneumonia, emesis, seizures, pancreatitis, burns, high altitude) history of exposure (e.g. trauma, near drowning, drug ingestion, toxic gases or chemicals exposure) or the physical findings (e.g. shock, chest trauma, long bone fractures). Because infection and the sepsis syndrome are major causes of acute lung injury, a thorough search must be made for signs and symptoms of an infectious cause. Note that many patients with acute lung injury may be febrile, whether or not an infection is clinically apparent.

Diagnostic Studies and Definitions These are directed at establishing etiology in most cases. Appropriate cultures for microorganisms and toxicology screens of blood and urine are useful in identifying underlying causes of acute lung injuries. Sputum or tracheal aspirate examination, bronchoscopy with bronchoalveolar lavage (with quantitative cultures, if available) are all useful in diagnosing pneumonia in ventilated patients, even those who are being treated with antimicrobial drugs. Other tests including electrolytes, other metabolic parameters, hematologic tests, etc. would depend on the underlying suspected disorder. As discussed previously, most causes of non-cardiogenic pulmonary edema (usually due to increased permeability) is due to acute lung injury. The pathophysiology of ALI is discussed elsewhere in this book. Criteria for diagnosing ALI remain controversial. The most accepted criteria are those of the American-European Consensus Conference Definition (Table 10.2).13 The problem with this and other definitions is the failure to link the underlying pathophysiology of acute lung injury to the functional abnormalities that are at the core of the definitions. It is difficult to correlate clinical signs or blood gas values to the actual structural damage to the capillary barrier. Again, there may be disorders (e.g. bacterial pneumonias) that could present with “ALI” by definition and not have a generalized structural defect. On the other hand there may be disorders which do cause structural damage, but do not affect oxygenation as much (e.g. venous air embolism). However, for practical purposes and for streamlining therapy, the American-European Consensus Conference Definition is useful. Table 10.2: American-European consensus conference definition of acute lung injury and acute respiratory distress syndrome Timing Acute Oxygenation (regardless of PEEP) PaO2 /FiO2 ≤ 300 mm Hg = acute lung injury PaO2 /FiO2 ≤ 200 mm Hg = acute respiratory distress syndrome Chest radiograph Bilateral infiltrates on frontal view Pulmonary artery wedge pressure ≤ 18 mm Hg when measured, or no clinical evidence of left atrial hypertension

Chest X-ray:14 Initially a routine chest X-ray may reveal distended blood vessels (especially at the apex), enlargement and loss of definition of hilar structures, development of septal lines (Kerley B lines), peribronchial and perivascular cuffing, and occasionally perihilar “haze” which may

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represent interstitial edema. Confluent, irregular, patchy increases in lung density throughout the lung fields that obscure vascular markings, may indicate alveolar edema. Air bronchograms may rarely be seen in severe cases. Blood gases: These are the most clinically relevant investigations in the management of ALI - the arterial PO2, PCO2, and pH are the most informative laboratory indicators of overall pulmonary function. Both right-to-left shunting at the flooded alveoli level as well as ventilation-perfusion mismatch contribute to hypoxemia. Elevated pCO2 can be due to several factors including underlying lung disease, increased metabolic production of carbon dioxide from increased work of breathing, increased wasted ventilation, or impaired ventilation caused by weak respiratory muscles. Acidbase disturbances are common in increased pressure edema but often do not correlate with severity, morbidity, or mortality. Measurement of biologic markers: Since ALI is a heterogeneous disease with differing etiologies there is no single reliable marker or prognosticator. Investigators have studied several such markers in blood/urine/tracheal secretions including lactate, bacterial lipopolysaccharide, TNF-alpha, interleukin-6, von Willebrand factor, surfactant protein D and markers of neutrophilic inflammation. Thus no ideal marker has been identified. TREATMENT6, 15 Successful treatment of pulmonary edema requires appropriate life support measures followed by specific therapy directed at the factors that led to water accumulation in the lung extravascular space. This also requires a correct diagnosis and an understanding of the nature of the underlying disease state and of the strategies that might prove useful in limiting further edema accumulation and favor fluid removal from the lungs. Essential requirements for patients with pulmonary edema include preservation of the airway, provision of adequate ventilation, and maintenance of satisfactory oxygenation. Morphine is generally not used in children due to risk of respiratory depression. Most children with acute presentations of pulmonary edema need to be admitted and monitored in a pediatric ICU setting. Pulse oximetry and frequent monitoring of blood gases as indicated by the severity are needed. Primary treatment of pulmonary edema is administration of oxygen. Facemasks, oxyhoods and CPAP may be used as appropriate. Indications for intubation include worsening hypoxemia despite O2 administration, increasing pCO2 or signs of impending respiratory fatigue. Rapid-sequence intubation techniques may be necessary to secure the airway. Mechanical ventilation with emphasis on oxygenation is essential in children who need intubation. Early institution of appropriate positive end-expiratory pressure (PEEP) is beneficial. PEEP increases functional residual capacity, expands fluid-filled alveoli, improves compliance and thus improves oxygenation. Further details on mechanical ventilation strategies in ALI/ARDS can be found elsewhere in the book. In patients with increased hydrostatic pressure edema, there are there are three major therapeutic options after emergency measures: vasodilators, diuretics, and inotropic agents. 1. Vasodilators: Their effects occur in minutes. Through dilation of veins, vascular capacitance is increased and blood is redistributed peripherally, thereby lowering the driving pressure for fluid filtration in the lungs; through dilation of arteries, systemic vascular resistance (cardiac

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afterload) falls, cardiac output and stroke volume increase, and the heart works more efficiently. The three classes of vasodilators that may be useful in pulmonary edema are the venodilators (e.g. nitrates like nitroglycerin), arteriolar dilators (e.g. phentolamine, hydralazine), and mixed dilators (e.g. nitroprusside). 2. Diuretics: Diuretics decrease LV volume and pressure and thus decrease lung filtration pressure post-renal water excretion. Furosemide, a potent loop diuretic is the drug of choice. It can be given IV as a bolus (1-4 mg/kg) or as a continuous infusion (0.5-4 mg/kg/hr). 3. Inotropes: Dopamine and its analogue dobutamine are the commonly used agents, while the newer agents including the inodilators amrinone and milrinone are often useful. The main strategies in patients with increased permeability edema/ALI include: 1. Minimize edema accumulation: Ensure lowest possible pulmonary microvascular pressure and reduce vascular volume. 2. Find and treat infection. 3. Supportive therapy: Administer oxygen, lung-protective strategies, optimize cardiac output. 4. Avoid hypotension, volume overload, infection, O2 toxicity. REFERENCES 1. Staub NC. Pulmonary edema. Physiol Rev 1974;54:678-811. 2. Crandall E, Matthay M. Alveolar epithelial transport: Basic science to clinical medicine. Am J Respir Crit Care Med 2001; 162:1021-29. 3. Taylor A. Capillary fluid filtration: Starling forces and lymph flow. Circ Res 1981;49:557-575. 4. Bhattacharya J. Physiological basis of pulmonary edema. In: Matthay MA, Ingbar D (Eds). Pulmonary Edema. New York: Marcel Dekker 1998;1-36. 5. Behrman. Nelson Textbook of Pediatrics, 17th ed., Copyright Saunders2004;1426-27. 6. Matthay MA, Martin TR. Mason. Murray and Nadel’s Textbook of Respiratory Medicine. 4th ed. Copyright; Saunders 2005;1502-32. 7. Bartsch P. High altitude pulmonary edema. Respiration 1997;64:435-443. 8. Maron MB, Pilati CF. Neurogenic pulmonary edema. In: Matthay MA, Ingbar D (Eds): Pulmonary Edema. New York: Marcel Dekker 1998;319-354. 9. Van Kooy MA, Gargiulo RF. Post-obstructive pulmonary edema. Am Fam Physician 2000;15;62(2):401-4. Review. 10. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334-1349. 11. Byrne K, Cooper KR, Carey PD, et al. Pulmonary compliance: Early assessment of evolving lung injury after onset of sepsis. J Appl Physiol 1990;69:2290-2295. 12. Robin E, Carroll C, Zelis R. Pulmonary edema. N Engl J Med 1973;288:239, 292 (2 parts). 13. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference of ARDS: Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149:818-824. 14. Suh R, Aberle DR: Radiographic manifestations of pulmonary edema. In: Matthay MA, Ingbar DH (Eds): Pulmonary Edema. New York: Marcel Dekker, 1998;85-119. 15. Textbook of Pediatric Intensive Care. Rogers MC, Nichols DG (Eds): 3rd edition. Copyright Williams and Wilkins 1996;432-42.

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Acute Renal Failure in Pediatric Intensive Care Unit

INTRODUCTION Metabolic abnormalities occur in the intensive care unit (ICU) and will need nephrology intervention. Acute renal failure (ARF) forms a component of the extensive indications for nephrology intervention. The etiology and outcome is different in community acquired ARF from that of ICU. ARF is a frequent accompaniment of severe sepsis, cardiogenic shock, medications and part of multi-organ dysfunction. Rarely it occur as an isolated phenomenon.1 The outcome is determined by the underlying disease, age of the patient and associated organ dysfunction rather than renal dysfunction per se. ARF in the ICU setting carries a high morbidity and mortality.2 Quite often, ARF in ICU setting is not marked by reduced urine output or it could be easily missed in the light of magnitude of other complications occurring in that patient. Hence serial and regular monitoring of renal function test is the best way to identify onset of renal dysfunction. Even the recording of elevated serum creatinine is not an indicator of early onset of renal failure as the serum creatinine rises only when more than 50% of renal function is lost. Hence the need for early biomarkers and presently the availability of the test for identifying kidney injury markers (KIM) is the hope on the horizon. DEFINITION Acute renal failure (ARF) is defined as a rapid fall over a course of hours or days in glomerular filtration rate (GFR) and the accumulation of nitrogenous wastes, including blood urea and creatinine. Clinically oliguria and anuria are important indicators of renal dysfunction especially in acute settings.3 10-15% of ARF can have near normal urine output defined, as polyuric ARF. The polyuric ARF with urine output >1 ml/kg/hr) is more commonly associated with exposure to nephrotoxic drugs like aminoglycoside, amphotericin, cis-platin, septicemia and burns. It indicates a physiological disturbance in the tubular epithelial cells and less of anatomical damage. Non oliguric ARF has better prognosis. Anuria or total cessation of urinary output should suggest complete bilateral ureteral

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obstruction; diffuse bilateral cortical necrosis, rapidly progressive glomerulonephritis or bilateral renal arterial or venous occlusion. INCIDENCE Thirteen percent of all admissions to the ICU develop ARF and are often multi factorial and associated with poor prognosis.4 Mortality rates in ARF vary from < 10% in patients with prerenal azotemia to approximately 80% in patients in ARF with multi organ dysfunction syndrome (MODS).5 ARF is an independent predictor of increased mortality rate. Therefore, prevention, early diagnosis and treatment of ARF are of paramount importance in ICU patients. ETIOLOGY AND CLASSIFICATION Etiology of ARF is functionally classified into prerenal, intra renal (intrinsic renal failure) and post renal (obstruction). Its frequency is different from that in the community, with a higher incidence of acute tubular necrosis (ATN) and less of prerenal azotemia. Other intrinsic disease of the kidney like acute nephritic syndrome, vasculitis, interstitial nephritis account for the minority of cases. Obstruction accounts for the least number. Pre-renal failure is an oliguric state resulting from diminished blood flow to the kidneys from true volume contraction or from decreased effective arterial blood volume (EABV). Prompt recognition and therapy of pre-renal conditions can prevent irreversible ischemic tubular necrosis. True volume contraction occurs in gastrointestinal losses, hemorrhage and increased insensible water losses as in febrile conditions, burns and third space losses as in septic shock, nephrotic syndrome and "capillary leak syndrome". Decreased EABV occurs in congestive heart failure, cardiogenic shock and cardiac tamponade, where decrease in renal perfusion occurs because of diminished cardiac output. Systemic vasodilatation as in sepsis, cirrhosis, severe anemia, antihypertensive agents can cause reduction in the EABV. Non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) can cause pre-renal ARF by impairing renal autoregulation. NSAIDs impair renal autoregulation by inhibiting afferent arteriolar dilatation by inhibiting the production of prostaglandin. These drugs have their adverse effects in the presence of preexisting renal disease or hypo perfusion states or along with nephrotoxins. If the NSAID induced renal ischemia is uncorrected prerenal failure progresses to ATN. NSAIDs also can cause ARF by inducing an acute interstitial nephritis (AIN). ACEI and ARB are used to treat high blood pressure, congestive heart failure and progressive proteinuric renal disease. In children who depend on angiotensin II-mediated efferent arteriolar vasoconstriction for the maintenance of the GFR as in hypovolemic states or renal artery stenosis, they can cause prerenal ARF. In Intrinsic renal failure the commonest cause in an ICU setting is ATN. ATN is caused by ischemic or cytotoxic injury to the epithelial cells of the proximal tubules and thick acesending loop of Henle. ATN may evolve from pre-renal failure if the insult is prolonged. ATN may also result from toxic injury of the tubular epithelial cells from drugs including aminoglycoside antibiotics, cisplatin, amphotericin-B, radio contrast dye and exogenous toxins such as ethylene glycol, methanol, heavy metals or endogenous toxins such as myoglobin and hemoglobin. Many primary or secondary glomerular diseases including HUS can present as ARF. Management involves treatment of the

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primary glomerular disease and supportive dialysis. ATN can occur following cardiac, aortic, hepatobiliary and urological surgery. Sepsis is a cause of ARF in critically ill patients.6 ARF occurs in 19% of patients with moderate sepsis, 23% with severe sepsis and 51% with septic shock when blood cultures are positive.7 The combination of ARF and sepsis is associated with 70% mortality as compared with 45% mortality among patients with ARF alone.6 The cause of ATN in sepsis, is hypotension, renal hypoperfusion and ischemic injury to proximal tubular cells. Important mechanisms of renal hypoperfusion are the combined effect of arterial vasodilation, intrarenal vasoconstriction, intrarenal microvascular injury caused by PMN-and complement-induced endothelial injury and intravascular thrombosis. The intrarenal vasoconstriction is due to the local release of endothelial-derived vasoconstrictors, including endothelin, thromboxane A2, and leukotrienes. Renal hypoperfusion also increases renal susceptibility to superimposed nephrotoxic events which are common in septic patients.8 In cardiogenic shock, ARF occurs in one third of the patients due to hypotension and can increase the mortality to 50%. MODS develop due to ischemia from reduced cardiac output. Hepatorenal syndrome is defined as functional renal failure in the setting of cirrhosis in the absence of intrinsic renal disease. It is characterized by intense constriction of renal cortical vasculature leading to oliguria and avid sodium retention. It can complicate fulminant failure, acute hepatitis and hepatic malignancy. The only established therapy which improves renal failure in this syndrome is liver transplantation. Continuous hemofiltration in an ICU is the main stay of support pending transplantation. Prevention includes avoidance of intravascular volume contraction, prevention of infection and discrete use of both hepatotoxic and nephrotoxic drugs. Avoidance of over usage of diuretics, frequent and large volume of ascitic fluid removal and lactulose usage are other prophylactic measures. Uric acid nephropathy occurs in tumor lysis syndrome or massive tissue necrosis and when the uric acid level is over 15 mg/dL. This can be prevented with alopurinol and vigorous alkaline hydration of urine to prevent precipitation. 50 ml of sodium bicarbonate solution is added to 950 ml of 5% dextrose and is given as maintenance IV fluid. Aim of this alkali therapy is to keep the urine pH above 7. Addition of potassium at 1 ml/100 ml depends on the serum potassium level. Many nephrotoxic antibiotics, radiographic contrast agents, cyclosporin A, and heme pigments cause both direct cellular toxicity and vasoconstriction in addition to prerenal failure. Certain medications, penicillamine and NSAIDs induce specific glomerulopathies or can induce acite interstitial nephritis. Postrenal failure results from lower tract obstruction or bilateral upper tract obstruction or unilateral obstruction in a solitary kidney. Removal of mechanical obstruction can restore or improve renal function. Ultrasonogram is of great utility to rule out obstruction. Crystalinduced tubular obstruction occurs in uric acid, nephropathy as in tumour lysis syndrome or during acyclovir, sulfonamides, methotrexate, triamterene, and ethylene glycol administration. INVESTIGATIONS In addition to investigation for the primary disease some of the investigations of relevance to renal failure are discussed in brief.

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Urine: Dipstick screening, microscopy and culture sensitivity. Urine sodium, creatinine, specific gravity on or urine osmolality. Blood chemistry: Blood urea, serum creatine, sodium, potassium, acid base status, calcium, phosphorus, alkaline phosphates, serum proteins, albumin and LDH. Hematology: Full blood count, platelets, differential count and smear. Radiology: X-ray chest indicate cardiomegaly, pulmonary congestion, pleural fluid in the presence of parenchymal infection if any. Urgent ultrasound to exclude, obstruction and other structural abnormalities and to assess kidney size and parenchymal change. Doppler study can identify renal artery or venosus thrombosis. Urinary diagnostic indices: Urine diagnostic indices differentiate between pre-renal azotemia and ATN (Table 11.1). Prompt recognition of pre-renal azotemia and correction of hypovolemia could prevent the development of ATN and it is probably the single most important intervention in the prevention of ATN in ICU. Table 11.1: Urinary diagnostic indices in ARF

Pre renal Urine analysis hyaline cast Specific Gravity > 1020 Urinary Sodium (mEq/L) 500 Fractional excretion of Sodium* (FeNa) 40 < 350 > 2

*FeNa = (Urine sodium/ serum sodium) × (Serum creatinine/urine creatinine) × 100

High FeNa is obtained in prerenal azotemia in children who have received diuretics or mannitol with in previous 24 hours, chronic interstitial nephritis with salt loosing states and in glycosuria. A low FeNa is obtained in acute glomular nephritis, pigment nephropathy, septicemia, burns and intrinsic ARF induced by radiographic contrast agents and aminoglycosides. However, low FeNa is of value as evidence of prerenal azotemia. TREATMENT In the ICU the primary goal of therapy is centered on preventive measures. Medical management is second, followed by dialysis or renal replacement therapy. Dialysis can be intra corporeal as in peritoneal dialysis or extra corporeal as in hemodialysis and other continuous renal replacement therapy. 1. Preventive Measures for ARF in ICU a. Serial monitoring of renal function, electrolytes, acid-base and serum calcium, magnesium and phosphorus status b. Prompt use of volume expansion for hypovolemic state. Saline infusion and consequent diuresis has been recognized in preventing ATN. In ICU, two or more factors combine in a synergistic fashion to induce oliguria and renal injury. ARF in such patients is termed as "Multi factorial

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c. d.

e. f. g. h.

i.

ARF". The combination of aminoglycosides and renal hypoperfusion increases the incidence of ARF. It is necessary to ensure adequate correction of fluid deficit and maximizing renal blood flow prior to administering of potential nephrotoxins, and in the presence of nephrotoxic compounds such as heme pigments and uric acid. Identifying pre-existing renal disease Minimizing the use of nephrotoxins and dose modifications in renal dysfunction. Once-daily dosing is recommended for all aminoglycosides, because it is as effective as divided dosing in treating infection and less possibility of nephrotoxicity. Avoiding use of vaso constrictive drugs (NSAIDs, Cyclosporin). Minimizing invasive lines to avoid nosocomial infections Early Identification of sepsis, peripheral circulatory or cardiac failure Loop Diuretics - The administration of high dose loop diuretics within 24 to 48 hours of the onset of established ATN, does not improve the GFR but increases urine output in a proportion of oliguric patients. Patients who are converted by diuretics from oliguric to sustained nonoliguric ATN have a better prognosis than unresponsive patients. In ARF, injection furosemide is given either as a single dose 2-4 mg/kg or as an infusion 0.5-1.0 mg/kg/hr. If there is no response to the first dose in about two hours, a second dose is given. Continuous IV infusion of a loop diuretic after an initial loading dose may confer a better diuretic response than a bolus dose of loop diuretic. If there is no diuresis of more than 1 ml/kg/hr, renal replacement therapy is necessary. Mannitol has no significant role in the treatment of ARF. Dopamine: Both loop diuretics and dopamine have been used alone or in combination to convert oliguric to non oliguric ARF. Low dose dopamine ( 4.0 mg/dl 2. B.urea > 150 mg/dl 3. Persistent metabolic acidosis 4. Hyperkalemic S.K > 6.0 mEq/L 5. Hyponatremia S.Na < 120 mEq/L b. Clinical 1. Refractory edema 2. Pulmonary edema 3. Uncontrollable hypertension c. Inborn errors of metabolism: 1. Hyper ammonia syndrome 2. Urea cycle metabolic disorder.

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d. Miscellaneous: 1. Neem Oil, Salicycilate, and Phenobarbitone poisoning 2. Hypernatremic, Hypercalcemia 3. Prophylactic PD in open heart surgeries 4. Reye's syndrome 5. Need to remove fluids in an edematous child or in congestive cardiac failure refractory to diuretics 6. Need for parentral nutrition, fluid administration for antibiotics in an oliguric septic child with high catabolism, 7. Need for fluid replacement in a hypovolemic child with "capillary leak syndrome" 8. Need for fluids in an oliguric hypovolemic child. Modalities of RRT Peritoneal dialysis (PD), intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT) and slow low efficiency daily dialysis (SLEDD) are acceptable therapies in ICU. Modalities of therapy depends upon the facilities available, personal available and experience. However PD remains as the choice of treatment in ICU in view of the simplicity of treatment, absence of the need for technical skills, heparin usage, safety in the presence of compromised circulatory volume and the ease and rapidity with which it can be instituted.

Peritoneal Dialysis In PD, a temporary or permanent PD catheter is placed. Standard peritoneal dialysis solutions can be used. Clearance is convective and diffusive. Increasing the dextrose concentration in the dialysate and increasing the frequency of exchanges can adjust the degree of ultrafiltration. Disadvantages include the need for an intact peritoneum, potential development of hyperglycemia, potential respiratory embarrassment due to increased abdominal pressure, risk of peritonitis, and lower clearance than can be obtained with RRT. For acute dialysis "Polyurethane catheter" is used. Commonly available are infant, pediatric and adult sizes. In continuous peritoneal dialysis or continuous cyclic peritoneal dialysis, soft silastic Tenckhoff catheter is used. The catheter is placed indefinitely since the biocompatibility of the catheter is such. In IPD a catheter is inserted for every dialysis, which may extend for a few days but generally not more than a week. More the days more is the possibility of infection. For this reason and to examine whether the renal function is picking up, the catheter is removed and PD is discontinued. If renal functions do not show recovery, PD is restarted at a different site using a new catheter. The dialysis fluid is commercially available and generally constitutes Sodium (mEq/L)130 140, Chloride (mEq/L)100 - 110, Acetate/lactate (mEq/L)35 - 45, Magnesium (mEq/L)0.5 - 1.5, Calcium (mEq/L)3.0 - 3.5, Osmolality (mOsm/Kg)340 - 360, pH 5.0 - 5.8. and dextrose either 1.5 grams or 1.7 grams or 4.5 grams in 100 ml of fluid. Hypertonic fluid is used when more fluid is to be removed. Isotonic fluid can be converted into hypertonic fluid by adding 100 ml of 25% dextrose to one liter of isotonic fluid. In newborns with low birth weight lactic acidosis may be profound. To prevent lactic acidosis, bicarbonate rather than lactate is used. This can be prepared in the hospital.

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Solution A : 440 ml of dextrose + 60 ml of NaHCO3 Solution B : 500 ml normal saline. Solution A 250 ml + Solution B 500 ml will give Na 140 mEq/L, HCO3 30 mEq/L and Dextrose 1.5 g/dl. Daily maintenance calcium must be given intravenously. It will precipitate if added with HCO3 containing PD fluid. Continuous Renal Replacement Therapies (CRRT) 1. Slow, continuous ultrafiltration (Fig. 11.1) Slow, continuous ultrafiltration (SCUF) is a form of CRRT that is not associated with fluid replacement and often is used in the management of refractory edema with or without renal failure. Its primary goal is fluid removal.

Fig. 11.1: Slow continuous ultrafiltration

2. Continuous venovenous hemofiltration (Fig. 11.2) Continuous venovenous hemofiltration (CVVH) is a form of CRRT in which blood is driven through a highly permeable membrane by a peristaltic pump by way of an extracorporeal circuit originating from a vein and terminating in a vein. The ultrafiltrate that is produced is replaced in part or completely with appropriate replacement solution to achieve blood purification and volume control. 3. Continuous arteriovenous hemofiltration (Fig. 11.3) Continuous arteriovenous hemofiltration (CAVH) is a form of CRRT in which blood is driven by the patient's blood pressure through a filter containing a highly permeable membrane by way of an extracorporeal circuit originating from an artery and terminating in a vein. The

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Fig. 11.2: Continuous venovenous hemofiltration

Fig. 11.3: Continuous arteriovenous hemofiltration

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Fig. 11.4: Continuous venovenous hemodialysis

ultrafiltrate produced is replaced in part or completely with appropriate replacement solution to achieve blood purification and volume control. 4. Continuous venovenous hemodialysis (Fig. 11.4) Continuous venovenous hemodialysis (CVVHD) is a form of CRRT in which the extracorporeal circuit includes slow, countercurrent dialysate flow into the ultrafiltrate-dialysate compartment of the hemofilter. Blood flow through the blood compartment of the membrane is driven by a peristaltic pump through a circuit beginning and terminating in a vein. Fluid replacement is not administered routinely, and solute clearance is mostly diffusive. 5. Continuous arteriovenous hemodialysis (Fig. 11.5) Continuous arteriovenous hemodialysis (CAVHD) is a form of CRRT in which the extracorporeal circuit includes slow, countercurrent dialysate flow into the ultrafiltrate-dialysate compartment of the hemofilter. Blood flow through the blood compartment of the membrane is driven by the patient's blood pressure through a circuit beginning in an artery and terminating in a vein. Fluid replacement in not administered routinely, and solute clearance is mostly diffusive. 6. Continuous venovenous hemodiafiltration (Fig. 11.6) Continuous venovenous hemodiafiltration (CVVHDF) is a form of CRRT in which the CVVH circuit is modified by the addition of slow, countercurrent dialysate flow into the ultrafiltratedialysate compartment of the hemofilter. Ultrafiltration volumes are optimized to exceed the desired weight loss to take advantage or convection. Fluid replacement is administered routinely as clinically indicated to replace fluid losses in part or completely. Solute removal is diffusive and convective.

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Fig. 11.5: Continuous arteriovenous hemodialysis

Fig. 11.6: Continuous venovenous hemodiafiltration

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Fig. 11.7: Continuous arteriovenous hemodiafiltration

7. Continuous arteriovenous hemodiafiltration (Fig. 11.7) Continuous arteriovenous hemodiafiltration (CAVHDF) is a form of CRRT in which the CAVH circuit is modified by the addition of slow, countercurrent dialysate flow into the ultrafiltratedialysate compartment of the hemofilter. Ultrafiltration volumes are optimized to exceed the desired weight loss to take advantage of convection. Fluid replacement is administered routinely as clinically indicated to replace fluid losses either in part or completely. Solute removal is diffusive and convective. Hemodialysis SLEDD Intermittent hemodialysis in ARF has been associated with poor outcome. In recent times with availability of biocompatible dialysis membrane its usefulness has been resurrected. However in pediatric ICU setting, it has limited value. CONCLUSION Every child in the ICU setting has the high possibility of developing ARF. This is more so in a septic child. Prevention includes measures to prevent hypovolemia, prompt correction of hypovolemia, prevention of infection, prompt recognition and treatment of infection, discrete use of combination of nephrotoxic medication and lastly the courage for early dialysis before irreversible multi-organ failure has occur.

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REFERENCES 1. Liano F, Junco E, Pascual J, Madero R, Verde E. The spectrum of acute renal failure in the intensive care unit compared with that seen in other settings. The Madrid Acute Renal Failure Study Group. Kidney Int 1998;(Suppl 66):S16-24. 2. Brivet FG, Kleinknecht DJ, Loirat P, Landais, Paul JM. Acute renal failure in intensive care units--Causes, outcome, and prognostic factors of hospital mortality: A prospective, multicenter study. Critical Care Medicine. 1996;24: 192-8. 3. Klahr S, Miller SB. Acute oliguria. N Engl J Med 1998;338:671-5. 4. Thadhani R, Pascual M, Bonventre JV. Acute Renal Failure. N Engl J Med 1996;334:1448-60. 5. Molitoris BA. Approach to acute renal failure. In: Critical Care Nephrology, 1st Edn, Eds Molitoris BA, Jaypee Brothers Medical Publications Ltd, New Delhi, 2006;129-37. 6. Schrier RW, Wang W. Acute Renal Failure and sepsis N.Engl J Med 2004;351:159-69. 7. Riedemann NC, Guo RF, Ward PA. The enigma of sepsis. J Clin invest 2003;112:460-7. 8. Abernethy VE, Lieberthal W. Acute renal failure in the critically ill patient. Crit Care Clin 2002;18:203-22. 9. Kraus M. Indications and modalities in critical care nephrology. In: Critical Care Nephrology, 1st Edn, Eds Molitoris BA, Jaypee Brothers Medical Publications Ltd, New Delhi, 2006;151-66.

Vikas Taneja, Manvinder Singh Sachdev, Kohli 133 ACUTE Vikas HEART FAILURE

Acute Heart Failure

12 INTRODUCTION The management of acute heart failure (AHF) requires an understanding of the pathophysiology and accurate diagnosis of AHF prior to initiating treatment. This chapter discusses the pathophysiology of AHF, followed by the etiology and management, with special reference to AHF in postoperative congenital heart disease. DEFINITION Acute heart failure (AHF) is a clinical syndrome that reflects the inability of myocardium to meet the metabolic requirements of the body including the growth process. It occurs in 30% of infants and children with congenital heart defects, majority in first year of life.1 FACTORS AFFECTING CARDIAC OUTPUT The cardiac output (CO) is dependent on stroke volume (SV) and heart rate (HR). The SV further depends on the preload, myocardial contractility and afterload.2 Preload, defined as the degree of end-diastolic fiber stretch, determines the end-diastolic volume. This in turn is influenced by the intravascular volume status of the patient and ventricular wall thickness. For clinical purposes, central venous pressure (CVP) is a reasonable reflection of the preload status. Myocardial contractility is characterized by the force and velocity of myocardial contraction, but, clinically the contractile state is often expressed as ejection fraction (LVEF). Afterload, the force resisting myocardial fiber shortening after stimulation from the relaxed state, is a reflection of the work the myocardium has to do. Clinically, the afterload is referred to as the resistance against which the heart has to function. The HR and rhythm are also important contributors to AHF. It may be worth noting that arrhythmia may be a cause or precipitator of AHF.

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FACTORS AFFECTING MYOCARDIAL PERFORMANCE Under most circumstances, the CO is directly proportional to the amount of blood coming into it. This is a direct effect of the muscle stretch which results in muscle to contract with a greater force. This is the Frank-Starling principle. This mechanism operates in AHF, but as ventricular function is abnormal, the response is inadequate. If the Frank-Starling curve is depressed, fluid retention, vasoconstriction, and a cascade of neurohumoral responses lead to the syndrome of AHF. Over time, LV remodeling with dilatation and hypertrophy further compromises cardiac performance, especially during physical stress.3 PATHOPHYSIOLOGY BASED ETIOLOGY OF AHF On the basis of pathophysiology, the etiology of AHF may be classified into: 1. Increased preload may stretch the muscle fiber beyond physiologic states resulting in an effective decrease in cardiac function. This is seen in volume loading conditions like L - R shunts, mitral regurgitation, aortic regurgitation and complete heart block (unusually increased end diastolic volume due to a highly prolonged diastole). 2. Impaired myocardial contractility results in a decreased myocardial function as in myocarditis (viral or metabolic), cardiomyopathy and anomalous left coronary artery from pulmonary artery (ALCAPA). 3. Increased afterload: When ventricles work against abnormally high afterload that result in myocardial failure, e.g. Coarctation of aorta (CoA), aortic stenosis, interrupted aortic arch. 4. Inadequate diastolic filling would result in a low CO due to decreased filling. This would typically be seen in tachyarrhythmias, constrictive pericarditis and ventricular hypertrophy. Under these conditions, initially, various compensatory mechanisms come into play, which have got salutary effects. But the same compensatory mechanisms if pressed into play indefinitely cause non-salutary effects and potentiate heart failure4,5 (Table 12.1). PATHOPHYSIOLOGY OF SYMPTOMS IN AHF Left Ventricle (LV) Failure In LV failure, as the CO declines, the left atrial pressure increases resulting in an increase in pulmonary venous pressure. Dyspnea or increased work of breathing correlates with elevated pulmonary venous pressure. When fluid extravasates into the interstitial space and alveoli, it significantly alters pulmonary mechanics and, results in ventilation/perfusion mismatch. This results in intrapulmonary shunting of unoxygenated blood. A combination of alveolar hyperventilation due to increased lung stiffness and reduced PaO2 is characteristic of LV failure. Arterial blood gas analysis reveals an increased pH and a reduced PaCO2 (respiratory alkalosis) with low SO2 reflecting increased intrapulmonary shunting. A raised PaCO2 signifies alveolar hypoventilation possibly due to respiratory muscle failure and requires ventilatory support. Right Ventricle (RV) Failure In RV failure, systemic venous congestive symptoms develop. Pleural effusions usually accumulate in the right hemithorax and later bilaterally. Hepatic dysfunction commonly occurs secondary to RV failure, with increase in bilirubin, prothrombin time, and hepatic enzymes (e.g. AST, ALT).

ACUTE HEART FAILURE Table 12.1: Salutary and non-salutary effects of compensatory mechanisms in acute heart failure

Compensatory mechanism

Salutary effects

Non-salutary effects

Increase in end diastolic volume and pressure

This increases myocardial contractory force through Frank-Starling mechanism

When end diastolic pressure reaches high levels, pulmonary and peripheral congestion and edema develops

Increase in sympathetic tone

This augments heart rate and myocardial contractility, which helps to maintain tissue perfusion pressure

When sympathetic action is intense, tachycardia and peripheral vasoconstriction (increased afterload) leads to substantial increase in myocardial oxygen consumption, increased cardiac work and reduced coronary perfusion

Stimulation of reninangiotensin aldosterone system

This causes renal retention of salt and water, which increases diastolic filling pressure It causes vasoconstriction to maintain tissue perfusion pressure

When these effects are excessive, it causes systemic and pulmonary venous congestion on one hand and increases afterload on the other. As cardiac function deteriorates, renal blood flow decreases in proportion to the reduced CO, the GFR falls, and blood flow within the kidney is redistributed. The filtration fraction and filtered Na decrease, but tubular reabsorption increases

Atrial Natriuretic Peptide (ANP) released in response to increase in atrial volume and pressure B-type Natriuretic Peptide (BNP) is produced in response to increase in ventricular pressure and volume

These peptides enhance When these effects are excessive, marked renal excretion of Na, but, in sodium and water retention occurs leading patients with AHF, the effect to fluid overload is blunted by decreased renal perfusion, receptor downregulation, and enhanced enzymatic degradation

Release of Arginine Vasopressin Peptide (AVP) in response to a fall in ECF volume and by various neurohormonal stimuli

It diminishes excretion of free water by the kidney and contributes to the hyponatremia of AHF

Ventricular hypertrophy

This provides more contractile Progressive hypertrophy leads to abnormal elements increasing diastolic relaxation leading to pulmonary myocardial contraction and systemic congestion

When these effects are excessive, marked sodium and water retention occurs leading to fluid overload

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Reduced aldosterone breakdown by the impaired liver further contributes to fluid retention. Similarly, decreased mental performance may result from chronic markedly reduced PO2, reflecting severely reduced cerebral blood flow and hypoxemia. It is worth noting that ventricular crosstalk, a significant phenomena seen in infants results in RV failure in LV failure. This explains the finding of hepatomegaly in isolated L to R shunts resulting in AHF.4,6 CLASSIFICATION AND ETIOLOGY OF AHF AHF can be classified in many ways.7 This can be: LV failure characteristically develops in congenital defects (e.g. large left to right shunts like ventricular septal defect, patent ductus arteriosus, common AV canal), ALCAPA, left sided obstructive lesions (aortic stenosis, CoA and other forms of interrupted aortic arch), most forms of cardiomyopathy, tachyarrhythmias, and myocarditis. Post-cardiopulmonary bypass is also an important cause of LV dysfunction. RV failure is most commonly caused by prior LV failure and tricuspid regurgitation. Mitral stenosis, pulmonary hypertension, pulmonary artery (PA) or valve stenosis are also causes. Systolic dysfunction: AHF commonly manifests as systolic dysfunction. Systolic dysfunction has numerous causes; the most common being myocarditis. More than 20 viruses have been identified as causal. Toxic substances damaging the heart include a variety of organic solvents, certain chemotherapeutic drugs (e.g. doxorubicin), β-blockers, Ca blockers, and antiarrhythmics. Diastolic dysfunction: (Resistance to ventricular filling not readily measurable at the bedside) accounts for 20 to 40% of cases of HF. It is generally associated with prolonged ventricular relaxation time, as measured during isovolumic relaxation (the time between aortic valve closure and mitral valve opening when ventricular pressure falls rapidly). Diastolic failure per se as a cause of AHF is rare except in setting of postoperative RV failure, e.g. Tetralogy of Fallot (TOF). High output failure is associated with a persistent high cardiac output (CO) that eventually results in ventricular dysfunction. Conditions associated with high CO include anemia, beriberi, thyrotoxicosis, pregnancy, advanced Paget’s disease, and arteriovenous fistula. AHF in such states is often reversible by treating the underlying cause. Low Output Failure This includes all causes discussed above as well as in postoperative congenital heart disease. AHF IN POSTOPERATIVE CONGENITAL HEART DISEASE Systemic Ventricular Failure The pathophysiology of postoperative AHF is based on the pathophysiology of the congenital heart defect as well as on the cardiopulmonary bypass. LV failure occurs postoperatively if the LV is subjected to volume overload, e.g. Systemic to PA shunts if the shunt is large, pulmonary atresia with remaining large aortopulmonary collaterals. Aortic regurgitation causes LV volume overload following aortic valvotomy for aortic stenosis,

ACUTE HEART FAILURE

or following VSD repair that results in distortion of aortic cusp. Postoperative mitral regurgitation can also cause LV volume overload after repair of endocardial cushion defects. LV failure also occurs due to myocardial ischemia following cardiopulmonary bypass. The risk of this depends on the duration of the aortic cross clamp time and myocardial preservation techniques. Myocardial dysfunction also occurs in d-TGA where the LV functions as the pulmonary ventricle and if surgery is delayed beyond the first month, the LV is unable to take the systemic afterload and fails. In patients with d-TGA undergoing atrial switch operation (Senning operation), the anatomic RV functions as the systemic ventricle and deterioration of the ventricle function has been reported postoperatively. RV Failure Postoperative RV failure most commonly occurs as a result of RV hypertension, e.g. in residual PA stenosis after repair of TOF, obstruction of the RV to PA conduit and acute pulmonary hypertension. Patients who have undergone Fontan procedure (cavo-pulmonary anastomosis for single ventricle complexes) often have significant RV failure in the early postoperative period. Pulmonary insufficiency especially after a pericardial patch is placed across the pulmonary valve annulus or a nonvalved RV to PA conduit is placed, is usually well tolerated but RV dysfunction if associated with pulmonary hypertension.8 In pediatrics, the age of onset of AHF is a useful guide to the underlying etiology. For the purpose of classification, the pediatric age range can be divided into three stages: Fetal development, infancy, and childhood and adolescence. In infancy the etiologies vary from birth to one year of age1,6 (Table 12.2). CLINICAL PRESENTATION Irrespective of the etiology, the first manifestation of AHF is usually sinus tachycardia. A sustained HR of more than 160 beats per min (bpm) in infants and more than 100 bpm in older children is typically seen with AHF. This represents the adaptive mechanism to increase the CO by increasing the HR when stroke volume is diminished. However, HR of more than 220 - 240 bpm in infants and 150-170 bpm in older children should raise the possibility of supraventricular tachycardia which would prove to be the underlying cause of AHF. An obvious exception to this finding occurs in AHF due to a primary bradyarrhythmia or complete heart block.9 Various clinical features are mentioned in Table 12.3. INVESTIGATIONS Diagnosis of AHF is based primarily on clinical grounds and supported by laboratory tests to define the nature of specific disease, functional status of myocardium and co-morbid features. Radiography It helps to assess cardiac size, as it is a direct evidence of cardiac enlargement. If the heart is not enlarged the diagnosis of AHF can be questioned except in few conditions like TAPVC with obstruction, constrictive pericarditis and restrictive cardiomyopathy. A cardiothoracic ratio more than 0.55 in infants and more than 0.5 in patients older than one year, on an inspiratory film suggests

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PEDIATRIC INTENSIVE CARE Table 12.2: Causes of AHF according to age at presentation

Age at presentation

Causes (by descending order of occurrence)

Fetus

Tachyarrhythmia 3° AV block Anemia Valvular insufficiency Arteriovenous malformation Premature closure of foramen ovale Fetomaternal transfusion

Neonatal

Birth asphyxia Tachyarrhythmia Large PDA Hypoplastic left heart syndrome, coarctation of aorta Obstructive TAPVC Critical aortic stenosis, Critical pulmonary stenosis Tricuspid regurgitation Truncus arteriosus Persistent pulmonary hypertension Myocarditis (coxsackie, adenovirus) Sepsis Cardiomyopathy Heart block Infant of diabetic mother Post-cardiopulmonary bypass

Infancy

Coarctation of aorta Large left to right shunts ( PDA, VSD, Atrioventricular septal defects) Common mixing lesions Tachyarrhythmias Post-cardiopulmonary bypass Anomalous left coronary artery from pulmonary artery Unobstructed TAPVC Myocarditis (coxsackie, adenovirus) Familial cardiomyopathy Pompe’s disease Carnitine deficiency Mitochondrial cardiomyopathy

More than 1 year old

Cardiomyopathy Rheumatic heart disease Congenital valve disease- MR, TR, AR sub-aortic stenosis Pulmonary atresia with large collaterals Postoperative- Tetralogy repair, Fontan, Senning, systemic to pulmonary shunts Myocarditis, endocarditis Collagen vascular disease Kawasaki’s disease Tachyarrhythmias Anemia

ACUTE HEART FAILURE Table 12.3: Pathophysiology of clinical features in acute heart failure

Symptom / sign

Pathophysiology

Tachypnea

Increase in left ventricular volume and pressure leads to increase in pulmonary venous pressure. This leads to increase in capillary permeability and accumulation of fluid in the interstitium and alveoli. Mediated by vagus nerve or J receptors in pulmonary interstitium

Dyspnea

Due to pulmonary venous congestion, Due to pulmonary edema

Wheezing

Due to compression of bronchi by dilated PA or atria Usually seen in older children

Feeding difficulty

Lack of energy to suck and tire quickly

Failure to thrive

Deficiency in calories due to poor intake and extra work of breathing causes increased metabolic demand

Irritability

Reduced O2 transport

Sweating

Increased sympathetic activity that occurs when they are challenged with eating in respiratory distress

Reduced urine output

Reduced renal perfusion

Tachycardia

Increased sympathetic activity as an adaptive mechanism to provide more O2 to tissues

Cool extremities, reduced capillary filling

Reduced tissue perfusion

Pulsus paradoxus

Due to fluctuations in CO with respiration

Increased precordial activity

Chamber dilatation or hypertrophy

Gallop sounds

Increased afterload, reduced compliance

Crepitations

Alveolar edema

Hepatomegaly and edema

Systemic venous congestion

cardiomegaly. In addition chest roentgenogram allows assessment of pulmonary venous congestion. Pulmonary venous markings are prominent in AHF as evidenced by Kerley A, B and C lines. Left lower lobe collapse due to compression of the left lower lobe bronchus by the enlarged left atrium can be seen. Pleural effusions are seen in systemic venous congestion. Pericardial effusion is suggested by globular appearance of the cardiac shadow. Parenchymal diseases can be ruled out especially coexistent pneumonia.10 Electrocardiography The electrocardiogram more often provides supportive data like ventricular hypertrophy, atrial enlargement or changes in the ST segment or T wave. ECG may also give a clue to diagnosis in certain conditions like arrhythmias, heart block, myocarditis and ALCAPA.11

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Echocardiography The echocardiogram has expanded the ability of the cardiologist to establish anatomic diagnosis, functional status and follow-up assessment of response to therapy. Two-dimensional Echo provides details of the cardiac anatomy in congenital heart disease. Assessment of regional wall motion abnormality by two-dimensional imaging helps in determining the etiology as well as response to therapy in acute heart failure. Continuous wave and color flow Doppler detects intracardiac shunting, valvular regurgitation and stenosis. They also help in calculating gradients across the stenotic lesions as well as the cardiac output. Antenatal echo can diagnose fetal AHF, which can manifest as fetal hydrops.12 Pulse Oximetry Pulse oximetry, and a hyperoxia test in newborns, may be useful. The systemic saturation on room air is a more reliable measure of oxygenation. The partial pressure of arterial oxygen (PaO2) when the patient is receiving 100% oxygen (hyperoxia test) helps in distinguishing intracardiac malformations from pulmonary disease in the setting of hypoxia.13 Blood Gas and Electrolytes In early AHF respiratory alkalosis is seen due to alveolar hyperventilation. As CO falls metabolic acidosis is usually seen. PaO2 are low due to pulmonary congestion and ventilation perfusion mismatch. Rising PaCO2 is an indicator of respiratory muscle fatigue or severe AHF whereby CO is so low that it affects cerebral perfusion leading to central hypoventilation. At this point ABG usually shows a combination of respiratory and metabolic acidosis. Plasma lactate is an important marker and can be followed up serially to determine the physiological condition as well as response to treatment.14 We use an algorithm following clinical signs and blood gas lactates serially to determine our treatment strategies (Table 12.4). Hyponatremia may be seen in AHF and reflects hemodilution due to water retention. Hyperkalemia may be associated with metabolic acidosis as well as due to reduced GFR. Hypochloremia, metabolic alkalosis and hypokalemia are usually caused by diuretic therapy and need regular electrolyte monitoring. Miscellaneous Tests Hypoglycemia has been associated with AHF in infants and hypocalcemia noted with LV failure in neonates. CPK MB and troponin I levels are supportive in detecting coronary insufficiency, myocarditis and asphyxia related AHF. Severe anemia can itself precipitate and accentuate AHF associated with any primary cardiac defect. Autoimmune disorders can be ruled out by RF, antidsDNA and ANA assays. Blood levels of carnitine, lactate and glucose help to detect mitochondrial cardiomyopathies.15 Cardiac Catheterization The need for cardiac catheterization in the evaluation of AHF has declined with the development of echocardiography. However interventional catheterization is still required to perform procedures

ACUTE HEART FAILURE Table 12.4: Algorithm for inotropic management in acute heart failure

Clinical condition

Interpretation

Treatment strategy

Tachycardia, poor pulses, cool extremities, delayed CFT, decreased urine output, low BP, lactate high

Low CO

Dopamine 10 ug/kg/min, dobutamine 10 ug/kg/min, may increase up to 15 ug/kg/min, try fluid bolus cautiously (5 ml/kg that too in aliquots, 5 ml for infants and 10 ml for children) elective ventilation

Tachycardia, poor pulses, cool extremities, CFT delayed, urine output low, BP maintained lactate high

Low CO

Add lasix infusion 0.05-0.1 mg/kg/hr Add inodilators

Tachycardia settling, good central pulses, cold extremities, urine output better, BP normal to high, lactate high

High afterload

Add milrinone

HR increases, good pulses, warm extremities, urine output decreases, BP normal to low, Lactate high

Relative hypovolemia (vasodilatation due to milrinone)

Give fluid challenge

HR increases, good pulses, cold extremities, urine output decreases, BP normal to high Lactate increases

High afterload

Increase milrinone

HR increases, low pulses, cold extremities, urine output high, BP low, Lactate increases

Hypovolemia

Give fluid bolus

HR settled, good pulses, Warm extremities, good urine output, normal BP, Normal lactate

CO optimized

Maintain same inotropic support, plan weaning and extubation

HR increases, good pulses, Warm extremities, urine output decreases, normal BP, Lactate increases

Fall in CO

Increase inotropic support, preferably milrinone

HR settled, good pulses, warm extremities, good urine output, normal BP, Normal Lactate

CO optimized

Add Digoxin, Taper IV inotropes

Tapering of inotropes • Add digoxin: Slow digitalization preferred • Once digitalization is done, taper Dopamine @ 0.1 ug/kg/min every 1-2 hours till 5 ug/kg/min. Follow the clinical signs and lactates. Tapering may have to be done slower than expected • Then taper dobutamine similar to dopamine. • Once dopamine and dobutamine have reached 5 ug/kg/min, oral vasodilator is added in the form of enalapril. First dose hypotension is to be looked for • Milrinone is decreased to half after 1st dose enalapril, and stopped after second dose • After this if hemodynamics maintained, dopamine is tapered as above and stopped followed by dobutamine

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like balloon atrial septostomy in TGA, valvotomies in stenotic lesions which help in the management of AHF. Myocardial biopsy for histological and PCR testing may be helpful in diagnosing underlying cause like myocarditis. MANAGEMENT The goal in management of AHF is to optimize the CO so as to meet the metabolic demands adequately.16 The goals are defined based on the pathophysiology of AHF and include: • Optimizing preload: Relief of pulmonary and systemic congestion • Increasing in myocardial performance • Optimizing the afterload • Optimizing the HR • Improving the oxygen carrying capacity of the blood • Removing the underlying cause. Optimize Preload This requires restriction of fluids (2/3 maintenance) as well as pharmacological therapy in the form of diuretics. Diuretics are used mainly to relieve the systemic and pulmonary congestion. Major diuretics used are loop diuretics, thiazides and aldosterone antagonists. These act directly on kidneys to inhibit solute and water reabsorption thereby promoting excretion of excess salt and water. Furosemide is the drug of choice in acute AHF. It has a rapid onset of action (2-5 min) as well as duration of action (3 hours). It can also be used as a continuous infusion in which case the hemodynamic instability and electrolyte disturbances are less. Side effects of furosemide include hypokalemia, metabolic alkalosis, hyponatremia and hyperuricemia. Ototoxicity has been reported rarely in children and is usually reversible.17-22 Thiazides have a slower onset of action and are available in oral form so their use in AHF is limited. They are commonly used for chronic CCF and are beyond the scope of this chapter. The aldosterone antagonist spironolactone is a weak diuretic and is rarely used alone as a diuretic. It is usually added to loop diuretics or thiazides to antagonize their kaliuretic action. It is given orally and the onset of action takes 2-3 days. Increase in Myocardial Performance Inotropes are the mainstay of treatment to optimize the CO.23 Initially precise control of blood pressures require inotropes as continuous infusions like dopamine and dobutamine and later oral inotropes in the form of digoxin can be added. Dopamine It is useful in AHF, especially in postoperative low cardiac output. It has β1 adrenergic and dopaminergic effects in lower doses and α adrenergic at higher doses. It is given as continuous infusion. Dose of 3-5 μg/kg/min has best dopaminergic action, improving renal flow and natriuresis. Dose of 5-15 μg/kg has inotropic effect and increases myocardial contractility. However, doses above 15 μg/kg/min lead to severe vasoconstriction, compromising renal flow, increasing systemic vascular resistance and LV afterload. It should not be combined with soda bicarbonate infusion.24,25

ACUTE HEART FAILURE

Dobutamine Dobutamine is a synthetically altered catecholamine with powerful inotropic effects, moderate chronotropy and vasodilatation. It differs from dopamine by its dominant action on β1 receptors and by not depending on norepinephrine stores to produce the desired effects. It causes inotropy with vasodilatation and thus increases the CO. The benefit over dopamine is that it does not increase the myocardial oxygen demand, is less arrhythmogenic and reduces the systemic resistance with minimal alteration of blood pressure and HR. Dobutamine does not stimulate the dopaminergic receptors and so does not alter renal blood flow.26-29 Epinephrine Has mixed β and α effects. It may improve CO in acute AHF and in postoperative situations with inotropic effect. Its use in AHF has gone down as it causes intense vasoconstriction and markedly increases the afterload. It can be arrhythmogenic by its excessive chronotropic action and causes down regulation of β receptors on long-term use. It should be given as short-term treatment for patients unresponsive to other inotropes.23 Isoproterenol Isoproterenol is a sympathomimetic amine and a pure β adrenergic agonist. By its β1 and β2 effects isoproterenol augments myocardial contractility and HR along with vasodilatation. Despite reducing afterload, it increases ventricular oxygen demand by its positive inotropic and chronotropic effects. It is useful in AHF complicated by increased reactive pulmonary vascular resistance or complete heart block. Its use is often limited by tachycardia.23 Inodilators Phosphodiesterase III inhibitors amrinone and milrinone are bipyridine derivatives. They increase cAMP by inhibiting phosphodiesterase III, an enzyme that reduces adenylcyclase activity.30, 31 These are potent vasodilators and inotropes. These are commonly used in low CO states as they optimize CO by altering afterload. Onset of action is slower than adrenergic agents so they require a loading dose to achieve full effect.32 In view of its vasodilating effects, blood pressure is to be monitored frequently and intravascular volume to be adequate. Milrinone is free of harmful side effects than amrinone. Side effects of amrinone include hypotension, ventricular ectopy and thrombocytopenia. Amrinone is used less frequently due to its long half-life.33-37 Vasodilators Vasodilators (Sodium nitroprusside and Nitroglycerine) are not an important modality for treatment of AHF in children. They play a vital role in management of postoperative low CO, severe atrioventricular valve regurgitation and dilated cardiomyopathy. They cause vasodilatation and reduce afterload by their direct action on the vascular smooth muscle and have no direct cardiac or renal effects.38, 39

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Digoxin Digoxin is the most widely used and studied drug. Mechanism of action is inhibition of sarcolemmal Na+K+-ATPase activity leading to increased intracellular calcium and hence increases ventricular contractility. It slows HR and conduction by blocking the AV node. Major indication in AHF is to improve myocardial contractility. It is also useful in treating fetal AHF induced by tachycardia. Anorexia, nausea, vomiting, visual disturbances, atrioventricular block and dysrrhythmias are the common side effects. Dose should be adjusted in the presence of hypokalemia, renal dysfunction and when combined with quinidine, verapamil and amiodarone.40, 41 ACE Inhibitors These are competitive inhibitors of angiotensin converting enzyme and reduce the production of vasoconstricting hormone angiotensin II. They also inhibit the breakdown of bradykinin, a potent vasodilator. Thus they cause vasodilatation, reduce afterload, increase renal blood and cause diuresis. ACE inhibitors are used to wean off intravenous inodilators. Captopril, the first known ACE inhibitor, is well tolerated. Side effects include rashes, taste impairment, mild GI disturbances and neutropenia. Potassium supplementation should be avoided to prevent hyperkalemia. Enalapril is a newer agent with the advantage of less frequent dosing. Blood pressure, renal function and neutrophil count should be monitored.42, 43 Beta-blockers Beta-blockers are not used in AHF in children but are worth mentioning. They are widely used nowadays in adults as it improves cardiac performance without increasing O2 consumption and enhances ventricular relaxation. The mechanism is by counteracting the deleterious effects of increased sympathetic activity. Up-regulation of β receptors have been described in patients on beta-blockers. Selective β blockers as metoprolol and carvedilol are more promising.44-47 RECENT ADVANCES Levosimendan Calcium sensitizers are a new class of inotropes that share the in vitro properties of calcium sensitization and phosphodiesterase inhibition. Levosimendan is a distinct calcium sensitizer, as it stabilizes the interaction between calcium and troponin C by binding to troponin C in a calciumdependent manner. It improves inotropy without adversely affecting lusitropy. It also exerts vasodilatory effects, possibly through activation of several potassium channels. Unlike conventional inotropes, levosimendan is not associated with significant increases in myocardial oxygen consumption, proarrhythmia, or neurohumoral activation.48 In large, well controlled trials in patients with decompensated heart failure, intravenous levosimendan was significantly more effective than placebo or dobutamine for overall hemodynamic response rate (primary endpoint). Significant benefits were also seen for mortality (versus placebo or dobutamine).49 The pharmacokinetic profile of levosimendan in children with congenital heart disease is similar to that in adult patients with congestive heart failure.50, 51

ACUTE HEART FAILURE

Neseritide B-type natriuretic peptide (BNP) is an endogenous cardiac neurohormone, produced in the ventricles in response to pressure and volume elevation. Neseritide is identical to endogenous BNP and serves to compensate for deteriorating cardiac function causing preload and afterload reductions, natriuresis, diuresis, suppression of the renin-angiotensin-aldosterone system, and lowering of norepinephrine. Based on its unique pharmacologic profile, neseritide results in clinically significant balanced vasodilatation of arteries and veins, and may be well suited for patients presenting with decompensated heart failure usually due to volume overload. In clinical trials, neseritide has been shown to decrease pulmonary capillary wedge pressure, pulmonary artery pressure, right atrial pressure, and systemic vascular resistance, as well as increase cardiac index and stroke volume index. HR variability also improved with neseritide.52 Experience with neseritide in pediatrics is limited though it has shown promising results (Table 12.5).53-55 MECHANICAL AFTERLOAD REDUCTION Intra-aortic Balloon Pump (IABP) Intra-aortic balloon counter pulsation provides circulatory support by decreasing left ventricular afterload during systole and augmenting aortic perfusion pressure during diastole. This is achieved by repetitive cycle synchronized pneumatic inflation and deflation of a catheter mounted balloon placed in the thoracic aorta. Before the onset of systole, the balloon is deflated thus reducing left ventricular afterload. Inflation of the balloon occurs immediately after the closure of the aortic valve thereby increasing aortic perfusion. This results in better myocardial perfusion during diastole. Cardiac output increases which results in increase in perfusion pressure in cerebral and renal vascular beds.56, 57 IABP has not been used widely as analogous clinical settings are few in children unlike adults and due to technical problems related to catheter size. They might be useful in coronary artery disease as in Kawasaki or ALCAPA and in postoperative setting with reduced cardiac output that is refractory to medical management. Technical obstacles in children include rapid heart rates, more compliant aortas, small femoral arteries and aortic collaterals that tend to make IABP less effective and more problematic.58 ECMO (Extracorporeal Membrane Oxygenation) Pediatric experience is in infants in postoperative state as a bridge before transplant.59, 60 VAD (Ventricular Assist Device) VAD is in developmental stages in children. It can be used as a bridge to transplant or in difficulty in weaning from bypass. The newly developed pulsatile, paracorporeal ventricular assist devices designed for long-term assist in children have demonstrated their ability to provide excellent results beyond the abilities of extracorporeal membrane oxygenation and centrifugal pumps, which are still the mainstay of mechanical support in children worldwide.60

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PEDIATRIC INTENSIVE CARE Table 12.5: Drug doses Diuretics Furosemide 0.5-1mg/kg/dose, max 2 mg/kg/dose IV, qid/bd; 0.05 mg/kg/hour infusion, Chlorthiazide 1-4 mg/kg/dose IV bd, 20-40 mg/kg/day PO bd Metolazone 0.2-0.4 mg/kg/day PO qd Spironolactone 1-3.5 mg/kg/day PO qd/bd Ionotropes Dopamine 2-20 μg/kg/min as infusion Dobutamine 2-20 μg/kg/min as infusion Adrenergic agent Epinephrine 0.05-1 μg/kg/min Norepinephrine 0.05-1 μg/kg/min Isoproterenol 0.05-1 μg/kg/min inotropic, 0.01-0.05 μg/kg/min for bradycardia Digoxin Term infant Infants < 2 years Child > 2 years

Total digitalization dose 30 ug/kg 30-40 ug/kg 40 ug/kg

Maintenance dose 8-10 ug/kg 10 ug/kg 10 ug/kg

For rapid digitalization ½ of loading dose is given initially, ¼ 6-12 hours later and remaining ¼ 24 hours after the first dose. Half-life of digoxin is 20 hours in infants and 40 hours in older children. PDEIII inhibitors Amrinone 0.75 mg/kg loading dose × 3 times, over 15 min each, then 5-10 ug/kg/min infusion Milrinone 50 ug/kg loading dose IV over 15-30 min, followed by 0.25-0.75 μg/kg/min infusion Vasodilators Sodium nitroprusside 0.5-8 μg/kg/min IV infusion (needs titration) Nitroglycerine 0.5-5 μg/kg/min IV infusion (needs titration) Prazosin 0.01-0.05 mg/kg/dose PO q tid, max dose 0.1 mg/kg ACE inhibitors Captopril 0.1-0.5 mg/kg/dose PO tid, upto 4 mg/kg/day Enalapril 0.1-0.4 mg/kg/day PO qd/bd Beta-blocker Atenolol 1-2 mg/kg/day PO qd Carvedilol 0.05 mg/kg/dose PO bd/tid, upto 0.5 mg/kg/dose Metoprolol 1-2 mg/kg/dose PO bd Esmolol 100-500 μg/kg IV loading dose in 1-2 min, 50-500 μg/kg/min infusion Miscellaneous drugs PGE1 0.05-0.1 μg/kg/min infusion Carnitine 20-35 mg/kg/dose PO tid Morphine 40 ug/kg loading followed by 40-80 ug/kg/hr as infusion Fentanyl 2 ug/kg loading followed by 1-5 ug/kg/hr as infusion Vecuronium 0.1 mg/kg prn, duration of action 45 min, no cardiovascular effects

ACUTE HEART FAILURE

Adjunctive Therapy

Position Semi-Fowler position either by cardiac chair or elevating head and shoulders to an angle of 45° improves pulmonary function by easing respiration and reducing pulmonary pooling.

Oxygen O2 through mask or nasal prongs with adequate humidification helps to loosen secretions and improve oxygenation. Caution must be applied for duct dependent lesions in neonatal period.

Positive Pressure Ventilation Patients in AHF usually are in severe respiratory distress, which add to the metabolic demands of the myocardium. Hence artificial ventilation and sedating and paralyzing the patient help to reduce the workload of the myocardium. Ventilation helps the myocardium by improving the oxygenation as well as in the cardiac physiology. Ventilatory rate and tidal volume are adjusted as per the age and according to the PCO2 levels. PEEP has both beneficial and detrimental effects on the heart depending on whether the AHF is primarily right sided or left sided. In RV failure PEEP increases the afterload on the RV by increasing the intra-alveolar pressures and compressing the pulmonary vascular bed thereby increasing the pulmonary vascular resistance. In LV failure PEEP helps by optimizing the preload to the LV and thereby improving the LV end diastolic volume. PEEP also helps by opening up the alveoli collapsed due to edema and thus improving the ventilation perfusion mismatch.61, 62 Weaning for AHF patients should be planned once the cardiac output has been optimized and the end organ damage has been reversed: warm peripheries, good urine output, good bowel sounds and normal lactates. The patient should be monitored during weaning for any increase in respiratory distress, decrease in peripheral temperatures and increase in lactates or fall in urine output. Accordingly the weaning process and extubation should be done. The inotropic support should not be changed prior to weaning.

PGE1 PGE1 is useful to maintain the ductal patency in duct dependent pulmonary and systemic circulations like TGA, Tricuspid atresia, HLHS to maintain pulmonary and systemic blood flow.

Diet Adequate calories and protein are required to meet the increased metabolic needs. Caloric requirement may be upto 130-170Cal/kg/day in infants. Nasogastric tube feeds help by saving the energy used in feeding in severely symptomatic children.63 Treatment of Underlying Condition Transcatheter interventions may have to be carried out in patients with frank AHF to treat underlying defects like critical aortic stenosis or CoA. Early surgical correction of large left to right shunts has to be planned after initial stabilization. Control of infection, anemia, arrhythmias, hypertension

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and metabolic deficiencies can help to control AHF early. Intravenous immunoglobulin has been proved to be useful in myocarditis. Role of steroids in rheumatic heart disease with AHF may be lifesaving but controversial. Treating the mother antenatally with digoxin helps to control supraventricular tachycardia causing failure in the fetus. The final option for end stage failure would be cardiac transplant.64 Predictors of Mortality Degree of functional capacity, ventricular function, ventricular arrhythmias and neurohumoral activities has predictive value over 1-5 years period. Most patients with clinically manifest failure progress to death within 10 years if the underlying condition is not treatable, despite the recent advances in the management. CONCLUSION Improvements in therapy of AHF are possible with increasing knowledge in pathophysiology of AHF and newer therapeutic measures based on these. Therapies under trial like gene therapy and stem cell transfer may give more promising results in future. REFERENCES 1. O’Laughlin MP. Congestive heart failure in children. Pediatr Clin North Am 1999;46(2):263-73. 2. Artman M, Graham TP. Congestive heart failure in infancy: Recognition and management. Am Heart J 1982; 103(6): 1040-55. 3. Artman M, Parrish MD, Graham TP. Congestive heart failure in children and adolescence: Recognition and management. Am Heart J 1983;105(3):471-80. 4. Freed MD. Congestive heart failure. In: Nadas’ Pediatric Cardiology 1994;63-72. 5. Packer M. The neurohumoral hypothesis: A theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol 1992;20:248-54. 6. Talner NS. Heart failure. In: Emmanouilides GC, Riemenschneider TA, Allen HD, Gutgessel HP, (Eds). Moss and Adams’ heart disease in infants, children and adolescents, including the fetus and young adult. 5th ed. Baltimore: Williams and Wilkins, 1995. 7. Erickson LC. Medical issues for the cardiac patient. In: Critical Care of Infants and Children. 1996;259-62. 8. Sanders SP, et al. Clinical and hemodynamic results of the Fontan operation for tricuspid atresia. Am J Cardiol 1982;49(7):1733-40. 9. Erickson LC. Congestive heart failure in Current Pediatric Therapy. Burg FD, Polin RA, Ingelfinger JR, Wald ER (Eds). Philadelphia, Pa: WB Saunders 1997;16. 10. Crowley JJ, Oh KS, Newman B, et al. Telltale signs of congenital heart disease. Radiol Clin North Am 1993;31(3): 573-82. 11. Johnsrude CL, Perry JC, Cecchin F, et al. Differentiating anomalous left main coronary artery originating from the pulmonary artery in infants from myocarditis and dilated cardiomyopathy by electrocardiogram. Am J Cardiol 1995; 75:71-4. 12. Colan SD, Borow KM, Neumann A. Left ventricular end systolic wall stress velocity of fibre shortening relation: a load independent index of myocardial contractility. J Am Coll Cardiol 1984;4:715-24. 13. Macnab AJ, Baker-Brown G, Anderson EE. Oximetry in children recovering from deep hypothermia for cardiac surgery. Crit Care Med 1990;18:1066-9. 14. Talner NS, et al. Congestive heart failure in infancy. 1: Abnormalities in blood gases and acid base equilibrium. Pediatrics 1965;35:20-6. 15. Benzing G III, Schubert W, Hug G, Kaplan S. Simultaneous hypoglycemia and acute congestive heart failure. Circulation 1969;40:209-11. 16. Balaguru D, Artman M, Auslender M. Management of Heart Failure in Children. Curr Probl Pediatr 2000;30:5-30. 17. Bailie MD, Linshaw MA, Stygles VG. Diuretic pharmacology in infants and children. Pediatr Clin North Am 1981; 28:217-29.

ACUTE HEART FAILURE 18. Singh NC, Kissoon N, al Mofada S, Bennett M, Bohn DJ. Comparison of continuous versus intermittent furosemide administration in postoperative pediatric cardiac patients. Crit Care Med 1992;20(1):17-21. 19. Luciani GB, Nichani S, Chang AC, Wells WJ, Newth CJ, Starnes VA. Continuous versus intermittent furosemide infusion in critically ill infants after open heart operations. Ann Thorac Surg 1997;64(4):1133-9. 20. Klinge JM, Scharf J, Hofbeck M, Gerling S, Bonakdar S, Singer H. Intermittent administration of furosemide versus continuous infusion in the postoperative management of children following open heart surgery. Intensive Care Med 1997;23(6):693-7. 21. Van der Vorst MM, Ruys-Dudok van Heel I, Kist-van Holthe JE, den Hartigh J, Schoemaker RC, Cohen AF, et al. Continuous intravenous furosemide in haemodynamically unstable children after cardiac surgery. Intensive Care Med 2001;27(4):711-5. 22. Salvador DR, Rey NR, Ramos GC, Punzalan FE. Continuous infusion versus bolus injection of loop diuretics in congestive heart failure. Cochrane Database Syst Rev 2005;20(3):CD003178. 23. Scholz H. Inotropic drugs and their mechanism of action. J Am Coll Cardiol 1984;4:389-98. 24. Eldadah MK, Schwartz PH, Harrison R, Newth CJ. Pharmacokinetics of dopamine in infants and children. Crit Care Med 1991;19(8):1008-11. 25. Watarida S, Shiraishi S, Sugita T, Katsuyama K, Nakajima Y, Yamamoto R, et al. Effects of docarpamine on hemodynamics after open heart surgery in children. Ann Thorac Cardiovasc Surg 2000;6(2):106-9. 26. Colluci WS, Wright RF, Braunwald E. New inotropic agents in the treatment of congestive heart failure. New Engl J Med 1986;314:349-55. 27. Dricoll DJ. Hemodynamic effects of dobutamine in children. Am J Cardiol 1979;43:581-90. 28. Habib DM, Padbury JF, Anas NG. Dobutamine pharmacokinetics and pharmacodynamics in pediatric intensive care patients. Crit Care Med 1992;20(5):601-8. 29. Berg RA, Donnerstein RL. Dobutamine infusions in stable, critically ill children: Pharmacokinetics and hemodynamic actions. Crit Care Med 1993;21(5):678-86. 30. Alousi AA, Johnson DC. Pharmacology of bipyridines: Amrinone and milrinone. Circulation 1986;73:10-21. 31. Edelson J. Pharmacokinetics of bipyridines: Amrinone and milrinone. Circulation 1986;73:145-55. 32. Laitinen P, Ahonen J, Olkkola KT, Peltola K, Rautiainen P, Rasanen J. Pharmacokinetics of amrinone in neonates and infants. J Cardiothorac Vasc Anesth 2000;14(4):365-6. 33. Ramamoorthy C, Anderson GD, et al. Pharmacokinetics and side effects of milrinone in infants and children after open heart surgery. Anesth Analg 1998;86(2):283-9. 34. Bailey JM, Miller BE, Lu W, et al. The pharmacokinetics of milrinone in pediatric patients after cardiac surgery. Anesthesiology 1999;90(4):1012-8. 35. Teshima H, Tobita K, Yamamura H, Takeda A, Motomura H, Nakazawa M. Cardiovascular effects of a phosphodiesterase III inhibitor, amrinone, in infants: Non-invasive echocardiographic evaluation. Pediatr Int 2002; 44(3):259-63. 36. Hoffman TM, Wernovsky G, Atz AM, Bailey JM, Akbary A, Kocsis JF, et al. Prophylactic intravenous use of milrinone after cardiac operation in pediatrics (PRIMACORP) study. Prophylactic Intravenous Use of Milrinone After Cardiac Operation in Pediatrics. Am Heart J 2002;143(1):15-21. 37. Hoffman TM, Wernovsky G, Atz AM, Kulik TJ, Nelson DP, Chang AC, et al. Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation 2003;107(7):996-1002. 38. Friedman WF, George BL. Treatment of congestive heart failure by altering loading conditions of the heart. J Pediatr 1985;106(5):697-706. 39. Zeng H, Sun L, Li W, Du J. Effect of intravenous nitroglycerin on hemodynamics in infants and children with congestive heart failure. Chin Med J (Engl) 2000;113(4):328-31. 40. Alpert BS, Barfield JA. Reappraisal of digitalis in infants with left to right shunts and heart failure. J Pediatr 1985; 106(1):66-8. 41. Lares-Asseff I, Juarez-Olguin H, Flores-Perez J, Bobadilla-Chavez J. Pharmacokinetics of digoxin in children with congestive heart failure aggravated by other diseases. Rev Invest Clin 2004;56(1):32-7. 42. Artman M, Graham TP Jr. Guidelines for vasodilator therapy of congestive heart failure in infants and children. Am Heart J 1987;113(4):994-1005. 43. The CONSENSUS Trial Study Group. Effects of Enalapril on mortality in severe congestive heart failure. New Eng J Med 1987;316:1429-35. 44. Shaddy RE, et al. The Pediatric Randomized Carvedilol Trial in Children with Heart Failure: Rationale and design. Am Heart J 2002;144(3):383-9. 45. Shaddy RE. Beta-blocker therapy in young children with congestive heart failure under consideration for heart transplantation. Am Heart J 1998;136(1):4-5.

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PEDIATRIC INTENSIVE CARE 46. Metra M, Giubbini R, Nodari S. Differential effects of beta-blockers in patients with congestive heart failure: Prospective, randomized, double-blinded comparison of long term effects of metoprolol vs carvedilol. Circulation 2000;102:54651. 47. Giardini A, Formigari R, Bronzetti G, Prandstraller D, Donti A, Bonvicini M, et al. Modulation of neurohormonal activity after treatment of children in heart failure with carvedilol. Cardiol Young 2003;13(4):333-6. 48. Ng TM. Levosimendan, a new calcium-sensitizing inotrope for heart failure. Pharmacotherapy 2004;24(10):1366-84. 49. Mebazaa A, Erhardt L. Levosimendan: A new dual-action drug in the treatment of acute heart failure. Int J Clin Pract 2003;57(5):410-6. 50. Nieminen MS. Levosimendan compared with dobutamine in low output patients. Minerva Anestesiol 2003;69(4): 258-63. 51. Turanlahti M, Boldt T, Palkama T, Antila S, Lehtonen L, Pesonen E. Pharmacokinetics of levosimendan in pediatric patients evaluated for cardiac surgery. Pediatr Crit Care Med 2004;5(5):457-62. 52. Burger AJ, Burger MR. Nesiritide: Past, present, and future. Minerva Cardioangiol 2005;53(6):509-22. 53. Mahle WT, Cuadrado AR, Kirshbom PM, Kanter KR, Simsic JM. Nesiritide in infants and children with congestive heart failure. Pediatr Crit Care Med 2005;6(5):543-6. 54. Marshall J, Berkenbosch JW, Russo P, Tobias JD. Preliminary experience with nesiritide in the pediatric population. J Intensive Care Med 2004;19(3):164-70. 55. Simsic JM, Scheurer M, Tobias JD, Berkenbosch J, Schechter W, Madera F, et al. Perioperative effects and safety of neseritide following cardiac surgery in children. J Intensive Care Med 2006;21(1):22-6. 56. Polock JC. Intra-aortic balloon pumping in children. Ann Thorac Surg 1980;29:522-41. 57. Veasy LG, Blalock RC, Orth JK, Boucek MM. Intra-aortic balloon pumping in infants and children. Circulation 1983; 68:1095-1107. 58. Park JK, Hsu DT, Gersony WM. Intra-aortic balloon pump management of refractory congestive heart failure in children. Pediatr Cardiol 1993;14(1):19-22. 59. Raithel SC, Pennington G, Boegner E, Fiore A, Weber TR. Extracorporeal membrane oxygenation in children after cardiac surgery. Circulation 1992;86(5 Suppl):II305-10. 60. Deiwick M, Hoffmeier A, Tjan TD, Krasemann T, Schmid C, Scheld HH. Heart failure in children - mechanical assistance. Thorac Cardiovasc Surg 2005;53(Suppl 2):S135-40. 61. Robotham JL, Lixfeld W, Holland L, MacGregor D, Bromberger-Barnea B, Permutt S, et al. The effects of PEEP on right and left ventricular performance. Am Rev Respir Dis 1980;121:677-83. 62. Robotham JL, Cherry D, Mitzner W, Rabson JL, Lixfeld W, Bromberger-Barnea B. A re-evaluation of hemodynamic consequences of intermittent positive pressure ventilation. Crit Care Med 1983;11:783-93. 63. Schwartz SM, Gewitz MH, See CC, et al. Enteral nutrition in infants with congenital heart disease and growth failure. Pediatrics 1990;86(3):368-73. 64. Ward KE, Mullins CE, Huhta JC, et al. Restrictive interatrial communication in total anomalous pulmonary venous connection. Am J Cardiol 1986;53(13):1131-6.

Suresh Gupta 151 INTENSIVE CARE AND EMERGENCY ROOM MANAGEMENT OF ARRHYTHMIA IN CHILDREN

13

Intensive Care and Emergency Room Management of Arrhythmia in Children

INTRODUCTION Disturbances of rate and rhythm of heart are not uncommon problems in children. The pediatricians working in emergency or intensive care settings are more likely to encounter these kinds of problems. Arrhythmias can occur in a normal heart or a diseased heart. The rhythm disturbances can be transient or permanent. The severity of arrhythmias may vary from absolutely asymptomatic to life threatening. The major risks associated with arrhythmias are syncope, shock and death from compromised cardiac output. It is important to recognize and differentiate normal rhythm disturbances from pathological disturbances to avoid unnecessary interventions. Normal rhythm disturbances include sinus arrhythmia, sinus bradycardia and extrasystoles. For emergency management point of view, the pathologic disturbances of rate and rhythm are best divided into those that cause rapid heart rates (tachyarrhythmias) and those that generate slow heart rates (bradyarrhythmias). A detailed description of individual arrhythmias is beyond the scope of this chapter but is available in scientific literature.1,2 NORMAL RHYTHM DISTURBANCES Sinus Arrhythmia It refers to the normal variation in sinus heart rate that occurs with respiration. It should not be confused with a significant rhythm disorder. During respiration, there is a normal slowing of the heart rate in expiration and acceleration during inspiration. This variation may be more pronounced in children. The sinus arrhythmia is characterized by normal P waves followed by normal P-R intervals and normal QRS complexes. The only variation that will be seen is the lengthening and shortening of the interval between systoles.

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Sinus Bradycardia In sinus bradycardia there is slowing of the impulses originating from the sinus node. This can be seen normally in many healthy individuals and athletes, but it also occurs during disease states such as hypothyroidism. Sinus bradycardia is characterized by a heart rate less than 2 standard deviation below the mean for a given age along with normal P waves, normal P-R intervals, and normal QRS complexes. Extrasystoles These are common phenomenons that are produced by electrical discharge from an ectopic focus anywhere in the myocardium. These are classified as premature atrial complexes or premature ventricular complexes depending on the site of ectopic focus. These are generally of no clinical or prognostic significance. Premature atrial complexes: These are characterized by appearance of an abnormally located P wave that has morphology different from the regularly recurring sinus P waves. These may occur in the normal or diseased myocardium. Premature ventricular complexes (PVCs): PVCs are categorized by QRS complexes that are premature, wide, bizarre and not preceded by a P wave. These are common in healthy children and adolescent. These are generally infrequent and disappear with exercise or tachycardia. PVCs need investigation only if these are: i. Sequential ventricular depolarization occurring without intervening sinus beats ii. Multi-focal in origin iii. Increasing with exercise iv. Interfering with normal repolarization (R on T phenomenon) v. Associated with underlying heart disease vi. Creating marked anxiety from the awareness of PVCs. PATHOLOGICAL RHYTHM DISTURBANCES The main aim of this section is to highlight clinical and managerial issues that are important in emergency and intensive care settings. This chapter describes simple and broad categorization of arrhythmias that will help the pediatricians to do quick assessment and management in emergency settings. Most of the cardiopulmonary arrests in children are due to progression of respiratory failure and shock rather than primary cardiac arrhythmias. High risk for arrhythmias is associated with severe electrolyte disturbances, myocarditis, drug intoxications, underlying congenital or acquired heart disease, prolonged QT syndromes etc.3-5 In acute care settings, the pediatric cardiac rhythm disturbances can be classified according to their effect on central pulses: i) Fast pulse rate (tachyarrhythmias), ii) Slow pulse rate (bradyarrhythmias), and iii) Absent pulse (collapse rhythm).

INTENSIVE CARE AND EMERGENCY ROOM MANAGEMENT OF ARRHYTHMIA IN CHILDREN

TACHYARRHYTHMIAS The tachyarrhythmias may be classified into those that are supraventricular in origin and those that are ventricular in origin. Examining the morphology of QRS complexes can do this. If the QRS complexes are normal and narrow, tachyarrhythmia is supraventricular in origin. If the QRS complexes are wide and bizarre, the tachyarrhythmia may be ventricular in origin or supraventricular in origin with aberrant conduction through the ventricular system.6 The tachyarrhythmias include sinus tachycardia, atrial tachycardia (supraventricular tachycardia), atrial fibrillation, atrial flutter and ventricular tachycardia. Hyperdynamic Cardiac Activity (Sinus Tachycardia) Increased heart rate and contractility are physiologic responses to catecholamine release. Catecholamine release may occur with stress or anxiety, exercise, fever or infection, pain, anemia, seizure, hypovolemia, hypoxia, drugs or medications/stimulants (e.g., amphetamines, cocaine, caffeine, ephedrine, antihistamines, phenothiazines, antidepressants, tobacco, theophylline, general anesthesia), vasodilatation (e.g. anaphylaxis), oncologic mass (pheochromocytoma, neuroblastoma), hypoglycemia, hyperthyroidism, or acidosis. True Arrhythmias (Supraventricular and Ventricular Tachycardias)

Supraventricular Tachycardia (Fig. 13.1)

7,8

It is the most common symptomatic arrhythmia in children. Electrocardiographically, SVT usually appears as a narrow complex tachycardia with or without obvious P waves preceding or following the QRS complexes. On rare occasions (e.g. conduction delay or antegrade conduction through an accessory pathway from the atria to the ventricle), SVT appears as a wide complex tachycardia. For practical reasons, all wide complex tachycardias should be considered ventricular tachycardia until proven otherwise. SVT can be initiated by a reentry, automatic, or trigger mechanism.

Fig. 13.1: Supraventricular tachycardia: Showing response after Adenosine administration

a. Reentry: It is the most common mechanism for tachycardia in children. A single impulse enters a closed circuit through which it conducts more than once. A reentry circuit may be small (a few atrial cells) or large and involve the AV node and an accessory pathway. Reentry can be started and stopped by stimulation and terminated by cardioversion. Examples of reentry tachycardia are: i. AV reentry, e.g. Wolff-Parkinson-White syndrome (WPW)

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ii. iii. iv. v.

AV node reentry. Atrial reentry. Persistent junctional reciprocating tachycardia (PJRT). Sinus node reentry.

b. Automaticity: It is spontaneous self-excitation. It normally occurs only in pacemaker cells (sinus node and AV node) and is manifested by spontaneous diastolic depolarization. With cellular injury or ischemia, spontaneous diastolic depolarization develops in non-pacemaker cells causing arrhythmia. Unlike reentry, this arrhythmia cannot be started or stopped by stimulation, and is not responsive to cardioversion. Examples of automatic tachycardia are: i. Atrial ectopic tachycardia (AET). ii. Junctional ectopic tachycardia (JET). c. Triggered: Triggered activity has some features of both reentry and automaticity. The clinical significance of triggered activity is not clear, but it is used to explain a few ventricular tachyarrhythmias such as “torsades de pointes” and digitalis toxic arrhythmia. Atrial Fibrillation and Atrial Flutter (Figs 13.2 and 13.3) These are most commonly found in diseased heart. These are frequently seen in children with large stretched atria resulting from diseases or surgical repair such as Ebstein anomaly, mitral regurgitation, or following Fontan procedure. The other causes include drugs, Wolff-Parkinson-White syndrome (WPW) and hyperthyroidism. In atrial fibrillation, the atrial excitement is irregularly irregular with an atrial rate of 300-500/ min and a ventricular rate of 120-180/min. The P waves are variable and abnormal. On the other hand atrial flutter is either regular or regularly irregular. The atrial rate is 250-400/min with ventricular rate of 100-320/min. The P waves are in saw-toothed pattern. In both the atrial fibrillation and atrial flutter, the QRS complexes are either normal or prolonged depending on aberrant conduction.

Fig. 13.2: Atrial fibrillation with rapid ventricular response

INTENSIVE CARE AND EMERGENCY ROOM MANAGEMENT OF ARRHYTHMIA IN CHILDREN

Fig. 13.3: Atrial flutter

Junctional ectopic tachycardia (JET) is characterized by rapid heart rate for a person’s age that is driven by a focus with abnormal automaticity within or immediately adjacent to the atrioventricular (AV) junction of the cardiac conduction system (i.e. AV node–His bundle complex). It does not have the features associated with reentrant tachycardia (e.g. AV node reentry) because this tachycardia does not respond to a single extrastimulus and does not convert with programmed stimulation or cardioversion, it may (or may not) have ventriculoatrial (VA) dissociation, and administration of adenosine results in VA dissociation without termination. JET primarily occurs in 2 forms: idiopathic chronic junctional ectopic tachycardia is observed in the setting of a structurally normal heart, and transient postoperative junctional ectopic tachycardia occurs following repair of congenital heart disease. In addition, nonparoxysmal junctional tachycardia, which is a related but rare pattern of arrhythmia, can be observed in the setting of digoxin toxicity. Ventricular Tachycardia (VT) (Fig. 13.4)9,10 The ECG characteristics of ventricular tachycardia include a ventricular rate of at least 120/min, wide QRS (>0.08 secs), P waves not identifiable and when present, may not be related to QRS complexes (AV dissociation), and T waves opposite in polarity to QRS complexes. SVT with aberrant conduction may look like VT aberrant conduction is present in less than 10% of children with SVT. The ventricular tachycardia is relatively organized: it can be sustained (>30 sec) or non-sustained (0.08 second (wide-complex tachycardia).

INTENSIVE CARE AND EMERGENCY ROOM MANAGEMENT OF ARRHYTHMIA IN CHILDREN

Narrow-Complex (5 mL of normal saline filled in the second syringe.

Electrical (Synchronized) Cardioversion If the patient is very unstable or IV access is not readily available, provide electrical (synchronized) cardioversion. Consider sedation if possible but don’t delay cardioversion. Start with a dose of 0.5 to 1 J/kg and if unsuccessful, repeat using a dose of 2 J/kg. If a second shock is unsuccessful or the tachycardia recurs quickly, consider antiarrhythmic therapy (amiodarone or procainamide) before a third shock.

Other Antiarrhythmic Drugs Consider amiodarone or procainamide for SVT unresponsive to vagal maneuvers and adenosine. Use extreme caution when administering more than one drug that causes QT prolongation (e.g. amiodarone and procainamide). Consider obtaining expert pediatric cardiologist consultation. Give an infusion of amiodarone or procainamide slowly (over several minutes to an hour), depending on the urgency, while one monitor the ECG and blood pressure. If there is no effect and there are no signs of toxicity, give additional doses if required. Do not use verapamil in infants because it may cause refractory hypotension and cardiac arrest and use with caution in children because it may cause hypotension and myocardial depression. Wide-Complex (>0.08 Second) Tachycardia Wide-complex tachycardia with poor perfusion is probably ventricular in origin but can also be supraventricular with aberrancy.6

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Electrical (Synchronized) Cardioversion Treatment of wide complex tachycardia with palpable pulses is also synchronized electrical cardioversion (0.5 J to 1 J/kg). If it does not delay cardioversion, try a dose of adenosine first to determine if the rhythm is SVT with aberrant conduction. If a second shock (2 J/kg) is unsuccessful or if the tachycardia recurs quickly, consider antiarrhythmic therapy (amiodarone or procainamide) before a third shock. Atrial Fibrillation or Flutter For stable patients The treatment options are: • Beta-blocker (e.g. propranolol - 1 mg/kg/dose PO q6h) • Digoxin: Total digitalizing dose (initial dosing) 10 mcg/kg IV in infants, 20 mcg/kg IV in older children; 1/2 dose stat, then 1/4 dose q8-12h × 2 (contraindicated in WPW) • Amiodarone: 5 mg/kg IV over 20-60 min • Cardioversion: 0.5-1 J/kg; may repeat prn up to a total dose of 2 J/kg. Administer cardioversion earlier if signs of severe cardiac failure manifest or if deterioration occurs during medical treatment. If patient is stable and presenting with >48 hours of signs of atrial dysrhythmia, consider anticoagulation prior to cardioversion. For patients in shock Immediate cardioversion: 0.5-1 J/kg; may repeat prn up to a total dose of 2 J/kg. Tachycardia with Hemodynamic Stability Because all anti-arrhythmia therapies have the potential for serious adverse effects, consider consulting an expert in pediatric arrhythmias before treating children who are hemodynamically stable. For SVT, one try vagal maneuver or adenosine. For VT, give an infusion of amiodarone slowly (minutes to an hour depending on the urgency) while you monitor the ECG and blood pressure. If there is no effect and there are no signs of toxicity, give additional doses. If amiodarone is not available, consider giving procainamide slowly (over 30 to 60 minutes) while you monitor the ECG and blood pressure. Do not administer amiodarone and procainamide together without expert consultation. BRADYARRHYTHMIAS A slow heart rate (97th percentile for age). Causes include myocarditis, endocarditis, increased vagal tone, drugs (digitalis, β-blockers, Ca++ blockers), surgical injury, and atrial enlargement secondary to cardiac diseases. No specific treatment is necessary for type of block except for treating the underlying cause.

Fig. 13.5: First degree heart block

b. Second Degree AV Block (Fig. 13.6) It is characterized by intermittent conduction to the ventricle. i. Second degree Mobitz type I block (Wenckebach) usually results from a conduction delay involving conduction tissue above the His bundle. It manifests on ECG rhythm strip as constant PP interval, and a gradual increase in the PR interval and decreased RR interval, prior to a dropped QRS complex. The causes are similar to those for first degree AV block. Mobitz type I AV block does not require treatment. ii. Second degree Mobitz type II block results from a conduction delay involving conduction tissue at or below the His bundle, and is considered potentially life threatening. Electrocardiographically, it is manifested by a sudden dropped QRS and a constant PR interval on the beats prior to and following the dropped beat. It is rare in children and is usually the result of surgical injury. Mobitz type II patients should be closely followed and, if symptomatic, should be treated by pacing.

c. Third Degree AV Block It is complete heart block; no atrial impulses are conducted to the ventricle. Electrocardiographically, the atrial and ventricular complexes are disassociated with a more rapid atrial rate. Compatibility with life depends upon the function of subsidiary pacemakers distal to the block. When the block is within the AV node, subsidiary pacemakers at the AV junction usually take over and pace the heart at a rate often >50 beats/minute. When the block is distal to the AV node, subsidiary pacemakers

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Fig. 13.6: Second degree heart block

tend to result in a profoundly slow heart rate, often 6 years of age and to children with creatinine clearance >30 ml/min/1.73m2. 1. All ARBs are contraindicated in pregnancy-females of childbearing age should use reliable contraception. 2. Check serum potassium, creatinine periodically to monitor for hyperkalemia and azotemia. 3. Losartan label contains information on the preparation of a suspension. 4. FDA approval for ARBs is limited to children =6 years of age and to children with creatinine clearance = 30 ml/min/ 1.73m2.

Contd...

VASODILATORS AND ANTIHYPERTENSIVES Contd... Class

Drugs

Dosage

Dosing interval

Comments

β-blockers

Atenolol

Initial: 0.5-1 mg/kg/day Maximum: 2 mg/kg/day up to 100 mg/day Initial: 2.5/6.25 mg/day Maximum: 10/6.25 mg/day Initial: 1-2 mg/kg/day Maximum: 6 mg/kg/day up to 200 mg/day Initial: 1-2 mg/kg/day Maximum: 4 mg/kg/day up to 640 mg/day

qd-bid

1. Noncardioselective agents (propranolol) are contraindicated in asthma and heart failure. 2. Heart rate is dose-limiting. 3. May impair athletic performance. 4. Should not be used in insulindependent diabetics. 5. A sustained-release formulation of propranolol is available that is dosed

Bisoprolol/HCTZ Metoprolol

Propranolol

qd qd

qd-bid Once-daily.

α and β blocker

Labetalol

Initial: 1-3 mg/kg/day Maximum: 10-12 mg/kg/day up to 1, 200 mg/day

bid

1. Asthma and overt heart failure are contraindications. 2. Heart rate is dose-limiting. 3. May impair athletic performance. 4. Should not be used in insulindependent diabetics.

Calcium channel blocker

Amlodipine

Children 6-17 years: 2.5-5 mg once daily Initial: 2.5 mg/day Maximum: 10 mg/day Initial: 0.15-0.2 mg/kg/day Maximum: 0.8 mg/kg/day to 20 mg/day Initial: 0.25-0.5 mg/kg/day Maximum: 3 mg/kg/day up to 120 mg/day

qd

1. Amlodipine and isradipine can be compounded into stable suspensions. 2. Felodipine and extended-release nifedipine tablets must be swallowed whole. 3. Isradipine is available in both immediate-release and sustainedrelease formulations; sustained release form is dosed qd or bid. 4. May cause tachycardia.

Felodipine Isradipine

Extended-release nifedipine Central α agonist)

Clonidine

Peripheral Doxazosin a antagonist Prazosin Terazosin Vasodilator

Hydralazine

Minoxidil

qs tid-qid

qd-qid

Initial: 0.2 mg/day Maximum: 2.4 mg/day

qd-bid

1. May cause dry mouth and/or sedation. 2. Transdermal preparation also available. 3. Sudden cessation of therapy can lead to severe rebound hypertension.

Initial: 1 mg/day Maximum: 4 mg/day Initial: 0.05-0.1 mg/kg/day Maximum: 0.5 mg/kg/day Initial: 1 mg/day Maximum: 20 mg/day

qd

1. May cause hypotension and syncope, especially after first dose.

Initial: 0.75 mg/kg/day Maximum: 7.5 mg/kg/day up to 200 mg/day Children 12 years: Initial: 5 mg/day Maximum: 100 mg/day

tid qd qid

qd-tid

1. Tachycardia and fluid retention are common side effects. 2. Hydralazine can cause a lupus-like syndrome in slow acetylators. 3. Prolonged use of minoxidil can cause hypertrichosis. 4. Minoxidil is usually reserved for patients with hypertension resistant to multiple drugs.

ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; bid, twice-daily; HCTZ, hydrochlorothiazide; qd, once-daily; qid, four times daily; tid, three times daily, † The maximum recommended adult dose should not be exceeded in routine clinical practice. Dosage regimens are based on limited published data and thus are not definitive.

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PEDIATRIC INTENSIVE CARE Table 14.3: Antihypertensive drugs for management of severe hypertension in children (taken from the fourth report on the diagnosis and treatment of high blood pressure in children and adolescents)

Drug

Class

Dose

Route

† Comments

Esmolol

β-blocker

100-500 mcg/kg/min

iv infusion

Very short-acting-constant infusion preferred. May cause profound bradycardia.

Hydralazine

Vasodilator

0.2-0.6 mg/kg/dose

iv, im

Should be given every 4 hours when given iv bolus. Recommended dose is lower than FDA label

Labetalol

α and β

bolus: 0.2-1.0 mg/kg/dose up to 40 mg/dose infusion: 0.25-3.0 mg/kg/hr

iv bolus or infusion

Asthma and overt heart failure are relative contraindications

blocker

Nicardipine

Calcium channel blocker

1-3 mcg/kg/min

iv infusion

May cause reflex tachycardia

Sodium nitroprusside

Vasodilator

0.53-10 mcg/kg/min

iv infusion

Monitor cyanide levels with prolonged (>72 hr) use or in renal failure; or coadminister with sodium thiosulfate.

Clonidine

Central α agonist

0.05-0.1 mg/dose po may be repeated up to 0.8 mg total dose

Side effects include dry mouth and sedation.

Enalaprilat

ACE inhibitor

0.05-0.1 mg/kg/dose up to 1.25 mg/dose

iv bolus

May cause prolonged hypotension and acute renal failure, especially in neonates

Fenoldopam

Dopamine receptor agonist

0.2-0.8 mcg/kg/min

iv infusion

Produced modest reductions in BP.

Isradipine

Calcium channel blocker

0.05-0.1 mg/kg/dose

po

Stable suspension can be compounded

Minoxidil

Vasodilator

0.1-0.2 mg/kg/dose

po

Most potent oral vasodilator; long-acting

ACE, angiotensin-converting enzyme; im, intramuscular; iv, intravenous; po, oral. * Useful for hypertensive emergencies and some hypertensive urgencies. † All dosing recommendations are based upon expert opinion or case series data except as otherwise noted. ‡ Useful for hypertensive urgencies and some hypertensive emergencies.

• Angiotensin receptor blockers (ARBs) • Adrenergic inhibitors β blockers α-Blockers Combined α- and β-blockers Peripheral adrenergic inhibitors

VASODILATORS AND ANTIHYPERTENSIVES

• • • •

Central α-agonists Calcium Channel blockers (CCBs) Direct vasodilators Vasopeptidase inhibitors (VPIs)

Diuretics Diuretics usually are the first-line agents in treating chronic pediatric hypertension and are benchmark against which the modern drugs like ACE inhibitors and CCBs are compared. Diuretics reduce volume, decrease peripheral vascular resistance, and reduce systemic blood pressure. They are used to treat hypertension either as monotherapy or in combination with other classes of drugs. Diuretics potentiate the antihypertensive effects of other antihypertensive drugs. Structural differences among the diuretics determine their site of action and their duration of activity.9 Loop diuretics work by blocking chloride re-absorption in the thick ascending loop of Henle and thus lead to marked natriuresis. The loop diuretics are considered to be more potent than the thiazides and have a rapid onset of action. Furosemide is the most commonly prescribed loop diuretic in children and is effective in those with hypertension due to renal disease, refractory edema, or congestive heart failure. Loop diuretics can cause electrolyte and volume depletion, and therefore should be used with considerable caution and under proper supervision.10 Thiazide diuretics often are given to treat mild hypertension and are the diuretics of choice in patients with normal glomerular filtration rate. Thiazide diuretics (except metolazone and indapamide) are ineffective when the glomerular filtration rate is less than 30% of normal and in children receiving nonsteroidal anti-inflammatory drugs (NSAIDs). Thiazide diuretics act at the distal convoluted tubule where they inhibit sodium and chloride reabsorption thus causing natriuresis. Thiazide diuretics can be administered once daily dosing. Spironolactone is the only potassium-sparing diuretic studied in children and is indicated for hypertension due to mineralocorticoid excess. In clinical hypertension, it is best to use the potassium sparing agents in combination with thiazide or loop diuretics. Adverse effects include hyperkalemia and gynecomastia with prolonged use. Diuretics are generally well tolerated in children; however, they should be avoided in patients with salt-wasting nephropathy or adrenal disorders and in athletic adolescents due to the possibility of cramps and dehydration. Long-term treatment is not effective due to the drugs effects on uric acid concentrations, bone growth, and reduction of serum potassium concentrations.11 Angiotensin-Converting Enzyme Inhibitors Angiotensin-converting enzyme (ACE) inhibitors are preferred antihypertensive agents to treat chronic pediatric hypertension due to their ease of administration and relative lack of severe adverse effects.12 They decrease blood pressure by inhibiting formation of angiotensin II and by inactivating the kinases that degrade bradykinin, a potent vasodilator. In uncomplicated stage 1 and 2 hypertension, ACE inhibitors as monotherapy are effective in 60 to 70% of patients. Captopril is the most widely studied ACE inhibitor in children. It prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor; lowers aldosterone secretion .It reduces both systemic vascular resistance and left ventricular pressure. Captopril has the shortest duration

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of action and generally is given 2-3 times/day. It is cleared renally and thus requires dosage adjustment in patients with renal failure.13 The ACE inhibitors do not have a dose-response effect and a precipitous drop in blood pressure may occur. Therefore, it seems reasonable to begin captopril therapy at 0.5 mg/kg in children 6 months of age or older. Neonates and young infants exhibit an increased sensitivity to captopril and other ACE inhibitors due to unknown reasons, thus warranting a lower initial dose of 0.10.2 mg/kg/dose as recommended by the International Collaborative Study Group. Enalapril has an intermediate and lisinopril longer duration of action permitting twice daily and once daily administration respectively. Studies involving enalapril in long-term control of pediatric hypertension are promising,14 while published studies of lisinopril’s safety and efficacy in children are not available.15 Rashes, taste disturbance, proteinuria, and bone marrow suppression are rare side effects of ACE inhibitors .The most serious adverse effect is significantly reduced renal function in the presence of bilateral renal artery stenosis hence this class of drugs are best avoided. Angiotensin Receptor Blockers (ARBs) Orally effective, ARBs represent an important therapeutic advance in the interruption of reninangiotensin cascade to lower the blood pressure by displacing angiotensin II from its receptor sites. In contrast to ACE inhibitors, ARBs do not interfere with bradykinin metabolism. In terms of their antihypertensive effects, ARBs and ACE inhibitors are similar.16 All the currently available ARBs are efficacious in the treatment of hypertension as monotherapy as well as in combination with a diuretic. They differ in their duration of action and receptor binding characteristics. Losartan is a relatively short-acting drug and is best given in a twice-daily schedule. ARBs have additive antihypertensive effects when combined with a diuretic. Like ACE inhibitors, ARBs also lessen proteinuria and are effective in patients with renal insufficiency. ARBs are very well tolerated by the patients but should be introduced cautiously in volume depleted or high renin patients and avoided in patients with bilateral renal artery stenoses or stenosis of a solitary kidney. Adrenergic Inhibitors Adrenergic inhibitors have always been used in the treatment of hypertension on assumption that an inappropriate level of sympathetic activity plays a pathogenetic role in hypertensive disorders. Thus, blockade of these receptors by pharmacologic means lowers the peripheral vascular resistance or cardiac output or both, in addition to modulating other presser mechanisms such as the renin– angiotensin system β-Adrenergic

Receptor Blockers

β-adrenergic blockers are not considered first- or second-line therapy in children but are given when calcium channel blockers and ACE inhibitors are ineffective. This may be due to questions regarding long-term effects of β-blockers on growth and lipid profiles, and their tendency to cause drowsiness and bronchoconstriction.17 These drugs decrease cardiac output, inhibit renin secretion, reduce plasma volume, reduce peripheral vascular resistance, and reset baroreceptor levels. Only

VASODILATORS AND ANTIHYPERTENSIVES

a few β-blockers have been administered extensively in children; for example, propranolol, atenolol, metoprolol, and labetalol. Propranolol has been used extensively to treat pediatric hypertension. It is a nonselective betablocker and acts on both beta1 and beta2 adrenergic receptors, which explains bradycardic and bronchospastic effects. Adverse effects are infrequent and include bradycardia, hypoglycemia, asthma attacks, night terrors, and heart block. Cardio selective agents such as atenolol and metoprolol may be given in patients with diabetes mellitus or congestive heart failure when other drugs fail or are not available. However, as dosages of these drugs are increased, cardio selectivity may be lost. Although data on long-term treatment of pediatric hypertension with atenolol and metoprolol are limited, both agents are efficacious as short-term therapy and may be preferred in treating chronic hypertension due to once-daily dosing and cardio selectivity. α-Blockers α-adrenergic receptor blocking drugs are not widely used in children, but can be used as monotherapy or in combination with diuretics, calcium channel blockers, or α-blockers. The first-dose hypotension mainly reported with prazosin can be avoided by giving the initial dose at bedtime and by adjusting the dosage gradually and not rapidly. This phenomenon, however, is uncommon with the secondgeneration α-blockers such as doxazosin and terazosin.18, 19 Esmolol is an ultrashort-acting β-adrenergic antagonist. It was given to children in hypertensive crises in loading doses of 100-500 mg/kg as a bolus over 1 minute followed by 25-100 mg/kg/ minute infusion. The usual maintenance dosage is 50-500 mg/kg/minute. Esmolol may cause bronchospasm and should be given with caution to patients with chronic lung disease. Combined α- and β-Blockers Labetalol and carvedilol are drugs that block both the β- and α-adrenergic receptors; their dominant adrenergic inhibition, however, is at the β-receptor site, whereas the α-blocker component is an ancillary effect. The latter phenomenon adds to the vasodilatory actions of these compounds. Labetalol is indicated for the treatment of hypertension, carvedilol is indicated for heart failure. Labetalol is also available for intravenous use to treat hypertensive emergencies and hypertensive urgencies. It can be given as a bolus or continuous infusion and does not cause reflex tachycardia or increased cardiac output associated with other agents (nitroprusside, diazoxide). Labetalol 0.2-1.0 mg/kg can be given as an intravenous bolus every 10 minutes; the maximum bolus dose is 20 mg. Dosages of 0.25-3 mg/kg/hour by intravenous infusion are recommended in children. Peripheral Adrenergic Inhibitors It is well known that sympathetic nervous system plays a role in the pathogenesis of hypertension. By causing depletion of nor epinephrine stores, reserpine lowers the peripheral vascular resistance and thereby the blood pressure. Reserpine is an effective but poorly tolerated drug. Reserpine causes a significant fall in blood pressure either as monotherapy or in combination with diuretics and/ or hydralazine. Reserpine may cause nasal stuffiness, increased gastric secretions, diarrhea, and marked depression. At the present time, there is no good reason to select reserpine over other well-

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tolerated adrenergic inhibitors such as β-blockers, α-blockers, and central α-agonists. These drugs rarely have been used over the last few years. Central α-Agonists The centrally acting drugs are one of the oldest classes of antihypertensive drugs; they are still used in the management of difficult-to-treat hypertension.21 Methyldopa, the prototypical drug in this class has a central nervous system action—stimulation of α receptors in the vasomotor center, which causes a reduction in sympathetic outflow with a resultant decrease in peripheral vascular resistance and a modest decrease in the heart rate/cardiac output. The second-generation alpha agonists such as clonidine are more specific for the central receptor and exert antihypertensive actions with fewer side effects as compared to methyldopa. Clonidine, guanabenz, guanfacine, and methyldopa have similar therapeutic effects but clonidine is the most widely used drug in this class. The dosage of central alpha agonists has to be adjusted upward (or downward) gradually. These drugs work best in conjunction with sodium restriction or diuretics. The most common side effects of the centrally acting drugs are sedation, dry mouth, and withdrawal syndrome characterized by severe rebound hypertension. Hemolytic anemia and hepatocellular dysfunction occasionally have been reported with methyldopa. Calcium Channel Blockers Calcium channel blockers affect blood pressure by decreasing vascular peripheral resistance reduce blood pressure by dilating peripheral arterioles in a dose-dependent fashion.22 They cause modest increases in heart rate and cardiac output shortly after starting treatment. There are two classes of calcium channel blockers, types l and II. Type II agents are more effective vasodilators and consequently are effective in treating hypertension. Extended-release formulations of type I drugs (verapamil, diltiazem) are administered for pediatric hypertension. Nifedipine, amlodipine, nicardipine, and felodipine are the available type II calcium channel blockers in children.23, 24 Nifedipine relaxes coronary smooth muscle and produces coronary vasodilatation, which, in turn, improves myocardial oxygen delivery. Used for hypertensive emergencies .It is absorbed rapidly when the immediate-release form is taken sublingually or swallowed; its short duration of action and unpredictable hypotensive effects limit long-term treatment. Amlodipine when administered once/day is also effective. Occasional adverse effects noted are fatigue, headache, dizziness, abdominal pain, peripheral edema, and chest pain. With once-daily dosing, effectiveness, and lack of reflex tachycardia, it has distinct advantages over nifedipine in pediatric patients.25, 26 Nicardipine has vasodilatory action similar to nifedipine. Unlike nifedipine, it does not alter cardiac contractility or cardiac function. Nicardipine may be selected for a child with compromised cardiac function. There are no pediatric studies of efficacy and safety to support isradipine.27, 28 Nicardipine was effective in controlling blood pressure rapidly in children in perioperative, intensive care, and emergency room settings. It can be administered intravenously and produces its effect by dilating peripheral arteries, thus reducing peripheral vascular resistance. Its advantages include lack of decreased cardiac output and limited effects on the chronotropic and dromotropic function of the heart.27, 28

VASODILATORS AND ANTIHYPERTENSIVES

Direct Vasodilators Hypertension is characterized by increased peripheral vascular resistance, and drugs that directly relax resistance vessels would seem to be desirable in the pharmacologic management of high blood pressure. However, the efficacy of direct vasodilators, such as hydralazine and minoxidil, is blunted and modified by reflex responses to vasodilatation. Certain important negative consequences of vasodilatation presently limit the use of these drugs as monotherapy for hypertension. Direct arterial dilation triggers baroreceptor-mediated sympathetic activation resulting in tachycardia and increased cardiac output. Secondly, direct vasodilators cause unpleasant side effects such as flushing, headache, and palpitations. Third, direct vasodilators cause significant fluid retention, which may decrease their therapeutic effectiveness. These disadvantages can be overcome by combining vasodilators with antiadrenergic agents and diuretics. When used in this fashion, vasodilators are effective in the long-term treatment of hypertension, especially in patients with resistant hypertension. Therapy with minoxidil, diazoxide and hydralazine has decreased because of availability of newer agents with fewer adverse effects.29, 30 Diazoxide can be given as a bolus or continuous infusion. As a bolus, it must be administered over 10-30 seconds and can frequently cause hypotensive complications in children. Diazoxide also can cause hyperglycemia, hyperuricemia, cardiac arrhythmias, headache, tachycardia, and flushing. The usual dose in children is 5 mg/kg. Hydralazine is a direct arteriolar vasodilator given as an intravenous bolus to treat hypertensive crises. It is less effective than diazoxide and sodium nitroprusside in reducing blood pressure and may cause reflex tachycardia. The effective dose for treating pediatric hypertensive crises is 0.10.2 mg/kg intravenously. Finally, administration of minoxidil to treat hypertensive urgencies has decreased markedly due to its adverse effects, including reflex tachycardia, hirsutism, and fluid retention.31, 32 Sodium nitroprusside is a vasodilator, acting equally on arteries and veins. It increases renal blood flow with minimal effects on cardiac output. It can control blood pressure precisely due to its rapid onset and offset when given by continuous infusion. The recommended starting dosage of nitroprusside in pediatric patients is 0.5-1 mg/kg/minute, with stepwise increases up to 8 mg/ kg/minute. Reflex tachycardia and accumulation of cyanide which result in clinical deterioration limit their use freely in children.33 Vasopeptidase Inhibitors (VPIs) VPIs represent a new class of drugs that exert cardiovascular effects via multiple mechanisms of action. These multiple actions lead to vasodilatation, physiologic natriuresis, and an improvement in cardiac function. Thus, profound cardiovascular and renal consequences ensue from VPIs, resulting in significant reductions in blood pressure The initial clinical experience in adults with one VPI, omapatrilat, suggested a possible high incidence of angioneurotic edema34 and has been withdrawn from market. Vasodilators in Pediatric Practice Systemic vasodilators are commonly used in the treatment of acute and chronic hypertension and are as detailed above.

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An effective pulmonary vasodilator must dilate the pulmonary vasculature more than the systemic vasculature.35 Endothelium-derived relaxing factor and nitric oxide (NO) dilate pulmonary arteries selectively through release of cyclic guanosine monophosphate (cGMP). Infants who have persistent pulmonary hypertension of the newborn (PPHN) have lower circulating cGMP, likely because of inadequate NO production needed to dilate the pulmonary vasculature after birth .The selectivity of NO for the pulmonary vasculature derives from its administration by inhalation and inactivation by binding to hemoglobin as soon as it enters the blood stream. Dose–response studies indicate that neonates achieve maximum improvement in oxygenation at 20 to 40 ppm. Prolonged treatment longer than 10 days has been associated with pulmonary toxicity demonstrated by detection of nitrotyrosine.36 Several other drugs have been used for treatment of PPHN, including tolazoline; PGE1, PGI2, PGD2, acetylcholine, isoproterenol, chlorpromazine, nitroprusside, and sildenafil .None of these drugs have proven to be selective for the pulmonary vasculature. Although tolazoline has been reported to improve oxygenation in approximately 60% of patients, high mortality persisted, and adverse effects occurred at an unacceptably high rate.37 Inhibition of phosphodiesterase 5 increases cGMP and dilates pulmonary arteries. Despite hopes that sildenafil, a phosphodiesterase 5 inhibitor, would be a specific pulmonary vasodilator, a small randomized study in infants following cardiac surgery found that sildenafil reduced systemic and pulmonary vascular resistance and worsened oxygenation and the aAO2 gradient.38 Studies of prostacyclin administered via the airway have shown promise in a small number of neonates who have PPHN, but controlled studies are needed to evaluate the efficacy of this prostanoid. For now, inhaled NO remains the only selective pulmonary vasodilator in neonates. Alternate drug treatment may still be successful at improving pulmonary perfusion in patients who have PPHN, but their effectiveness must be confirmed in appropriate controlled trials. REFERENCES 1. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004;114 (2 suppl 4th report):555-76. 2. Flynn JT. Evaluation and management of hypertension in childhood. Prog Pediatr Cardiol 2001;12:177-88. 3. Bartosh SM, Aronson AJ. Childhood hypertension. An update on etiology, diagnosis, and treatment. Pediatr Clin North Am 1999;46:235-52. 4. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: The JNC 7 Report .JAMA 2003;290:197. 5. Gulati S.Childhood hypertension.Indian Pediatrics 2006; 43:326-33. 6. Luma GB, Spiotta RT. Hypertension in children and adolescents . Am Fam Physician 2006;1158-68. 7. Wells TG. Trials of antihypertensive therapiesin children. Blood Press Monit 1999;4:189-92 8. Temple ME, Nahata MC .Treatment of Pediatric Hypertension Pharmacotherapy 2000;20(2):140-50. 9. Miller K. Pharmacologic management of hypertension in pediatric patients. Drugs 1994;48:868-87 10. Ram CVS, Fenves A. Clinical pharmacology of antihypertensive drugs 2002;20:265-80. 11. Falkner B, Lowenthal DT, Affrime MB. The pharmacodynamic effectiveness of metoprolol in adolescent hypertension. Pediatr Pharmacol 1982;2:49-52 12. Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation. 1998;97:1411-20. 13. Schneeweiss A. Cardiovascular drugs in children. Angiotensin converting enzyme inhibitors in pediatric patients. Pediatr Cardiol 1990;11:199-207. 14. Wells T, Frame V, Soffer B, Shaw W et al. A double-blind, placebo controlled, dose-response study of the effectiveness and safety of enalapril for children with hypertension. J Clin Pharmacol 2002;42:870-80.

VASODILATORS AND ANTIHYPERTENSIVES 15. Soffer B, Zhang Z, Miller K, Vogt BA, Shahinfar S. A double-blind, placebo controlled, dose-response study of the effectiveness and safety of lisinopril for children with hypertension. Am J Hypertens 2003;16:795-800. 16. Toto R, Schultz P, Raij L, et al. Efficacy and tolerability of losartan in hypertensive patients with renal impairment. Hypertension. 1998;31:684-91. 17. Sorof JM, Cargo P, Graepel Jet al. Beta-blocker/thiazide combination for treatment of hypertensive children: A randomized double-blind, placebo-controlled trial. Pediatr Nephrol 2002;17:345-50. 18. Sheps SG, Roccella EJ. Reflections on the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Curr Hypertens Rep 1999;1:342-5. 19. Cubeddu LX. New alpha1-adrenergic receptor antagonists for the treatment of hypertension. Am Heart J. 1988;116:11360. 20. Vaughan CJ, Delanty N. Hypertensive emergencies.Lancet 2000;356:411-720. 21. Yiu V, Orrbine E, Rosychuk RJ et al. The safety and use of short-acting nifedipine in hospitalized hypertensive children. Pediatr Nephrol 2004; 19: 644-50. 22. Hohn AR. Diagnosis and management of hypertension in childhood. Pediatr Ann 1997;26:105-10. 23. Adelman RD, Coppo R, Dillon MJ. The emergency management of severe hypertension. Pediatr Nephrol 2000;14: 422-7. 24. Trachtman H, Frank R, Mahan JD, Portman, et al. Clinical trial of extended- release felodipine in Pediatric essential hypertension. Pediat Nephrol 2003;18:548-53. 25. Tallian KB, Nahata MC, Turman MA, et al. Efficacy of amlodipine in pediatric patients with hypertension. Pediatr Nephrol 1999;13:304-10. 26. Johnson CE, Jacobson PA, Song MH. Isradipine therapy in hypertensive pediatric patients. Ann Pharmacother 1997;31:704-7. 27. Evans JHC, Shaw NJ, Brocklebank JT. Sublingual nifedipine in acute severe hypertension. Arch Dis Child 1988; 63:975-7. 28. Michael J, Groshong T, Tobias JD. Nicardipine for hypertensive emergencies in children with renal disease. Pediatr Nephrol 1998;12:40-2. 29. Groshong T. Hypertensive crises in children. Pediatr Ann 1996;25:368-76. 30. Sadowski RH, Falkner B. Hypertension in pediatric patients. Am J Kidney Dis 1996;27:305-15. 31. Khatri I, Uemura N, Notargiacomo A, Freis ED. Direct and reflex cardio stimulating effects of hydralazine. Am J Cardiol. 1977;40:38-42. 32. Ram CVS. Direct vasodilators. Hypertension Primer. Dallas: American Heart Association 1999;385-387. 33. Campese VM. Minoxidil: a review of its pharmacological properties and therapeutic use. Drugs. 1981;22:257-278 34. Walters M, Reid J. Vasopeptidase inhibition: cardiovascular therapy for the new millennium? J Hum Hypertens. 2000;14:537-39. 35. Christou H, Adatia I, Van Marter LJ, et al. Effect of inhaled nitric oxide on endothelin-1 and cyclic guanosine monophosphate plasma concentrations in newborn infants with persistent pulmonary hypertension. J Pediatr 1997;130 (4):603-11. 36. Tworetzky W, Bristow J, Moore P, et al. Inhaled nitric oxide in neonates with persistent pulmonary hypertension. Lancet 2001;357 (9250):118-20. 37. Nuntnarumit P, Korones SB, Yang W, et al. Efficacy and safety of tolazoline for treatment of severe hypoxemia in extremely preterm infants. Pediatrics 2002;109(5):852-6. 38. Stocker C, Penny DJ, Brizard CP, et al. Intravenous sildenafil and inhaled nitric oxide:a randomised trial in infants after cardiac surgery. Intensive Care Med 2003;29(11):1996-2003.

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S Prabhu, Sanjay B Prabhu, Gautam Ghosh

Hypertensive Crisis

15 INTRODUCTION Hypertension that represents a threat to life or to the function of vital organs has been called Hypertensive crisis . This has been subdivided into two categories–the hypertensive emergency and hypertensive urgency. Hypertensive emergency describes hypertension of such a level that it is warrants treatment to reduce it within minutes to hours to avoid life threatening complications. Target organs may show signs of damage or may be in imminent danger. Hypertensive urgency describes blood pressure that is markedly increased but can be more gradually reduced within a few days to avoid serious sequelae.1 Hypertensive emergency was called malignant hypertension and was equated with hypertension and end organ damage as bilateral retinal hemorrhages, exudates and /or papilledema, hypertensive encephalopathy and hypertensive cardiac failure. The Second Task force on Blood Pressure Control in Children defines severe hypertension as above 99th percentile for that age.2 PATHOPHYSIOLOGY The exact pathophysiology underlying the development of hypertensive crisis is unknown. Humoral factors (particularly the renin-angiotensin axis) and local products produced by the vasculature (eg, prostaglandins, free radicals) in critically elevated blood pressure have been hypothesized . The pathological hallmark, as seen histologically, in severe hypertension with target organ damage is fibrinoid arteriolar necrosis. Sudden fall in blood pressure is not well tolerated due to loss of autoregulation and may result in cerebral infarction, transverse ischemic myelopathy or blindness due to infarcts in watershed

HYPERTENSIVE CRISIS

areas. The neonate is more at risk for intraventricular hemorrhages if blood pressure drops suddenly. These complications are more likely in long standing hypertension than that of acute onset. ETIOLOGY In children, the majority of cases of hypertensive crisis have some form of underlying renal disease. The commonest causes are renal scarring due to reflex nephropathy or obstructive uropathy, various forms of glomerulopathy and renovascular disease. Other etiologies include end stage renal failure, inherited kidney disorders, hemolytic uremic syndrome coarctation of aorta and pheochromocytoma.3, 4 In the neonate, the common etiologies are umbilical artery catheter associated renal and aortic thrombosis, pulmonary disease and coarctation of the aorta. Various etiological causes of severe hypertension are listed in Table 15.1. Table 15.1: Etiology of hypertensive crisis in children Neonates Renal and aortic thrombosis Chronic pulmonary disease Coarctation of aorta. Children (Abrupt increase in blood pressure in patients with chronic hypertension) Renovascular hypertension Parenchymal renal disease (chronic) Acute glomerulonephritis /other glomerulopathies Scleroderma and other collagen vascular diseases Vasculitis Renin-secreting or aldosterone-secreting tumor Pheochromocytoma Autonomic hyperactivity in presence of Guillain-Barré or other spinal cord syndromes Withdrawal from antihypertensive agents (usually centrally acting agents such as clonidine)

EVALUATION Findings on initial history taking and physical examination should be used to differentiate hypertensive emergency from hypertensive urgency and thus determine the course of treatment. The history should include information about previously diagnosed hypertension, including duration, severity, and general level of control. History of preexisting or impending/ongoing end-organ damage (ie, renal insufficiency or failure, congestive heart failure, previous cerebrovascular accident) and the child’s compliance with previous medical therapy should be inquired into.5, 6 Physical examination should focus on factors that distinguish a hypertensive emergency from a less critical situation. Blood pressure should be measured, if possible, in both supine and standing positions. Fundoscopic findings should be noted and may include changes consistent with chronic hypertension. Acute changes include arteriolar spasm (focal or diffuse), retinal edema, retinal hemorrhages (superficial and flame-shaped, or deep and punctate), retinal exudates (hard or “cotton wool”), or papilledema. The visual symptoms are caused by cortical damage, vitreous hemorrhage or anterior ischemic neuropathy which is seen especially if the blood pressure is reduced too quickly. The patients demonstrate loss of pupillary reflex and loss of accommodation.

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Cardiovascular examination should concentrate on evidence of heart failure (i.e. rales, elevated jugular venous pressure, S3). The latter may result in arterial compromise and is usually manifested by pulse deficits that may cause cerebral, limb, or gut ischemia. A new or increased murmur of mitral insufficiency may be heard as a result of the increase in left ventricular afterload. A careful, directed neurologic examination can reveal signs of impending or ongoing neurologic compromise. Signs of hypertensive encephalopathy include disorientation, a depressed level of consciousness and, in some cases, focal neurologic deficits and generalized or focal seizure activity. Hypertensive encephalopathy is a diagnosis of exclusion, which requires that the presence of other lesions (i.e. stroke, subarachnoid hemorrhage, mass lesions) be ruled out . It is thought to be caused by cerebral edema resulting from the loss of cerebral vascular autoregulatory function in the presence of severe hypertension. Neonates present with cardiac failure, lethargy, seizures and failure to thrive. However occasionally, even in the presence of severe hypertension, some neonates remain asymptomatic.7 The reported incidence of target organ damage in hypertensive crisis are hypertensive retinopathy in 27%, encephalopathy in 25%, Convulsions in 25%, left ventricular hypertrophy in 13%, facial palsy in 12% and visual symptoms and hemiplegia in 8%. Laboratory tests should be performed immediately after presentation and can provide crucial clues to underlying conditions. • A complete blood cell count may confirm the presence of microangiopathic hemolytic anemia. • Urinalysis may reveal hematuria or casts in the presence of azotemia or renal failure. • Elevated serum urea nitrogen and creatinine levels. • Metabolic acidosis, and hypocalcemia detected on blood chemistry tests often indicate renal insufficiency. • Hypokalemia is seen in secondary aldosteronism. • Left ventricular hypertrophy and changes consistent with ischemia or infarction may be detected on electrocardiogram. • A chest film can reveal evidence of pulmonary edema . • A two-dimensional echocardiography can be used to differentiate purely diastolic dysfunction from systolic cardiac dysfunction when signs of heart failure are present. These findings can help in drug selection, particularly for long-term treatment. Finally, it is important to consider secondary causes of hypertension (e.g. renovascular hypertension) that may have precipitated the crisis. Thus, further testing (e.g.renal arterial Doppler ultrasonography, renal magnetic resonance angiography, contrast angiography) may be necessary to confirm diagnosis. Before initiating drug therapy. • Metanephrine levels can be measured by performing a spot urine test to rule out the presence of pheochromocytoma . • Plasma aldosterone and renin levels should be tested to rule out primary hyperaldosteronism in patients with significant hypokalemia who are not taking diuretics at the time of presentation. TREATMENT The goal of treatment is to prevent adverse effects of severe hypertension by controlled reduction of blood pressure. This ensures preservation of normal organ function and complications of therapy

HYPERTENSIVE CRISIS

due to sudden fall in B.P as ischemic neuropathy of the optic nerve, transverse ischemic myelopathy and renal impairment.8 Short acting, parenteral antihypertensives are recommended along with careful blood pressure monitoring to prevent complications arising from loss of autoregulatory control. The antihypertensives then could be tailored accordingly depending on the response. In hypertensive emergency blood pressure is decreased by 25-30% in first eight hours, 25-30% over next 24-36 hrs and the remaining over 48-72 hrs. Therapy with enteral antihypertensives is instituted in 8-12 hrs of parenteral treatment and latter gradually withdrawn over 24 hrs. There are no absolute recommendations regarding preferences of pharmacological agents. The preferred choice is sodium nitroprusside, labetalol, nitroglycerine and more recently nicardipine. HYPERTENSIVE EMERGENCY The child has to be admitted to the PICU and short acting agents are preferred. Sodium nitroprusside is the drug of choice for hypertensive emergencies. It acts rapidly and the dose can be titrated every few minutes to achieve the desired fall in BP. It should be given as an IV infusion that needs to be light protected. The patient should be monitored for cyanide toxicity especially in the presence of renal failure or if nitroprusside is to be used for more than 72 hours, thiocyanate levels should be monitored. Evidence for cyanide toxicity may manifest as dizziness, hypoxia or metabolic acidosis. Also, strict monitoring of pupillary reflexes, visual acuity and level of consciousness is mandatory. If BP were to fall or pupillary reflex is lost due to sudden fall in BP a saline infusion is given. Fenoldopam mesylate (Corlopam) is approved by the US Food and Drug Administration for treatment of hypertensive crisis. This selective dopamine receptor agonist causes peripheral vasodilatation and increases renal blood flow and glomerular filtration rate, which often improves renal function in patients who present with renal insufficiency . Few minor side effects, such as headache, dizziness, and flushing are reported . Patients should be closely monitored for dose-related tachycardia, which tends to diminish over time. Fenoldopam may also cause significant hypokalemia. The efficacy of fenoldopam appears to be similar to that of nitroprusside in treatment of severe hypertension. Sublingual nifedipine is very commonly used, but is criticized as it causes unpredictable or uncontrolled fall in blood pressure. However, complications of sudden fall have been rarely reported in children and can be minimized with a low starting dose of 0.1-0.25 mg/kg. Despite the very real dangers of rapid acute reduction in BP it has been widely used with a fairly good safety profile in children. Oral antihypertensives should be started early so that they may become effective when parenteral therapy is being tapered. Diuretics are to be used only in volume overloaded states such as acute glomerulonephritis. Table 15.2 shows the various agents available, the dosage regimens recommended, and complications of usage.9-10 HYPERTENSIVE URGENCY Children with hypertensive urgency do not need IV medications; they can be treated with oral medications to gradually bring down the BP to normal over 48 hours. However they need to be under close medical supervision as they have the potential to progress into an emergency. Oral agents as nifedipine, clonidine, captopril and labetalol are commonly used.

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PEDIATRIC INTENSIVE CARE Table 15.2: Antihypertensive drugs for management of severe hypertension in children1,3 Drug

Class

Dose

Route

Comments

Most useful—Used for hypertensive emergency Esmolol

β-Blocker

100–500 µg/kg per min

IV infusion

Very short-acting; constant infusion preferred. May cause profound bradycardia. Produced modest reductions in BP in a pediatric clinical trial.

Hydralazine

Vasodilator

0.2–0.6 mg/kg per dose

IV, IM

Should be given every 4 h when given IV bolus. Recommended dose is lower than FDA label.

Labetalol

α- and β-Blocker

Bolus: 0.2–1.0 mg/kg per dose up to 40 mg/dose Infusion: 0.25–3.0 mg/kg per h

IV bolus or infusion

Asthma and overt heart failure are relative contraindications.

Nicardipine

Calcium channel blocker

1–3 µg/kg per min

IV infusion

May cause reflex tachycardia.

Sodium nitroprusside

Vasodilator

0.53–10 µg/kg per min

IV infusion

Monitor cyanide levels with prolonged (>72 h) use or in renal failure; or coadminister with sodium thiosulfate.

1-3 ug/kg/min increase to Ug/k/min

IV infusion

Onset of action 2-5 min, duration 5- 10 min after discontinuation

0.25 mg/kg–0.5 mg/kg

po

Unpredictable and often uncontrolled fall of blood pressure, might be used if no access to parenteral agents.

po

Side effects include dry mouth and sedation.

Nitroglycerine

Nifedipine

Calcium channel blocker

Occasionally useful–Used for hypertensive urgencies Clonidine

Central α-agonist

0.05–0.1 mg/dose, may be repeated up to 0.8 mg total dose

Enalaprilat

ACE inhibitor

0.05–0.1 mg/kg per IV bolus dose up to 1.25 mg/dose

May cause prolonged hypotension and acute renal failure, especially in neonates.

Fenoldopam

Dopamine receptor agonist

0.2–0.8 µg/kg per min

IV infusion

Produced modest reductions in BP in a pediatric clinical trial in patients up to 12 years.

Isradipine

Calcium channel blocker

0.05–0.1 mg/kg per dose

po

Stable suspension can be compounded.

Minoxidil

Vasodilator

0.1–0.2 mg/kg per dose

po

Most potent oral vasodilator, long-acting.

SPECIAL SITUATIONS Rennin dependant hypertension such as in renovascular disease or renal parenchymal diseases, require ACE inhibitors but caution is necessary, if main renal artery stenosis is diagnosed. Renal impairment with salt and water retention may justify dialysis and diuretics.

HYPERTENSIVE CRISIS

In cerebrovascular disease or raised intracranial pressure labetalol is preferred. Children with pheochromocytoma, phenoxybenzamine plus or minus a beta blocker are used. In neonates nitroprusside and nicardipine have been used initially, to be followed by nifedipine or captopril. Data is lacking in neonates with hypertension on the level of hypertension at which therapy should be initiated, consequences of non treatment and pharmacokinetics of antihypertensive agents.11 CONCLUSION Severe hypertension in childhood thus, is a life threatening problem which needs judicious treatment to avoid complications of serious sequelae of inadequate treatment or serious complications of over enthusiastic therapy. Therapeutic success for optimal patient outcomes is achieved by slow and safe reduction of blood pressure aimed at avoiding hypertensive sequelae and allowing at the same time preservation of target organ function. REFERENCES 1. Adelman RD, Coppo R, Dillion MJ. The emergency management of severe hypertension. Pediatr Nephrol 2000; 14:422-7. 2. National heart, Lung and Blood institute. Report of the second task force on blood pressure control in children 1987;79:1-25. 3. Mitsnefes MM. Hypertension in children and adolescents; Pediatr Clin N Am 2006;53:493–512. 4. Dillon MJ. The diagnosis of renovascular disease. Pediatr Nephrol 1997;11:366–72. 5. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation and treatment of high blood pressure in children and adolescents. Pediatrics 2004;114:555-76. 6. Tamilarasi V, Prabha S. Renal Emergencies, Indian Journal of Practical Pediatrics 2002;4(3):49-54. 7. Skalina ME, Annable WL, Kliegman RM, et al. Hypertensive retinopathy in the newborn infant. J Pediatr 1983;103:781-6. 8. Woroniecki RP, Flynn JT.How are hypertensive children evaluated and mananaged ? A Survey of North American Pediatric nephrologists. Pediatr Nephrol 2005;20:791-7. 9. Norwood VF. Hypertension, Pediatrics 2002;14:448-53. 10. Gulati S. Childhood hypertension, Indian pediatrics 2006;43:326-33. 11. Shafi Tariq. Hypertensive urgencies and emergencies, Ethnicity and disease 2004:14(Suppl 2);S2:32-37.

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16

Kundan Mittal, HK Aggarwal

Physiology of Fluids and Electrolytes

INTRODUCTION Certain Useful Definitions1 Osmolarity: Osmolarity is defined as the number of osmoles of solute per liter of solution. Normal Osmolarity of extracellular fluid (ECF) is 285-309 mosmol/L Glucose BUN Osmolarity = 2 × Sodium + ————— + ————— 18 2.8 Tonicity: Tonicity is the total concentration of solute, which exerts an osmotic force across a membrane in vivo. Since BUN is not involved in exerting osmotic force thus tonicity can be calculated as: Glucose Tonicity = 2 × Sodium + ————18 Osmolality: It measures the osmotically active particles in one kilogram of solvent. Osmole: Amount of substance that yields, in ideal solution, that number of particles that would reduce the freezing point of a solvent by 1.86°C. Concentration: It refers to the amount of solute in a given fluid volume. Molarity: It refers to number of moles per liter of solution. Molality: It refers to the number of moles per kilogram of solvent. Mole: Mole is the amount of a substance that contains the number of molecules equal to Avogadro number (number of molecules in one mole of substance). Solute: Substance dissolved in a solution. Solvent: Liquid that contains a substance in solution. Permeability: Capability of a substance, molecule, or ion to move across a membrane.

PHYSIOLOGY OF FLUIDS AND ELECTROLYTES

Electrolytes: Electrolytes are compounds that, when dissolved in water or another solvent, form or dissociate into ions, e.g. sodium, potassium, chloride, magnesium, etc. Equivalence: It is defined as combining power of ions. Thus one equivalence of an ion defined as the amount of the ion which replaces or combines one mole of hydrogen ion. Fluid management is the most commonly encountered problem in critical care units. To manage this, it is important to understand the kinetic physiology of body fluids and the molecules dissolved in it. Clinical disorders of fluids and electrolytes metabolism, regardless of etiology are the result of disturbance in physiology. Maintenance of intravascular volume is critical and any disturbance in volume status can lead to increase in morbidity and mortality. WATER METABOLISM The beginning of life depends entirely on water. Water acts as a solvent and transports various nutrients and oxygen from blood to cells. It also gives shape to cells and maintains body temperature. Humans cannot adapt to a chronic water deficit, so fluid losses must be replaced if physiological function is to continue unimpaired. Water is an important constituent of the body besides protein, fat, carbohydrates and minerals and it varies with age as shown in Figure 16.1.2 It decreases from 75% at birth to 60% at one year of life and continues to be the same till puberty. Total body water becomes important during states of dehydration. Total body water (TBW) is further divided into three compartments namely: Extracellular fluid (ECF), Intracellular fluid (ICF) and transcellular fluids. Extracellular fluids have high concentrations of sodium, chloride, and bicarbonates and lesser concentrations of potassium, calcium, phosphate and sulfate ions. Intracellular fluid has high concentrations of potassium, phosphate, and magnesium and lesser concentrations of sodium, chloride, and bicarbonates ions (Fig. 16.1 and Table 16.1). Hydrostatic and osmotic pressures regulate the movements of water and electrolytes from one compartment to another compartment.3-6

Fig. 16.1: Distribution of total body water

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PEDIATRIC INTENSIVE CARE Table 16.1: Electrolyte concentration in some transcellular fluids (mmol/l) Fluid (s)

Na+

K+

Cl–

HCO3–

Gastric juice Pancreatic juice Bile Ileal fluid Colonic fluid Sweat Burn

20-100 120 150 140 140 65 140

5-10 5-10 5-10 5 5 8 5

120-160 10-60 40-80 105 85 39 110

0 80-120 20-40 40 60 16 3-5

REGULATION OF WATER Water balance exists when water intake equals water output: 1. The volume of water gained each day varies from individual to individual. 2. About 60% of daily water comes from drinking, 30% comes from what we perceive as solid foods, and 10% from the metabolism. 3. Thirst is the primary mechanism which controls water intake. It derives from the osmotic pressure of extracellular fluids and a thirst center in the hypothalamus. Once water is taken in, the resulting distention of the stomach will inhibit the thirst mechanism. 4. The distal convoluted tubules and collecting ducts of the nephrons regulate water output. 5. Antidiuretic hormone (ADH) from the posterior pituitary causes a reduction in the amount of water lost in the urine. 6. When drinking adequate water, the ADH is inhibited, and more water is lost in urine. Differences between Children and Adults 1. Fetus has larger water content which decreases to puberty level by one year of age. 2. Infants have larger body surface area as compare to body mass. This results in greater water loss and dehydration. 3. Children up to two years of age have higher metabolic rate. 4. Kidneys are immature in infants so more water is needed to excrete waste products. 5. Small children depend on adults for their fluid requirement. ELECTROLYTES METABOLISM Electrolytes of importance in the human body are sodium, potassium, calcium, magnesium, phosphate, bicarbonate and H+ ion. Fluid balance is linked to electrolyte balance. Electrolyte establishes osmotic pressure and is mainly responsible for movement of fluids across cell membranes. Electrolytes are substances that dissociate in solution to form charged particles or ion and those which do not dissociate are called as non-electrolytes. Positively charged particles are known as cations while negatively charged ions are called as anions. Distribution of electrolytes in various body fluids is show in Figure 16.2. FUNCTIONS OF ELECTROLYTES 1. Carry electric current thus promote neuromuscular excitability and vital cellular functions 2. Regulation of acid-base

PHYSIOLOGY OF FLUIDS AND ELECTROLYTES

Fig. 16.2: Composition of ECF, ICF and transcellular fluids

3. Essential minerals. 4. Controls osmosis and osmolarity Electrolytes balance is maintained by: Aldosterone: Increases sodium, chloride and H2O and decreases potassium level. Atrial natriuretic peptide: It has opposite effect to that of aldosterone. Antidiuretic hormone: It increases water and decreases solutes. Parathyroid hormone: Increases Ca2+ and decreases phosphates level. Calcitonin: Calcitonin has opposite effect to that of parathyroid hormone. Sodium (Normal Range 135-145mEq/L) Sodium is predominantly present in ECF and it enters the body through gastrointestinal tract except intravenous therapy. It is eliminated by kidney, sweat or gastrointestinal tract. The average sodium intake is 2-3mEq/100kcal/ day. Sodium is responsible for 90-95% osmotic pressure and is regulated by aldosterone, ADH and renin angiotensin- aldosterone and atrial natriuretic peptide. The resting cell membrane is impermeable to sodium. An abnormal serum sodium concentration does not necessarily imply abnormal sodium balance. Thus, most instances of abnormal sodium level are associated with abnormal serum osmolarity.7-9 Potassium (Normal Range 3.5-5.0 mEq/L) Potassium is the second most abundant cation in the body and ICF. Total body potassium is approximately 50 mEq/kg of body weight of which 95% is present in cells. The difference between ECF and ICF is maintained by Na–K–ATPase pump. It is less in females as compare to males and decreases with age. Despite the fact that potassium is mostly found in the intracellular space, 90%

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is available for exchange, hence allowing for major shifts between various compartments. Potassium is also exchanged for H+ thus regulating the pH of ICF. The ECF concentration of potassium is significant because the individual ionic species are under the influence of gradient across the cell membrane: electrical and chemical. It is more significant in case of excitable tissue. The occurrence of the action potential in its various phases is as a result of rapid changes in membrane permeability to sodium, potassium and calcium, thereby altering their resting concentrations and propagating the flow of currents (Fig. 16.3).6 Potassium is primarily regulated by aldosterone. Calcium (Normal Range 8.8-10.4 mg/dl) Calcium is one of the major divalent ions in the body. It is mainly ingested in diet, absorbed in intestine, filtered from glomeruli of kidney, reabsorbed in renal tubules and eliminated in urine. Approximately 99% of calcium is present in bone. Remaining 1% is present in body fluids. Calcium performs number of physiological and biological functions, such as muscle contraction, cell motility and modulation of cell membrane permeability to sodium and potassium. It plays important role in action potential of excitable tissues. Regulation of calcium primarily depends upon parathyroid hormone (PTH), calcitonin and vitamin D. Magnesium (Normal Range 1.7-2.3 mg/dl) Magnesium is the fourth most abundant divalent ion in body and second most prevalent intracellular cation. Magnesium is essential for the function of more than 3000 cellular enzymes in the human body specifically involved in neuromuscular activity, nerve transmission in CNS and myocardial functioning, including related to the transfer for phosphate groups, all reactions that require adenosine triphosphate (ATP). It also plays important role in the function of cell membrane Na– K–ATPase pump. The average adult contains 24g of magnesium. Values for children in different age groups are not well defined. The normal values in serum depend upon daily intake both in children as well as in adults. The daily requirement in children is 150 mg/day approximately. Hypomagnesemia is common in ICU and is an important prognostic marker. Phosphates (Normal Range 2.2-4.4 mg/dl) Phosphorus is an important intracellular anion and serves number physiological roles in various capacities or forms. It forms essential component of phospholipids, nucleic acids and play role in acid-base buffer system and cellular metabolism by forming high-energy rich bonds. Approximately 1% of total phosphorus in body is in ECF with major part present in bones (85%) and ICF. The normal concentration varies in serum with age and 55% of which is in ionized form and physiologically active. Various factors modulate the serum level of phosphorus which includes insulin, vitamin D3, PTH, and level of renal functions. There is inverse relationship with Ca2+, PTH and calcitonin. Chloride (Normal Range 98-108mEq/L) Chloride is a most important extracellular anion in extracellular fluid, which diffuses easily between interstitial space and intracellular fluid. It helps in balancing osmotic potential and electrostatic equilibrium between different fluid compartments. It plays a key role in HCl formation in the

PHYSIOLOGY OF FLUIDS AND ELECTROLYTES

stomach. Chloride level is controlled by aldosterone. Deficiency of chloride can lead to muscle spasms and coma. REGULATION OF ELECTROLYTES 1. The concentrations of the cations, especially sodium, potassium, and calcium, are very important especially for an action potential. 2. Sodium ions account for 90% of the positively charged ions in extracellular fluids; the action of aldosterone on the kidneys regulates sodium reabsorption. 3. Aldosterone also regulates potassium ions; potassium ions are excreted when sodium ions are conserved. 4. Calcium concentration is regulated by parathyroid hormone, which increases the concentrations of calcium and phosphate ions in extracellular fluids and by calcitonin, which does basically the reverse. 5. Generally, the regulatory mechanisms that control positively charged ions secondarily control the concentrations of anions. Maintenance Requirement of Fluids and Electrolytes Maintenance requirements of fluids and electrolytes depend upon the metabolic rate of the child. This in turns depends upon age, body weight, temperature, type of activity and presence of illness. Maintenance requirements of fluid and electrolytes are calculated to replace losses through kidney, lungs, skin and gastrointestinal tract. Fluids and electrolytes have to be adjusted as disease state or abnormal conditions. Different formulae have been used to calculate the fluids and electrolytes requirement.10, 11 1. Holliday and Segar method: Based on body weight and caloric expenditure: Body weight Caloric expenditure 1-10 kg 100 kcal/kg/24 h 4 ml/kg/h 10-20kg 1000 kcal + 50 kcal/kg/24 h 6 ml/kg/h >20kg 1500 kcal + 20 kcal/kg/24 h 7 ml/kg/h Water 100 ml/100 kcal/24 h Sodium 3 mmol/100/24 h Potassium 2 mmol/100 kcal/24 h 2. Body surface area method: Water 1500 ml/M2/24 h Sodium 30-50 mEq/M2/24 h Potassium 20-40 mEq/M2/24 h 3. Fluid and electrolyte requirement in specific conditions: • Replace fluid for intraoperative, third space loss, and any extraordinary loss during surgical procedure. • Postoperative: Give 85% of maintenance in first 24 hours and give normal maintenance requirement for next 24h. • Many situations of gut surgery will require higher fluid replacement. There may be gut loss that may not always be calculated by Right aspirates as wall edema and intestinal losses

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can remain unaccounted for the first few days after major intestinal surgery. These children mat need 1.5 times their daily maintenance requirements. Hypotonic fluids should also be avoided. • Third space losses: Replacement guidelines: Major surgery 10 ml/kg/h Minor surgery 5 ml/kg/h Extremities 2 ml/kg/h • Burns: 1. Parkland formula ( 4 ml/kg/% of burn + Maintenance), 2. Brooks formula (2 ml/kg/% of burn + Maintenance) 3. Shriner burns institute (5000ml/m2 for burns area + 2000 ml/m2 for body surface are exclude burn area). Parenteral Fluids (Table 16.2) Classification of parenteral fluids: It helps us to understand the use of proper intravenous fluids in critical care units. 1. Maintenance fluids: Designed to replace fluid normally lost through gastrointestinal tract, kidney, skin and respiratory system, e.g. isolyte P. 2. Replacement fluid: They contain sodium in 130-155mEq/l and are usually isotonic. 3. Balanced salt solution: Fluids which mimics ECF 4. Crystalloid solutions: They are used to expand ECF and contains crystalline dissolved in water 5. Colloids solution: Colloids are particles in suspension and of larger molecular weight than crystalloids. 6. Special solutions: Hypertonic solutions, e.g. magnesium sulphate. Table 16.2: Composition of various parenteral fluids +

Fluid

Na

NS 0.9% D5 saline 0.18% D5 1/2NS DNS 3% NaCl RL D5 RL Dextrose 5% Dextrose 10% Hartman’s Hoemacel Hetastarch Albumin 4.5% Plasma Bicarbonate

154 30 77 154 513 130 130 131 145 154 100 pg/ml but levels come down later and may be inappropriately low in prolonged septic shock.51, 52 Actions of VP are mediated via its three receptor subtypes designated as V1 (V1R/V1a), V2 (V2R) and V3 (V1b).47, 48 V1 vascular receptors are located on vascular smooth muscle and mediate vasoconstriction. Additionally, V1 receptors are found in the kidney, myometrium, bladder, adipocytes, hepatocytes, platelets, spleen, and testis. V1-receptor activation mediates vasoconstriction by receptor-coupled activation of phospholipase. C and release of Ca++ from intracellular stores via the phosphoinositide cascade.53, 54 V2 renal receptors (V2R), which cause the antidiuretic effects of vasopressin, are present in the renal collecting duct system and endothelial cells. Kidney V2 receptors interact with adenylyl cyclase to increase intracellular cyclic adenosine monophosphate (cAMP) and cause retention of water.55 V3 pituitary receptors (formerly known as V1b) have central effects, such as increasing adrenocorticotropic hormone (ACTH) production, activating different G proteins, and increasing intracellular cAMP.56 VP also acts on oxytocin receptor which is important from the point of view of its vasodilator action on certain vital organs through nitric oxide (NO) mediated pathway. Blood flow within the coronaries, as well as the cerebral, pulmonary, and renal vascular beds, is preserved, promoting shunting to those areas. This regional vasodilation is likely the result of a complex interplay of vasopressin activity at V1 and endothelial V3 and oxytocin receptor sites producing an increase in nitric oxide release. In addition to these direct effects, vasopressin may also enhance or restore catecholamine sensitivity. Synthetic vasopressin (8-arginine vasopressin) acts at the same receptor sites as endogenous vasopressin, producing an identical physiologic response.47, 57 Terlipressin is a long acting analogue of vasopressin that has been shown to have higher affinity for vascular receptors than vasopressin and has demonstrated potent vasopressor effects in adult patients with norepinephrine resistant septic shock.58 Clinical Use Vasopressin is now emerging as a rational therapy in the management of septic shock and vasodilatory shock (systemic inflammatory response syndrome [SIRS] with hypotension) from other causes. It is primarily used in catecholamine resistant vasodilatory shock. Most form of shock like states cause high levels of vasopressin levels in the body. But hemorrhage and septic shock cause biphasic changes in vasopressin concentrations, high concentrations in early shock, which decreases as the shock state progresses. It has been observed by Landry et al52 and also corroborated in other studies as well.51, 59 Probable reason for this VP deficiency is depletion of neurohypophyseal stores after prolonged stimulation. Apart from this, autonomic insufficiency which leads to impaired release of VP and elevated endogenous NO and norepinephrine levels that have a central inhibitory effect on vasopressin release have also been implicated for its low level in this condition. Many patients of septic shock show poor response to conventional catecholamine, probably related to receptor down regulation, and increased NO level and activation of K+ ATP channels in blood vessel smooth muscle cells.50, 51 In contrast septic shock patients are exquisitely sensitive to low dose vasopressin.51, 59, 60 In many studies VP infusion in the dose of 0.01-0.04 U/min resulted

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in improved mean arterial pressure and permitted withdrawal of catecholamines.51, 59, 61, 62 Apart from this it has also been found to improve urine output. Although pediatric studies are few, its benefit has been demonstrated even in children.63-66 Recently reports with the use of terlipressin have also been published.67-69 Although vasopressin has shown promise in treatment of advanced vasodilatory shock, there are still no randomized controlled proving its efficacy. Further trials will be needed to standardize the exact timing and dose for its use in such situations. Pharmacokinetics Because vasopressin is destroyed by gastric trypsin, it must be administered parenterally. Vasopressin is rapidly degraded by enzymes in the liver and kidneys, with elimination halflife of approximately 10 to 35 minutes.47, 57 Renal insufficiency and hepatic failure prolong its halflife.

Dosing, Preparation and Administration Vasopressin is available as a 20-unit/ml injection. For continuous intravenous infusion, it should be diluted with normal saline or 5% dextrose to a final concentration of 0.1 to 1 unit/ml. Administration through central venous access is recommended to minimize the risk of extravasation. Although the stability of vasopressin infusions with other drugs has not been studied, a recent report on bolus vasopressin administration found it to be compatible with most of the drugs used commonly in the ICU. Studies of vasopressin in adults with vasodilatory shock have used infusion rates of 0.01 to 0.1 units/min. In pediatric patients, a vasopressin dose of 0.3 to 2 milliunits/kg/min (equivalent to 0.0003 to 0.002 units/kg/min or 0.01 to 0.12 units/kg/hr) is recommended, based on the report by Rosenzweig.63 The infusion should be titrated to optimize blood pressure and perfusion. It has been suggested that vasopressin infusions may be tapered over a 2 to 3 hour period, once blood pressure and the doses of concomitant catecholamine infusions are stabilized.

Drug Interactions The vasoconstrictive effects of vasopressin are counteracted by vasodilators such as nitroglycerin or nitroprusside. The antidiuretic effect of vasopressin is increased by concomitant administration of carbamazepine chlorpropamide, fludrocortisone, and tricyclic antidepressants. The antidiuretic effect of vasopressin may be reduced by concurrent use of demeclocycline, heparin or lithium. Adverse Effects High dose vasopressin administration has been associated with hypertension, bradycardia, arrhythmias, and myocardial infarction. These adverse effects have been reported most frequently in patients with cardiovascular disease. Administration of vasopressin without adequate fluid resuscitation may also result in significant ischemia of other organs, including the gastrointestinal tract and kidneys. The development of ischemic skin and mucous membrane lesions is a known complication of vasopressin therapy; resulting from the intense vasoconstriction produced within the capillaries.70 Ischemic lesions have been estimated to occur in as many as 10 to 30% of patients receiving low-dose vasopressin infusions. Extravasation of vasopressin from an infusion site can

INOTROPES AND VASOPRESSORS

also produce intense local vasoconstriction, which may result in severe tissue necrosis and gangrene. The skin, particularly around the site of infusion, should be closely inspected on a regular basis to identify any signs of decreased perfusion. Other adverse effects associated with vasopressin include: venous thrombosis, tremor, vertigo, sweating, hyponatremia, urticaria, abdominal cramps, vomiting, and bronchial constriction. Hypersensitivity reactions, including anaphylaxis, have also been reported. Because of the ability of vasopressin to rapidly increase extracellular water content, it should be used with caution in patients with chronic nephritis and congestive heart failure. One of the earliest inotropes mostly used in situations of poor cardiac performance (congestive cardiac failure) and for rhythm abnormalities such as atrial fibrillation, and tachycardic rhythms: Digoxin will be discussed in the following section, followed by the clinical pharmacology and practical use of various inotropes and vasopressors in the PICU . DIGOXIN A digitalis glycoside has been used in congestive cardiac failure for long time.71, 72 Mechanism (s) of Action Electrolyte changes occur with each heart beat (action potential). • At rest – Sodium is high outside – Potassium is high inside – Free calcium is low inside • After the action potential goes through: – Sodium is higher inside – Potassium is lower inside – Free calcium is higher inside Something has to put things back where they belong after the action potential. That something is the Na/K ATPase (actually many copies of this tiny pump per cell). Digoxin inhibits the Na/ K ATPase pump slowing the depolarization of SA node and increases the refractory period of AV node. • Positive inotropic effect • Negative chronotropic effect of digoxin • Stimulates vagus centrally • Increases refractoriness of AV node • Decreases ventricular response to atrial rate • Controls heart rate in atrial fibrillation • Slows depolarization rate of SA node • Decreases sinus rate • Decreases heart rate in sinus tachycardia • Decreases sympathetic tone • Contractility and stroke volume increase

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It is potentially invaluable in patients with atrial fibrillation and coexistent heart failure, improving control of the ventricular rate and allowing more effective filling of the ventricle. Digoxin is also used in patients with chronic heart failure secondary to left ventricular systolic impairment, in sinus rhythm, who remain symptomatic despite optimal doses of diuretics and angiotensin converting enzyme inhibitors, where it acts as an inotrope. Practical Aspects The Digitalis Investigation Group’s large study found that digoxin was associated with improvement in the symptoms of patients with congestive heart failure, when added to treatment with diuretics and angiotensin converting enzyme inhibitors. Importantly, there were greater absolute and relative benefits in the patients who had resistant symptoms and more severe impairment of left ventricular systolic function. However, although there was a reduction in the combined end points of admission and mortality resulting from heart failure. Table 17..3 depicts comparative pharmacokinetics of various oral preparations of digoxin. Table 17.3: Comparative pharmacokinetics of digoxin dose forms

Oral absorption Time to peak (min)

Tablets

Elixir

Capsules

60% 90

80% 45-60

75-90% 60-90

Maintenance dose is 10 microgram/kg daily. Reduced maintenance dose should be given, when renal impairment is present, and when used with drugs that increase digoxin concentrations (amiodarone, verapamil). Concentrations should be monitored, especially in cases of uncertainty about whether therapeutic levels have been achieved (range 6 hours after dose: 1.2-1.9 ng/ml). Potassium concentrations (avoid hypokalemia) and renal function should be monitored. Adverse Effects Digoxin toxicity may be associated with: (a) adverse symptoms (for example, nausea, vomiting, headache, confusion, visual symptoms); and (b) dysrhythmias (for example, atrioventricular junctional rhythms, atrial tachycardia, atrioventricular block, ventricular tachycardia). Serious toxicity should be treated by correcting potassium concentrations and with drugs such as Beta 2 blockers and glycoside binding agents (cholestyramine), and in severe cases by specific digoxin antibodies (Digibind). SUMMARY Practical approach to the patient who may require inotropes (Table 17.4) Drip dose calculation (rule of six) Dopamine, dobutamine 6 mg/kg body weight in 100 ml: 1 ml/hr = 1 microgram/kg/min Epinephrine, Norepinephrine 0.6 mg/kg body weight in 100 ml: 1 ml/hr = 0.1 microgram /kg/min.

INOTROPES AND VASOPRESSORS Table 17.4: Selecting inotropic and vasopressor agents for specific hemodynamic disturbances in children Hemodynamic pattern

Blood pressure

SVR

Normal

Decreased

Elevated

Stroke index high

None or Dopamine

None

Stroke index low to normal

Dobutamine or Dopamine

Dopamine and Epinephrine and add Norepinephrine Consider Vasopressin

Cardiogenic shock

Dobutamine or Epinephrine or Milrinone Levosimendan Dopamine (Not available)

Dobutamine + Milrinone Nitroprusside

CHF

Dobutamine or Dopamine or Milrinone

—

Dobutamine plus Nitroprusside

Bradycardia

None

Isoproterenol Epinephrine

None

Septic shock

Dobutamine plus Nitroprusside

Guidelines 1. 2. 3. 4. 5.

Aggressively sustain the blood pressure Assess the patient rapidly and thoroughly Ensure adequate volume status (CVP8-12) Consider the administration of a small bolus of inotrope Wean the inotropes as rapidly as you can.

The assessment of response to inotropic support is undertaken utilizing a few clinical pointers: 1. Improvement in blood pressures 2. Improvement in thermoregulation 3. Increased urine output 4. Increased oxygenation 5. Decreased base deficit and lactate 6. Shift of mixed venous concentration towards normal 7. The core- peripheral temperature gradient narrows 8. Cardiac output returns to normal 9. Patient looks better. REFERENCES 1. Goldberg LI, Raifer SI. Dopamine receptors: applications in clinical cardiology. Circulation 1985;72:245. 2. Zaritsky A. Essentials of critical care pharmacology. In Chernow B, editor: Baltimore, Williams and Wilkins, 1994. 3. Girardin E, Berner M, Rouge JC, et al: Effect of low dose dopamine on hemodynamic and renal function in children. Peditr Res 1989;26:200.

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PEDIATRIC INTENSIVE CARE 4. Ichai C, Soubielle J, Carles M, et al. Comparison of the renal effects of low to high doses of dopamine and dobutamine in critically ill patients: a single-blind randomized study. Crit Care Med 2000;28:921. 5. Bellomo R, Chapman MJ, Finfer S, et al. Low dose dopamine in patients with early renal dysfunction. ANZICS Clinical Trials Group. Lancet 2000;356:2139. 6. Carcillo JA, Fields AI. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med2002;30:1365. 7. Ushay HM, Notterman DA. Pharmacology of pediatric resuscitation. Pediatr Clin North Am 1997;44:207. 8. Wessel DL. Managing low cardiac output syndrome after congenita! heart surgery. Crit Care Med 2001;29:S220. 9. MacLeod CM. Drugs used in acutely ill patient. Dis Mon 1993;39:362. 10. Eldadah MK, Schwartz PH, Harrison R, et al. Pharmacokinetics dopamine in infants and children. Crit Care Med 1991;19:1008. 11. Berg RA, Pad bury JF, Donnerstein RL, et al. Dobutamine pharma cokinetics and pharmacodynamics in normal children and adolescents. J Pharmacol Exp Ther 1993;265:1232. 12. Lemaire F. Effect of catecholamines on pulmonary right-to-left shunt. Int Anesthesiol Clin 1983;21:43. 13. Rennotte MT, Raynaert M, et al. Effects of two inotropic drugs, dopamine and dobutamine, on pulmonary gas exchange in artificially ventilated patients. Intensive Care Med 1989;15:160. 14. Van den Berghe G, de Zegher F, Lauwers P. Dopamine suppresses pituitary function in infants and children. Crit Care Med 1994;22:1747. 15. Siwy BK, Sadove AM. Acute management of dopamine infiltration with Regitine. Plast Reconstr Surg 1987;80: 610. 16. Leirer CV, Unverferth DV. Drugs five years later. Dobutamine. Ann Intern Med 1983;99:490. 17. Ruffolo RR Jr, Spradio TA, Pollock GD, et al. Alpha and beta adrenergic effects of the sterioisomers of dobutamine. J Pharmacol Exp Ther 1981;219:447. 18. Berg RA, Pad bury JF, Donnerstein RL, et al. Dobutamine pharmacokinetics and pharmacodynamics in normal children and adolescents. J Pharmacol Exp Ther 1993;265:1232. 19. Martinez AM, Padbury JF, Thio S. Dobutamine pharmacokinetics and cardiovascular responses in critically ill neonates. Pediatrics 1992;89:47. 20. Habib DM, Padbury JF, Anas NG, et al. Dobutamine pharmacokinetics and pharmacodynamics in pediatric intensive care. Crit Care Med 1992;20:601. 21. Berner M, Rouge JC, Friedli B. The hemodynamic effect of phentolamine and dobutamine after open-heart operations in children: influence of the underlying heart defect. Ann Thorac Surg 1983;35:643. 22. Bohn DJ, Poirier CS, Edmonds JF, et al. Hemodynamic effects of dobutamine after cardiopulmonary bypass in children. Crit Care Med 1980;8:367. 23. Hoffman BB. Catecholamines, sympathomimetic drugs and adrenergic receptor antagonists. In: Hardman JG, Limbird LE (Eds). Goodman and Gillman’s the pharmacologic basis of therapeutics. New York, McGraw Hill 2001. 24. Moran JL et al. Epinephrine as an inotropic agent in septic shock: A dose profile analysis. Crit Care Med 1993;21:70. 25. Borthne K, Haga P, Langslet A, et al. Endogenous stimulates both alpha 1 and beta adreno- receptors in myocardium from children with congenital heart defects. J Mol Cell Cardiol 1995;27:693. 26. Fisher DG, Schwartz PH, Davis AL. Pharmacokinetics of exogenous epinephrine in critically ill children. Crit Care Med 1993;21:111. 27. Solomon SL, Wallace EM, Ford-Jones EL, et al. Medication errors with inhalant epinephrine mimicking an epidemic of neonatal sepsis. N Engl ] Med 1984;310:166. 28. Brown MJ, Brown DC, Murphy MB. Hypokalemia from beta2- receptor stimulation by circulating epinephrine. N Engl J Med 1983;309:1414. 29. Lippmann M, Reisner LS. Epinephrine injection with enflurane anesthesia: incidence of cardiac arrhythmias. Anesth Analg 1974;53:886. 30. Schlepper M, Thormann J, Kremer P, et al. Present use of positive inotropic drugs in heart failure. J Cardiovasc Pharmacol 1989;14(Suppl 1):S9. 31. Stiles GL. Adrenergic receptor responsiveness and congestive heart failure. Am J Cardiol 1991;67:13C. 32. Moolhoff T, Loick HM, Van Aken H, et al. Milrinone modulates endotoxemia, systemic inflammation and subsequent acute phase response after cardiopulmonary bypass. Anesthesiology 1999;90:70-80. 33. Chaterjee K. Phosphodiesterase inhibitors: alterations in systemic and pulmonary hemodynamics. Basic Res Cardiol 1989;84(Suppl 1):213. 34. Chang, et al. Milrinone: systemic and pulmonary hemodynamic effects in neonates after cardiac surgery. Crit Care Med 1995;23:1907.

INOTROPES AND VASOPRESSORS 35. Bailley JM, Miller BE, et al. The pharmacokinetics of Milrinone in pediatric patients after cardiac surgery. Anesthesiology 1999;90:1012. 36. Barton P, Garcia J, et al. Hemodynamic effects of IV Milrinone lactate in pediatric patients with septic shock. A prospective, double blind, randomized, placebo controlled, interventional study. Chest 1996;109:1302. 37. Karlsberg RP, Dewood MA, DeMaria AN, et al. Comparative efficacy of short term intravenous infusions of milrinone and dobutamine in acute congestive failure following acute myocardial infarction.Clin Cardiol 1996;19:21. 38. Young RA, Ward A Milrinone. A preliminary review of its pharmacological properties and therapeutics use. Drugs 1988;36:158. 39. Ramamoorthy C, et al. Pharmacokinetics and side effects of Milrinone in infants and children after open heart surgery. Anaesth Analg 1998;86:283. 40. Lindsay CA, Barton P, et al. Pharmacokinetics and pharmacodynamics of milrinone lactate in pediatric patients with septic shock. J Pediatr 1998;132:329. 41. Fukuoka T, Nishimura M, Imanaka H, et al. Effects of norepinephrine on renal functions in septic patients with normal and elevated serum lactate levels. Crit Care Med 1989;17:1104. 42. Hesselvik JF, Brodin B. Low dose norepinephrine in patients with septic shock and oliguria: Effects on after load, Urine flow and oxygen transport. Crit Care Med 1989;17:179. 43. Martin C, Viviand X, Leone M, et al. Effects of norepinephrine on the outcome of septic shock. Crit Care Med 2000;28:2758. 44. Norepinephrine bitartrate injection. In: USP package insert. Chicago, Abbot laboratories, 1999. 45. Goldstein DS, Eisenhofer G, et al. Sources and significance of plasma levels of catecholamines and their metabolites in humans. J Pharmacol Exp The 2003;305:800. 46. Siwy BK, Sadove AM. Acute management of dopamine infiltration with Regitine. Plast Reconstr Surg 1987;80: 610. 47. Holmes CL, Patel BM, Russell JA, et al. Physiology of vasopressin relevant to management of septic shock. Chest 2001;120:989-1002. 48. Ranger GS. The physiology and emerging role of antidiuretic hormone. IJCP 2002;56:777-82. 49. Jackson E. Vasopressin and other agents affecting the renal conservation of water. In: Hardman JG, Limbird LE (Eds). Goodman and Gilman’s the pharmacological basis of therapeutics. New York, McGraw Hill, 2001. 50. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Eng J Med 2001;345:588-95. 51. Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano Y, Boyle WA. Hemodynamic and metabolic effects of low dose vasopressin infusion in vasodilatory Septic shock. Crit Care Med 2001;29:487-93. 52. Landry DW, Levin HR, Gallant EM, Ashton RC, Seo S, Alessandro DD, O2 MC, Oliver JA. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997;95:1122-25. 53. Thibonnier M. Signal transduction of V1-vascular vasopressin receptors. Regul Pept 1992;38:1-11. 54. Briley EM, Lolait SJ, Axelrod J, et al. The cloned vasopressin V1a receptor stimulates phospholipase A2, phospholipase C, and phospholipase D through activation of receptor-operated calcium channels. Neuropeptides 1994;27:63-74. 55. Orloff J, Handler J. The role of adenosine 3, 5-phosphate in the action of antidiuretic hormone. Am J Med 1967;42:757-68 56. Thibonnier M, Preston JA, Dulin N, et al. The human V3 pituitary vasopressin receptor: ligand binding profile and density-dependent signaling pathways. Endocrinology 1997;138:4109-4122. 57. Pitressin® product information. Monarch Pharmaceuticals. July 1998. Available at http:// www.kingpharm.com/uploads/pdf inserts/Pitressin PI.pdf 58. O’Brien A, Clapp L, Singer M. Terlipressin for nor epinephrine resistant shock. Lancet 2002;359:1209-1210. 59. Malay MB, Ashton RC, Landry DW, Townsend RN. Low dose vasopressin in the treatment of vasodilatory septic shock and (discussion). J Trauma 1999;47:699-705. 60. Wenzd V, Lindner KH. Employing vasopressin during cardiopulmonary resuscitation and vasodilatory shock as a life sparing vasopressor. Cardiovascular Research 2001;51:529-41. 61. Landry DW, Levin HR, Gallans EM, Seo S, Alessandro DD, Oz MC, Oliver JA. Vasopressin presser hypersensitivity in vasodilatory septic shock. Crit Care Med 1997;25:1279-82. 62. Holnes CL, Walley KR, Chittock DR, Lehman T, Russell JA. The effects of vasopressin on hemodynamics and renal function in severe septic shock: A case series. Intensive Care Med 2001;27:1416-21. 63. Rosenzweig EB, Starc TJ, Chen JM, et al. Intravenous arginine-vasopressin in children with vasodilatory shock after cardiac surgery. Circulation 1999;100 (Suppl.):II-182- II-186. 64. Katz K, Lawler J, Wax J, et al. Vasopressin pressor effects in critically ill children during evaluation for brain death and organ recovery. Resuscitation 2000; 47:33-40.

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PEDIATRIC INTENSIVE CARE 65. Bojko T, Wirywan B, SapsM, et al. Usefulness of vasopressin in pediatric vasodilatory shock. Pediatr Crit Care Med 2000;IS:100. 66. Liedel JL, Meadow W, Nachman J, et al. Use of vasopressin in refractory hypotension in children with vasodilatoy shock: Five cases and a review of literature, Pediatr Crit Care Med 2002;3:15. 67. Rodriguez-Núñez A, Fernández-Sanmartin M, Martinón-Torres F, González-Alonso N, Martinón-Sánchez JM. Terlipressin for catecholamine-resistant septic shock in children. Intensive CareMed 2004;30:477-480. 68. Matok I, Leibovitch L, Vardi A, Adam M, Rubinstein M, Barzilay Z, Paret G. Terlipressin as rescue therapy for intractable hypotension during neonatal septic shock. Pediatr Crit Care Med 2004;5:116-118. 69. Rodriguez-Núñez A, et al. Rescue treatment with terlipressin in children with refractory septic shock: A clinical study. Crit Care Med 2006;10:R20. 70. Dunser MW, Mayr AJ, Tur A, et al. Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: Incidence and risk factors. Crit Care Med 2003;31:1384-8. 71. Zaritsky A. Essentials of critical care pharmacology. In: Chernow B (Ed). Baltimore, Williams and Wilkins, 1994. 72. Schmidt TA, Allen PD, Colucci WS, et al. No adaptation to digitalization as evaluated by digitalis receptor (Na, K-ATPase) quantification in explanted hearts from donors without heart disease and from digitalized recipients with end stage heart failure; A J CardioI 1993;71:110.

Krishan Chugh, MVH Chandramouli MULTIORGAN DYSFUNCTION SYNDROME 221

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Multiorgan Dysfunction Syndrome

Multiorgan dysfunction syndrome (MODS), systemic inflammatory response syndrome and sepsis are major clinical issues in pediatric intensive care units (PICUs). MODS represents the ultimate complication of infection, trauma and critical illness. EPIDEMIOLOGY Epidemiology of MODS in children has been detailed in several studies.1-4 Wilkinson et al first reported in 1986 the incidence and mortality of MODS as 27% and 54%, respectively, in 831 consecutive children admitted to a single PICU. Prior to this investigation, only data on adult MODS were available in the literature. Reported incidences for SIRS (82%), sepsis (21-23%), MODS (1127%), severe sepsis (4%), and septic shock (2%) indicate that SIRS occurs more frequently than any other diagnostic category in PICUs.1- 4 In addition, mortality rates of pediatric patients with MODS and a specific diagnostic category reveal interesting findings. Reported mortality rates are 52% for patients with MODS and septic shock, 40% for patients with MODS and severe sepsis, 25% for MODS and SIRS, and 12% for MODS without SIRS. Further analysis showed that, patients having secondary MODS had higher mortality rates (74% vs 30%), longer duration of MODS (10.9+ 11.6 days vs 3.6+3.7 days), longer duration of PICU stay (24.6+24 days vs. 7.9+14.2 days), and worse PRISM scores (26.1+14.7vs.20.1+13) compared with patients having primary MODS.4 Incidence of secondary MODS was lower than primary MODS (12% vs. 88%), and the risk of mortality was 6.5 times higher among children with secondary MODS. Primary MODS is considered the direct result of a well-defined insult in which organ dysfunctions occur early and can be attributed to the insult itself. However, secondary MODS may be the consequence of the host’s response. DEFINITION MODS can be defined as simultaneous occurrence of two or more organ dysfunctions.5 Organ systems typically included in the diagnostic criteria of pediatric MODS are cardiovascular, pulmonary,

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neurological, hematologic, renal, hepatic and gastrointestinal. Currently used diagnostic criteria for pediatric MODS are displayed in Table 18.1. MODS has also been described as primary MODS and secondary MODS. Primary MODS: It is defined as the occurrence of two simultaneous organ dysfunctions within the first week after PICU admission without subsequent evidence of sequential organ dysfunction. Secondary MODS: It is defined as one of the following: 1. Appearance of MODS more than 7days after admission to PICUs; or 2. Diagnosis of MODS 7 days or less after PICU admission, with subsequent sequential organ dysfunctions defined as an interval longer than 72 hours between time of MODS onset and attainment of maximum number of simultaneous organ dysfunction. ;

Table 18.1: Criteria for dysfunction5

Cardiovascular system 1. Systolic BP < 40 mm Hg (if age < 1year) or < 50 mm Hg (if age ≥ 1 year) 2. HR < 50 beats/min or > 220 beats/min (if age < 1 year) or < 40 beats/min or > 200 beats/min (if age ≥ 1 year) 3. Cardiac arrest 4. Serum pH < 7.2 with a normal PaO2 value 5. Intravenous infusion of inotropic agents (excluding dopamine < 5mg/kg/min) Respiratory system 1. RR > 90 breaths/min (if age < 1 year) or > 70 breaths/min (if age ≥ 1year) 2. PaCO2 > 65 mm Hg (8.7 kPa) 3. PaO2 < 40 mm Hg (5.3 kPa) in the absence of cyanotic congenital heart disease 4. Mechanical ventilation (for >24 hours in a postoperative patient) 5. PaO2/FiO2 < 200 in the absence of cyanotic congenital heart disease Neurologic system 1. Glasgow coma score < 5 2. Fixed dilated pupils Hematological system 1. Hemoglobin level < 50 g/l (< 5 g/dl) 2. White blood cell count < 3000 cells/dl 3. Platelet count < 20000 platelets/dl 4. D-Dimer > 0.5 mg/ml with prothrombin time >20 seconds or thrombin time > 60 seconds Renal system 1. Serum urea nitrogen > 100 mg/dl 2. Serum creatinine > 2 gm/dl without pre-existing renal disease 3. Dialysis Hepatic system 1. Total bilirubin > 3 mg/dl Gastrointestinal system 1. Blood transfusion of > 20 ml/kg in 24 hours because of gastrointestinal hemorrhage

ETIOLOGY A number of clinical conditions can lead to multiorgan dysfunction: • Sepsis • Acute asphyxia

MULTIORGAN DYSFUNCTION SYNDROME

• • • • • • • • • •

Inborn errors of metabolism Acute respiratory failure Acute renal failure Pancreatitis Intracranial hemorrhage Neurodegenerative disease Postoperative cardiac surgery Trauma Orthotropic liver transplantation, and Intussusception.

PATHOPHYSIOLOGY The development of MODS includes a complicated network of inter and intracellular actions. Because MODS can involve a variety of pathologic changes, different concepts of pathophysiology of MODS have been generated shown in Table 18.2. Although numerous unifying hypotheses for the pathophysiology of MODS are proposed, one that appears to encompass most of the associated research is the “ vicious reciprocal cycle of ischemia/reperfusion and inflammation.” Contributing to this vicious cycle of MODS (Flow chart 18.1) which mediates so called collateral damage associated with critical illness, is endothelial activation/injury, enhanced oxidant stress, altered apoptosis, and dysregulated coagulopathy. Each of these pathogenic processes contributes to, and is affected by both ischemia/reperfusion and inflammation. Table 18.2: Conceptual models of multiorgan failure (MODS) Pathologic process

Manifestations

Therapeutic implications

Uncontrolled infection

Persistent infection, nosocomial ICUacquired infection, endotoxemia

Aggressive use of antibiotics and source control measures

Systemic inflammation

Cytokinemia, leukocytosis, increased capillary permeability

Neutralization of specific cytokines or of activational pathways

Immune paralysis

Nosocomial infection, increased antiinflammatory cytokine levels

G-CSF, interferon

Tissue hypoxia

Increased lactate

Augmentation of DO2

Microvascular coagulopathy and endothelial activation

Increased procoagulant activity, decreased anticoagulant activity, increased von Willebrand factor, increased capillary permeability

Augmentation of anticoagulant mechanisms

Dysregulated apoptosis

Increased epithelial and lymphoid apoptosis, decreased neutrophils apoptosis

Caspase inhibition

Gut–liver axis

Increased infection with gut organism endotoxemia, Kupffer’s cell activation

Selective digtestive tract decontamination, enteral feeding

Modified from Marshall JC: Inflammation, coagulopathy, and the pathogenesis of multiorgan dysfunction. Crit Care Med 2001;29(7 Suppl):S99-S106.

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PEDIATRIC INTENSIVE CARE Flow chart 18.1: Pathophysiology of multi-organ dysfunction (MODS)

ENDOTHELIAL ACTIVATION/INJURY Endothelium regulates vasomotor tone, cellular trafficking, angiogenesis, coagulation and capillary permeability and in general acts as a multifunctional biosensor.6 A variety of insults, including decreased cardiac output, enhanced capillary leak, constricted arterioles, generalized vasoplegia, impaired erythrocyte, and leukocyte deformability as well as an activated, procoagulant endothelial phenotype, can impair microcirculatory flow and accordingly affect endothelial behavior. The endothelial response to ischemia/reperfusion is characterized by four major activities: vasomotor, coagulation, permeability and inflammation. Vascular endothelial damage associated with dysregulated coagulation and fibrinolysis is linked to thrombocytopenic MODS.7

MULTIORGAN DYSFUNCTION SYNDROME

APOPTOSIS Apoptosis is a physiologic mechanism where by activation of a specific DNA program induces cell death. It is, therefore a regulatory process for the proliferation and differentiation of cells. However, pathologic activation of apoptosis seems to be involved in the pathogenesis of MODS. Early lymphocyte apoptosis is associated with poor outcome in human sepsis.8-10 Evidence also shows neutrophil and macrophage apoptosis in the pathogenesis of MODS. Two Hit Theory Any severe impact to the human body, such as prolonged shock or traumatic or surgical injury, can directly induce the development of organ dysfunction. Possible mechanisms include ischemia, reperfusion injury, or immediate tissue destruction due to trauma. Such an event is called a first hit. This first hit may be severe enough to induce SIRS. Even if the first hit does not induce a primary MODS, a “second hit” such as infectious insult (e.g. pneumonia, bacteremia due to catheter infection), could further activate an immune system that is already primed by the first hit. The “ two- hit” theory hypothesises that a second ( or third ) insult amplifies the inflammatory response to the first hit in such a way that SIRS occurs. If these events are followed by multiple organ dysfunction, the term secondary MODS is used. Flow chart 18.2: Shift of the hemostatic balance toward a procoagulant state in sepsis. PAI, plasminogen activator inhibitor, TFPI, tissue factor pathway inhibitor. ( Modified from Levi M, Tencate H: Disseminated intravascular coagulation.N Eng J Med 1999;341:586-92)

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Altered Coagulation (Flow chart 18.2) Cytokines released during inflammation activate endothelium, and neutrophils and release tissue factor which activate coagulation cascade. Activated endothelium exhibits procoagulant state leads to intravascular thrombin formation. Generalized activation of coagulation system leads to disseminated intravascular coagulation. The embolization of micro-vessels by the continuous and latent coagulation is important in the development of microcirculatory dysfunction and organ failure. Monitoring and Laboratory Tests Because of the delayed onset nature of MODS, monitoring is essential for at least 10 days beyond the critical illness period. Baseline and subsequent functions of the organ systems that need to be monitored are listed in Table 18.3. Table 18.3: Monitoring of organ systems at risk of failure Pulmonary ABG and pH Change of ventilatory requirements Pulmonary function tests Chest imaging

Renal Urine examination BUN and creatinine Fractional excretion of sodium Drug levels Renal imaging

Cardiovascular Vital signs and capillary refill Hemodynamic measurements Cardiac index Preload and afterload ECG Cardiac enzymes Echocardiography

Metabolic Acid- base status Serum glucose Lactate and pyruvate levels Serum and urine amino acids

Neurologic Complete examination EEG ICP monitoring Neuroimaging

Hepatic Transaminases Bilirubin Ammonia

Hematologic Hemoglobin and hematocrit WBC and differential count Platelet count PT and PTT

Gastrointestinal Amylase, lipase Enteral feed tolerance

Fibrinogen and fibrin split products

Treatment Guidelines of MODS There is no evidence based medicine approach to reduce SIRS in pediatric patients with MODS. Thus, treatment should aim to limit inflammation and ischemia/reperfusion.

MULTIORGAN DYSFUNCTION SYNDROME

Clinically relevant interventions include: 1. Ensure adequate cardiac output and treat shock states by early goal directed initial resuscitation. 2. Treat infections early with appropriate antibiotics. 3. Resect foci of infected/necrotic tissue as early as possible. 4. Resolve/avoid metabolic acidosis. 5. Eliminate medical errors. 6. Start early enteral nutrition. 7. Maintain strict glycemic control. 8. Give stress bleeding prophylaxis. Newer therapies: These therapies requires larger randomised controlled trials to prove their efficacy in treatment. Immunomodulation: Nonspecific immunomodulation: Immune-enhancing diets Hemofiltration Plasmafiltration Specific immunomodulation: Modulation of the coagulation system Antithrombin 111 Activated protein C supplementation Tissue factor pathway inhibitor Molecules active against bacteria: Immunoglobulins Recombinant bactericidal/permeability–increasing protein Polyclonal antiendotoxin antibodies Molecules with anti- or procytokine effects: Monoclonal antibodies to TNF Bio- engineered soluble TNF receptors. PROGNOSIS There are several scoring systems to measure the severity and outcome of MODS. Currently PELOD (pediatric logistic organ dysfunction) is the only validated MODS scoring system used in children. Mortality depends on the number of organs affected: Two organs, 29%; three organs, 38%; four organs, 84%; five or more 100%. REFERENCES 1. Wikinson JD, Pollock MM, Glass NL, et al. Mortality associated with multiorgan dysfunction system and sepsis in pediatric intensive care unit. J Pediatr 1987;111:324–28. 2. Tantalean JA, Leon RJ, Santos AA, et al. Multiple organ dysfunction syndrome in children. Pediatr Crit Care Med 2003;4:181-85.

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PEDIATRIC INTENSIVE CARE 3. Kutko MC, Calarco MP, Flaherty MB, et al. Mortality rate in pediatric septic shock with and without multiple organ system failure. Pediatr Crit Care Med 2003;4:333-37. 4. Proulx F, Fayon M, Farell CA, et al. Epidemiology of sepsis and multiorgan dysfunction syndrome in children Chest 1996;109:1033-37. 5. Proulx F, BB, Lacorix J. Paediatric multiple organ dysfunction syndrome intensive care world 1997;14:7882. 6. Arid WC. Endothelium as an organ system. Critical Care Med 2004;32(Suppl):S 271-79. 7. Veno H, Hirasawa H, Oda, et al. Coagulation/fibrinolysis abnormality and vascular endothelial damage in the pathogenesins of thrombocytopenic multiple organ failure. Crit Care Med 2002;30:3242-48. 8. Le Tulzo, YL, Pangault C, Gacouin A, et al. Early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome Shock 2002;18:487-94. 9. Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with septic shock and multiorgan dysfunction, Crit Care Med 1999;27:1230-51. 10. Hotchkiss RS, Tinsley KW, Swanson PE, et al . Sepsis induced apoptosis causes progressive, profound depletion of B and CD4+ T lymphocytes in humans. J Immunol 2001;166:6952-63.

M Jayashree NONINVASIVE AND INVASIVE HEMODYNAMIC MONITORING IN THE PICU 229

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Noninvasive and Invasive Hemodynamic Monitoring in the PICU

Intensive monitoring of critically ill patients should involve an integrated assessment of tissue perfusion, oxygen delivery and cellular health at both the regional and global levels. Monitoring is not therapy and as clinicians/intensivists we must learn what variables to measure, measure them correctly, institute effective therapies where available and do this with minimum risk to the patient. Monitors used for purpose of patient monitoring present raw data without much intelligent integration. Hence these devices should serve as adjunct and not replacement for clinical skills. The objectives of monitoring in a critically ill child are: 1. Diagnostic: To assess the severity of the underlying condition. 2. Therapeutic: To indicate the need and timing for intervention 3. Assess response to therapy 4. Prognostic: Trends during monitoring help in the prediction of outcome 5. Warning: Audiovisual alarms in various monitors alert the clinician to untoward events. An ideal monitoring system should have the following prerequisites: 1. Ability to track rapid changes in monitored parameters 2. Data should be specific and reproducible 3. The equipment must be user friendly 4. Requirement of low maintenance 5. Minimum risk to patients. HEMODYNAMIC MONITORING Hemodynamic monitoring is defined as measurement and interpretation of biologic signals that describe performance of the cardiovascular system. Hemodynamic monitoring systems are used to guide therapies designed to support the cardiovascular system in cases of circulatory instability. Adequate oxygen delivery to all tissue beds is the fundamental goal of resuscitative measures.

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Global oxygen delivery (DO2) equals the product of cardiac output (CO) and arterial content of oxygen (CaO2). Cardiac output in turn depends on heart rate (HR) and stroke volume which is determined by preload, afterload and myocardial contractility. The determinants of CaO2 are hemoglobin (Hb), oxygen saturation (SaO2) and dissolved O2 (PaO2).Thus it is clear that adequacy of circulation can be assessed by an integrated monitoring of heart rate, blood pressure, cardiac output, Hb %, SaO2 and PaO2. Of the variables that determine or depend on cardiac output, only the heart rate and blood pressure can be easily measured. Stroke volume (SV) and systemic vascular resistance (SVR) have to be measured indirectly by examining the quality of pulses and tissue perfusion. CLINICAL HEMODYNAMIC PARAMETERS Heart rate: The typical physiological response to a fall in CO is tachycardia secondary to the compensatory sympathetic activity. Monitoring the change in trends of heart rate in response to therapy or intervention is very useful. Blood pressure: Blood pressure measurement is integral in the support of the critically ill patients. Cardiac output and systemic vascular resistance determine the mean blood pressure. It is very important to remember that pressure does not equal flow. When cardiac output falls, normal blood pressure is maintained by compensatory vasoconstriction causing high systemic vascular resistance. Hypotension is therefore a late sign of cardiovascular decompensation. Hence as clinicians one must not feel reassured by the presence of a normal blood pressure. Forward flow to vital organs, necessary for oxygen delivery depends on the presence of a pressure gradient or perfusion pressure. MAP is more appropriate than isolated systolic or diastolic BP for goal directed therapy in shock. Systemic perfusion: Since pressure does not equal flow, evaluation of indirect signs of blood flow and SVR is required. This can be done by monitoring the perfusion, i.e the presence and volume of central and peripheral pulses and assessing the end organ perfusion and function. A discrepancy in the volume of peripheral and central pulses may be caused by vasoconstriction or decreased cardiac output. A narrow pulse pressure suggests increased SVR compared to a wide pulse pressure which suggests decreased SVR. End organ perfusion: Decreased skin perfusion manifests as prolonged capillary refill and may be a sign of shock and decreasing cardiac output provided temperature abnormalities as cause for poor perfusion are ruled out. Mottling, pallor, delayed capillary refill and peripheral cyanosis are indicative of poor skin perfusion. Urine output is directly proportional to renal blood flow and glomerular filtration rate thereby making it a very good indicator of renal perfusion. Altered consciousness of any degree may be an indicator of impaired brain perfusion HEMODYNAMIC MONITORS Electrocardiography Monitoring (ECG) Most critically ill patients are always on continuous ECG monitoring. It is non-invasive, simple and useful in detection of cardiac rhythm disturbances and myocardial ischemia. However, it does not give any information on the functional status of the myocardium.

NONINVASIVE AND INVASIVE HEMODYNAMIC MONITORING IN THE PICU

Blood Pressure Monitoring

Noninvasive BP Monitoring (NIBP) The oscillometric technique is the most commonly used technique to measure arterial pressure. Mean arterial pressure (MAP) is most accurate by this method and diastolic pressure is the least accurate. The blood pressure readings are influenced by cuff size and placement and flow in the limb. Accurate blood pressure measurement requires the use of a proper sized cuff. Current recommendations require the use of a cuff that covers 40% of the mid upper arm circumference. The major limitations of NIBP are: • Readings can be fallacious in presence of hypoperfusion or peripheral vasoconstriction. • It gives intermittent readings and hence may not be useful in patients who require continuous monitoring. • Accuracy of readings are dependant on appropriate cuff size and placement.

Invasive BP Monitoring (IBP) Invasive BP monitoring is considered the gold standard for arterial pressure monitoring in an ICU. It is indicated in situations where there is need for continuous, reliable BP recording along with the need for frequent arterial sampling. The BP measured by this method is unaffected by poor flow or perfusion in the limb. IBP is a relatively safe procedure. Some of the complications include hemorrhage, hematoma, arterial thrombosis, vasospasm, ischemia and infection. DETERMINANTS OF CARDIAC OUTPUT The three major determinates of stroke volume include preload, contractility and afterload. Preload Assessment Ensuring optimum preload is the primary cornerstone of therapy in pediatric septic shock. Central venous pressure (CVP) is the most commonly used measure of preload. The trends of CVP recordings are more important than a single value. It is important to recognize the optimal value that supports adequate cardiac output for an individual patient rather than aiming for a standard value. It is a useful measurement when it is low indicating need for volume expansion. Observation of the response to volume helps in deciding adequacy of fluids and need for vasoactive drugs. An initial high value of CVP, however, should prompt more careful evaluation before attributing it to fluid overload. Pericardial effusion, tamponade, constrictive pericarditis, high ventilatory pressure/PEEP, pulmonary thromboembolism, pulmonary hypertension are some of the conditions where the CVP may be misleadingly high in spite of poor ventricular filling. An echocardiography may assist in better evaluation at this juncture. Pulmonary Artery Catheter The pulmonary artery catheter (PAC) was introduced into clinical practice as early as the 1970’s. The PAC allows continuous pressure measurement in the RA (CVP) and the pulmonary artery (PA). Cardiac output measurement can be made intermittently or continuously by the thermodilution method. Some catheters continuously measure mixed venous saturation (SVO2).Given the fallacies of CVP in certain situations, it may be difficult for a clinician to draw conclusion on the type of

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shock based on CVP measures alone. PA catheter measurements are very useful in such situation allowing more accurate assessment of left ventricular preload thus helping in qualifying the shock as cardiogenic, hypovolemic or distributive. However, the procedure is invasive and carries with it the risk of ventricular arrhythmias, infective endocarditis, tamponade and thrombosis with infarction. Contractility Assessment

Echocardiography The most common tool used for assessment of contractility in the PICU is the 2-D echocardiography. The echocardiography is a non-invasive indirect assessment of cardiac output. It estimates the ejection fraction (EF) which is a measure of myocardial contractility. However, it will be unreliable in condition of high SVR, obstructive lesions like aortic stenosis, where there will be good EF despite inadequate stroke volume. Similarly pharmacologic vasodilatation can increase stroke volume even with poor contractility. Afterload assessment: Ventricular afterload is difficult to assess in a precise or continuous manner and hence has to be derived from physical assessment of pulses, pulse pressure and capillary refill time. Cardiac output assessment: Assessment of cardiac output in the PICU setting is challenging and subject to a variety of potential errors. Thermodilution: This is the most common method for determining cardiac output in clinical practice. CO measurements are made intermittently with a PAC using bolus injections of iced or room temperature saline. The accuracy is reduced in the setting of poor technique, tricuspid regurgitation and septal defects. Pulse contour analysis: Analysis of the arterial pulse contour on a beat to beat basis can be used to estimate continues CO. It requires both a CVP and a femoral arterial catheter placement. The readings can be affected by vasoconstrictors. Thoracic electrical bioimpedance: The measurement is based on the observation that blood flow in the thoracic aorta can be quantified by continuously assessing the impedance to an AC current applied to thorax. Esophageal Doppler: A Doppler probe placed in the esophagus calculates stroke volume from the velocity of blood flow in the aorta. It also provides indirect measures of preload and afterload. Mixed venous oxygen saturation: Mixed venous oxygen saturation (SVO2) has been used as a surrogate for the adequacy of oxygen delivery (DO2). Normal SVO2 is more than 75%. When oxygen delivery declines, oxygen extraction by the tissues increases, thus decreasing the oxygen content of the blood entering the right heart. A low SVO2 may therefore indicate that DO2 is inadequate. Reduction in SVO2 may serve as a warning that something is wrong and alert the clinician. Some condition like anemia, hypermetabolic state and abnormal HBS can have low SVO2 in absence of low cardiac output. Similarly normal or high SVO2 does not always mean well for the patient; e.g. in severe sepsis patients are unable to utilize the oxygen delivered to the tissues.

NONINVASIVE AND INVASIVE HEMODYNAMIC MONITORING IN THE PICU

METABOLIC INDICATORS OF TISSUE PERFUSION AND O2 DELIVERY The microcirculation is the final pathway before delivery of oxygen to the cell by diffusion. The adequacy of the microcirculation and tissue perfusion can be monitored by looking at indicators that reflect tissue hypoxia. Serum lactate has been the most prominent and widely used metabolic indicator of tissue perfusion. It has been shown to correlate to mortality risk in postoperative cardiac surgery patients. Lactate/pyruvate ratios have also been used as surrogate for tissue hypoperfusion. Gastric tonometry has been studied extensively in adults as an indicator of adequacy of splanchnic tissue oxygen delivery. Unfortunately due to technical limitations this is not a widely adopted parameter in PICU setting.

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Praveen Khilnani, Joe Carcillo

Septic Shock

20 INTRODUCTION In past decade great strides have been made in the management of patients with severe sepsis and septic shock. Consensus definitions of sepsis were first published1 and recently updated in a consensus conference.2 Better understanding of pathophysiology, new interventions and better use of existing therapies in the past decade included the publication of surviving sepsis campaign guidelines3 and pediatric considerations.4 In 2002 Carcillo, et al published American College of Critical Care Medicine clinical guidelines for hemodynamic support of neonates and children with septic shock.5 These guidelines (will here on be referred to as pediatric sepsis guidelines ) were widely disseminated through the Society of Critical Care Medicine(SCCM) and the American Heart Association (AHA), as well as translated into Spanish and Portugese. These guidelines have been tested and the outcomes published by many centers.6-10 One Institution that put guidelines into practice reported improvement in outcomes 1-3% in previously healthy and 7-10% in chronically ill children,11 in line with best practice outcomes as targeted by the 2002 guidelines.12-14 According to WHO 2006 data , pneumonia, diarrhea, neonatal sepsis are top on the list of killers. Considering above facts sepsis is clearly the top killer in 80% of the children in the world. Currently existing guidelines seem to be applicable to the developed countries and little is published regarding appropriate application of these guidelines in the developing countries especially in resource limited countries. At the World Federation of Pediatric Intensive Care and Critical Care Society (WFPICC) Congresss in Geneva june 2007, Dr Carcillo discussed the modification of guidelines published in 2002 in Critical Care Medicine especially for resource limited countries where simple things such as early fluid therapy, early antibiotics, oxygen by nasal cannula , vasopressors by peripheral intravenous(IV) access to achieve a goal directed therapy can potentially avoid further deterioration, improve outcomes and possibly avoid intubation and ventilation.

SEPTIC SHOCK

Development of Consensus for Application of Pediatric Sepsis Guidelines in India It is well known that in pediatric age group hypovolemia is the most common cause of shock and it is relatively easy to treat. Septic shock is the prototype combination of hypovolemia, cardiogenic and distributive shock, with considerably high mortality and difficult to treat in a peripheral setting with limitation of resources. This issue of practice and feasibility of delivery of care in the first hour in pediatric and neonatal patient with suspected sepsis, based on availability of equipment and availability of resources was discussed at great length by a panel of experts at the annual conference of Indian Academy of Pediatrics (Pedicon 2007), in Intensive care chapter session in Mumbai earlier this year and later at the National Congress on Pediatric Critical Care, in Delhi. Discussion also included issues such as rapid cardiopulmonary assessment to detect reliable clinical indicators of early sepsis and septic shock, differentiation of presence of fever and tachycardia from warm septic shock, indications for admission to the PICU, early fluid therapy and practical feasibility of rapid administration of fluid boluses in line with time limited expectations in the pediatric sepsis guidelines , inotropic and vasopressor support, steroid therapy, institution of early mechanical ventilation , initial early empirical antibiotic therapy , glycemic control and overall outcomes of sepsis. This article is intended to highlight the important points in the upcoming guidelines for management of pediatric and neonatal sepsis that are feasible , and of practical use to the practitioner in resource limited countries (countries such as India and Africa) with relatively higher infant mortality rates as compared to the western countries. Definitions Following are the definitions published in 2005,2 related to sepsis and septic shock. Table 20.1 shows age-specific ranges for physiologic and laboratory variables.

SIRS (Systemic Inflammatory Response Syndrome) The presence of at least two of the following four criteria, one of which must be abnormal temperature or leukocyte count: 1. Core temperature of >38.5°C or 180 >180 >180 >140 >130 >110

34 >22 >18 >14

Leukocyte count × 1000/cu m

SBP

>34 >19.5 or 17.5 or 15.5 or 13.5 or 11 or 50% FiO2 to maintain saturation >92% OR Need for nonelective invasive or noninvasive mechanical ventilation (d) Neurologic dysfunction: Glasgow Coma Score 3 points from abnormal baseline Hematologic dysfunction: Platelet count–80,000/mm3 or a decline of 50% in platelet count from highest value recorded over the past 3 days (for chronic hematology /oncology patients) OR International normalized ratio >2 Renal dysfunction: Serum creatinine >2 times upper limit of normal for age or 2-fold increase in baseline creatinine Hepatic dysfunction: Total bilirubin >4 mg/dL (not applicable for newborn)OR ALT 2 times upper limit of normal for age {BP, blood pressure; ALT, alanine transaminase.(a) See Table 20.1; (b) acute respiratory distress syndrome must include a PaO2/FiO2 ratio 10 mcg/kg/min) should preferably, be given via central line to prevent ischemic necrosis of the skin.

Dobutamine It is selective beta 1 agonist. It causes an increase in cardiac contractility and reduces peripheral resistance. The reduction in afterload and improved myocardial performance lowers ventricular filling pressures. Usual dose is 5 to 20 mcg/kg/min. It should not be used alone in septic shock due to risk of further drop in blood pressure. Dopamine or adrenaline can be used to prevent hypotension due to their vasoconstrictive action.

SEPTIC SHOCK

Adrenaline (Epinephrine) It is an alpha and beta adrenergic agonist. It is used in situations where dominant hemodynamic feature is peripheral vascular failure as in septic shock. At higher doses severe vasoconstriction can lead to lactic acidosis and renal and splanchnic ischemia. The usual dose is 0.1 mcg/kg/min to 1 mcg/kg/min. It should be titrated closely and minimum dose should be used for required effect.

Noradrenaline (Norepinephrine) An alpha and beta agonist (alpha > beta effect).Cardiac contractility is increased but it also causes massive increase in myocardial oxygen consumption and afterload, so cardiac output may not actually increase. Usual dose is 0.05 -1 mcg/ kg/ min.In warm septic shock with hypotension despite use of adrenaline secondary to intense vasodilatation, noradrenaline may be useful in increasing peripheral vascular resistance to improve blood pressure.

60 Minutes Recognize Catecholamine Resistant Shock

Hydrocortisone therapy should be reserved for use in children with catecholamine resistance and suspected or proven adrenal insufficiency. Patients at risk include children with severe septic shock and purpura,children who have previously received steroid therapies for chronic illness, and children with pituitary or adrenal abnormalities. There is no clear consensus for the role of steroids or best dose of steroids in children with septic shock. Dose recommendations vary from 1 to 2 mg/ kg for stress coverage (based on clinical diagnosis of adrenal insufficiency) to 50 mg/kg for empirical therapy of shock followed by the same dose as a 24 hours infusion.21-24 At this point in time a decision to admit the patient to a PICU facility should have been made with further management guided by CVP monitoring, attaining normal mean arterial pressure and a mixed venous oxygen saturation >70%. Up to this point most of the interventions can be performed in a peripheral setting.

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Further Management in PICU

60 Minutes Caution should be used in using afterload reduction indiscriminately in septic shock without simultaneous inotropic support. Both nitroprusside and nitroglycerin lower systemic vascular resistence in children and are useful afterload reducing agents. These agents act via generation of nitric oxide. Nitroprusside has potent peripheral arterial vasodilating effects. Nitroglycerin is more potent venodilator and pulmonary vasodilator. Close monitoring and volume augmentation are frequently required when vasodilators are used to decrease pulmonary vascular resistance. Amrinone and milrinone are newer inotropic agents with properties of afterload reduction and myocardial diastolic relaxation(lusotropic effect).19,20 Milrinone is commonly used for cardiogenic shock which is frequently associated with septic shock.. Cold shock with normal blood pressure: • 1° goals:

Titrate epinephrine, ScvO2 > 70%, Hgb > 10 g/dL

• 2° goals:

Add vasodilator

(Nitrosovasodilators, milrinone, imrinone and others) with volume loading, consider levosimendan

60 Minutes Cold shock with low blood pressure: • 1° goals:

Titrate epinephrine, ScvO2 > 70%, Hgb > 10 g/dL

• 2° goals:

Add norepinephrine Add dobutamine if ScvO2 > 70%,

Consider milrinone, enoximone or levosimendan

Vasopressin In severe warm shock with hypotension resistant to noradrenaline,vasopressin may be tried. Terlipressin is also available.Vasopressin therapy should be considered in warm shock unresponsive to fluid and norepinephrine. Vasopressin does not use catecholamine receptors, and its efficacy is therefore not affected by ongoing alpha-adrenergic receptor down-regulation. Actions of VP are mediated via its three receptor subtypes designated as V1 (V1R/V1a), V2 (V2R) and V3 (V1b)25,26 V1 vascular receptors are located on vascular smooth muscle and mediate vasoconstriction. Additionally, V1 receptors are found in the kidney, myometrium, bladder, adipocytes, hepatocytes, platelets, spleen, and testis. V1-receptor activation mediates vasoconstriction by receptor-coupled activation of phospholipase.27,28

60 Minutes Warm Sock with low blood pressure: • 1° goals: • 2° goals:

Titrate norepinephrine, ScvO2 > 70% Consider vasopressin, terlipressin or angiotensin

Add dobutamine or low dose epinephrine if ScvO2 < 70%

≤

SEPTIC SHOCK

C and release of Ca++ from intracellular stores via the phosphoinositide cascade29,30 V2 renal receptors (V2R), which cause the antidiuretic effects of vasopressin, are present in the renal collecting duct system and endothelial cells. Kidney V2 receptors interact with adenylycyclase to increase intracellular cyclic adenosine monophosphate (cAMP) and cause retention of water.31 V3 pituitary receptors (formerly known as V1b) have central effects, such as increasing adrenocorticotropic hormone (ACTH) production,activating different G proteins, and increasing intracellular cAMP.32 VP also acts on oxytocin receptor which is important from the point of view of its vasodilator action on certain vital organs through nitric oxide (NO) mediated pathway. Blood flow within the coronaries, as well as the cerebral, pulmonary, and renal vascular beds, is preserved, promoting shunting to those areas. This regional vasodilation is likely the result of a complex interplay of vasopressin activity at V1 and endothelial V3 and oxytocin receptor sites producing an increase in nitric oxide release. In addition to these direct effects, vasopressin may also enhance or restore catecholamine sensitivity. Synthetic vasopressin (8-arginine vasopressin) acts at the same receptor sites as endogenous vasopressin, producing an identical physiologic response.25,33 Terlipressin is a long acting analogue of vasopressin that has been shown to have higher affinity for vascular receptors than vasopressin and has demonstrated potent vasopressor effects in adult patients with norepinephrine resistant septic shock.34 Although angiotensin can also be used to increase blood pressure in patients who are refractory to norepinephrine, its clinical role is not as well defined.35 Phenylephrine is a another pure vasopressor with no beta adrenergic activity.36 Its clinical role is also limited. Vasopressors can be titrated to end points of perfusion pressure (MAP-CVP) or systemic vascular resistance that promote optimum urine output and creatinine clearance,37-40 but excessive vasoconstriction compromising microcirculatorly flow should be avoided. Nitric oxide inhibitors and methylene blue are considered investigational therapies.41-43 Studies have shown an increased mortality with non-selective NO synthase inhibitors suggesting that simply increasing blood pressure at the expense of excessive vasoconstriction has adverse effects.44 Low dose arginine vasopressin (AVP; in doses ≤ 0.04 units/kg/min)) as an adjunctive agent has short-term hemodynamic benefits in adults with vasodilatory shock. It is not currently recommended for treatment of cardiogenic shock, hence it should not be used without ScvO2 /cardiac output monitoring. Because vasopressin is destroyed by gastric trypsin, it must be administered parenterally. Vasopressin is rapidly degraded by enzymes in the liver and kidneys, with elimination halflife of approximately 10 to 35 minutes.25,36 Renal insufficiency and hepatic failure prolong its halflife. DOSING, PREPARATION AND ADMINISTRATION Vasopressin is available as a 20-unit/ml injection. For continuous intravenous infusion, it should be diluted with normal saline or 5% dextrose to a final concentration of 0.1 to 1 unit/ml. Administration through central venous access is recommended to minimize the risk of extravasation. Although the stability of vasopressin infusions with other drugs has not been studied, a recent report

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on bolus vasopressin administration found it to be compatible with most of the drugs used commonly in the ICU. Studies of vasopressin in adults with vasodilatory shock have used infusion rates of 0.01 to 0.1 units/min. In pediatric patients, a vasopressin dose of 0.3 to 2 milliunits/kg/min (equivalent to 0.0003 to 0.002 units/kg/min or 0.01 to 0.12 units/kg/hr) is recommended, based on the report by Rosenzweig.45 The infusion should be titrated to optimize blood pressure and perfusion. It has been suggested that vasopressin infusions may be tapered over a 2 to 3 hour period, once blood pressure and the doses of concomitant catecholamine infusions are stabilized. Vasopressin has been shown to increase mean arterial pressure, systemic vascular resistance, and urine output in patients with vasodilatory septic shock and hyporesponsiveness to catecholamines. 45,46-53 Terlipressin, a long acting form of vasopressin, has been reported to reverse vasodilated shock as well.54,55 The effect of low-dose AVP on clinically important outcomes such as mortality remains uncertain. The Vasopressin and Septic Shock Trial (VASST), a randomized controlled clinical trial that compared low-dose AVP to norepinephrine in patients with septic shock, showed no difference between regimens in the 28-day mortality primary end-point.56 The safety and efficacy of low-dose AVP has yet to be demonstrated in children with septic shock, and awaits the results of an ongoing randomized controlled trial.57 THERAPEUTIC END POINTS Therapeutic endpoints are capillary refill of 1 mL/kg/hr, normal mental status, decreased lactate, and increased base deficit and superior vena cava or mixed venous oxygen saturation of >70%. When employing measurements to assist in identifying acceptable cardiac output in children with systemic arterial hypoxemia such as cyanotic congenital heart disease or severe pulmonary disease, arterial-venous oxygen content difference is a better marker than mixed venous hemoglobin saturation with oxygen. Optimizing preload optimizes cardiac index. As noted above, blood pressure by itself is not a reliable endpoint for resuscitation.

CONCLUSION Pediatric recommendations for management of severe sepsis in children include a more likely need for endotracheal intubation and mechanical ventilation due to low functional residual capacity.

SEPTIC SHOCK

Infants and children are recognized to have more difficult intravenous access, therefore necessitating use of intraosseous access as required. Early fluid resuscitation based on weight with 40-60 mL/kg or higher may be needed. Decreased cardiac output and increased systemic vascular resistance tends to be most common hemodynamic profile. Dopamine is recommended as the initial agent for hemodynamic support. Pediatric recommendations include greater use of physical examination therapeutic endpoints. Issue of high-dose steroids for therapy of septic shock remains unsettled, although recommendation include use of steroids for catecholamine unresponsive shock in presence of a suspected or proven adrenal insufficiency. There is greater risk of hypoglycemia with aggressive glucose control. REFERENCES 1. Bone RC, Balk RA, Cerra FB,et al. Definitions for Sepsis and Organ Failure and Guidelines for the use of Innovative Therapies in Sepsis THE ACCP/SCCM consensus conference committee:Chest 1992;101:1644-55). 2. Goldstein B, Giroir B, Randolph A, et al; and the Members of the International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics* Pediatr Crit Care Med 2005;6:2-8. 3. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock.Crit Care Med 2004;32(3):858-73. 4. Carcillo JA, Fields AI. Task Force Committee Members: Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med 2002;30:1365-78. 5. Parker MM, Hazelzet JA, Carcillo JA. Pediatric considerations. Crit Care Med 2004;32(11):Supplement S591S594. 6. Wills BA, Nguyen MD, Ha TL, Dong TH, Tran TN, Le TT, et al. Comparison of the three fluid solutions for resuscitation in dengue shock N Engl J Med 2005;353(9):877-89. 7. Maitland K, Pamba A, English M, Peshu N, Marsh K, Newton C, Levin M Randomized trial of volume expansion with albumin or saline in children with severe malaria:preliminary evidence of albumin benefit. Clin Infect Dis 2005;40(4):538-45. 8. Han YY, Carcillo JA, Dragotta MA, Bills DM, Watson RS, Westerman ME, Orr RA. Early reversal of pediatricneonatal septic shock by community physicians is associated with improved outcome. Pediatrics 2003;112(4):793-99. 9. Ninis N, Phillips C, Bailey L, Pollock JI, Nadel S, Britto J, et al. The role of healthcare delivery on outcome of meningococcal disease in children: Case-control study of fatal and non-fatal cases BMJ 2005;330(7505):1475. 10. Oliveira, et al. An outcomes comparison between ACCM-PALS implementation with and without continuous S CVO 2 monitoring for Pediatric Septic Shock. 11. Karapinar B, Lin JC, Carcillo JA. ACCM guidelines use, correct antibiotic therapy, and immune suppressant withdrawal are associated with improved survival in pediatric sepsis, severe sepsis, and septic shock. Crit Care Med 2004;32(12)Suppl: 573-A161. 12. Nhan NT, Phuong CXT, Kneen R, et al. Acute management of dengue shock syndrome: A randomized doubleblind comparison of 4 intravenous fluid regimens in the first hour. Clin Infect Dis 2001;32:204-12. 13. Booy R, Habibi P, Nadel S, de Munter C, Britto J, Morrison A, Levin M. Meningococcal Research Group. Reduction in case fatality rate from meningococcal disease associated with improved healthcare delivery. Arch Dis Child 2001;85(5):386-90. 14. Kutko MC, Calarco MP, Flaherty MB, Helmrich RF, Ushay HM, Pon S, Greenwald BM. Mortality rates in pediatric septic shock with and without multiple organ failure. Pediatr Crit Care Med 2003;4(3):333-37. 15. Ranjit S, Kisson N, Jayakumar I. Aggressive management of dengue shock syndrome may decrease mortality rate: A suggested protocol. Pediatr Crit Care Med 2005;6(4):412-19. 16. Ngo NT, Cao XT, Kneen R, et al. Acute management of dengue shock syndrome: A randomized doubleblind comparison of 4 intravenous fluid regimens in the first hour. Clin Infect Dis 2001;32:204-13. 17. Ceneviva G, Paschall JA, Maffei F, et al. Hemodynamic support in fluid-refractory pediatric septic shock. Pediatrics 1998;102:e19. 18. Barton P, Garcia J, Kouatli A, et al. Hemodynamic effects of i.v. milrinone lactate in pediatric patients with septic shock: A prospective, double-blinded, randomized, placebo-controlled, interventional study. Chest 1996; 109:1302-12.

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PEDIATRIC INTENSIVE CARE 19. Lindsay CA, Barton P, Lawless S, et al. Pharmacokinetics and pharmacodynamics of milrinone lactate in pediatric patients with septic shock. J Pediatr 1998;132:329-34. 20. Irazuzta JE, Pretzlaff RK, Rowin ME. Amrinone in pediatric refractory septic shock: An open-label pharmacodynamic study. Pediatr Crit Care Med 2001;2:24-28. 21. De Kleijn ED, Joosten KF, Van Rijn B, et al. Low serum cortisol in combination with high adrenocorticotrophic hormone concentrations are associated with poor outcome in children with severe meningococcal disease. Pediatr Infect Dis J 2002;21:330-36. 22. Riordan FA, Thomson AP, Ratcliffe JM, et al. Admission cortisol and adrenocorticotrophic hormone levels in children with meningococcal disease: Evidence of adrenal insufficiency? Crit Care Med 1999;27:2257-61. 23. Min M, U T, Aye M, et al. Hydrocortisone in the management of dengue shock syndrome. Southeast Asian J Trop Med Public Health 1975;6:573-79. 24. Sumarmo, Talogo W, Asrin A, et al. Failure of hydrocortisone to affect outcome in dengue shock syndrome. Pediatrics 1982;69:45-49. 25. Holmes CL, Patel BM, Russell JA, et al. Physiology of vasopressin relevant to management of septic shock. Chest 2001;120:989-1002. 26. Ranger GS. The physiology and emerging role of antidiuretic hormone. IJCP 2002; 56:777-82. 27. Jackson E. Vasopressin and other agents affecting the renal conservation of water. In: Hardman JG, Limbird LE (Eds): Goodman and Gilman’s the pharmacological basis of therapeutics. New York, McGraw Hill, 2001. 28. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Eng J Med 2001;345:588-95. 29. Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano Y, Boyle WA. Hemodynamic and metabolic effects of low dose vasopressin infusion in vasodilatory Septic shock. Crit Care Med 2001;29:487-93. 30. Landry DW, Levin HR, Gallant EM, Ashton RC, Seo S, Alessandro DD, O2 MC, Oliver JA. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997;95:1122-25. 31. Thibonnier M. Signal transduction of V1-vascular vasopressin receptors. Regul Pept 1992;38:1-11. 32. Briley EM, Lolait SJ, Axelrod J, et al. The cloned vasopressin V1a receptor stimulates phospholipase A2, phospholipase C, and phospholipase D through activation of receptor-operated calcium channels. Neuropeptides 1994;27:63-74. 33. Orloff J, Handler J. The role of adenosine 3, 5-phosphate in the action of antidiuretic hormone. Am J Med 1967;42:757-68. 34. Thibonnier M, Preston JA, Dulin N, et al. The human V3 pituitary vasopressin receptor: Ligand binding profile and density-dependent signaling pathways. Endocrinology 1997;138:4109-22. 35. Pitressin® product information. Monarch Pharmaceuticals. July 1998. Available at http://www. kingpharm.com/uploads/pdf inserts/Pitressin PI.pdf 36. O’Brien A, Clapp L, Singer M. Terlipressin for nor epinephrine resistant shock. Lancet 2002;359:1209-10. 37. Yunge M, Petros A. Angiotensin for septic shock unresponsive to noradrenaline. Arch Dis Child 2000;82(5):38889. 38. GregoryJS,Binfiglio NF,dasta JF, et al. Experience with phenylephrine as a component of pharmacologic support of septic shock. Crit Care Med 1991;19:1340-95. 39. Redl-Wenzl EM, Armbruster C, Edelman G, et al. The effects of norepinephrine on hemodynamics and renal function in severe septic shock. Intens Care Med 1993;19(3):151-54. 40. Greenhalgh DG, Warden GD. The importance of intra-abdominal pressure measurements in burned children. J Trauma 1994;36(5):685-90. 41. Meadows D, Edwards JD, Wilkins RG, et al. Reversal of intractable septic shock with norepinephrine therapy. Crit Care Med 1988;16:663-66. 42. Desjars P, Pinaud M, Potel G, et al. A reappraisal of norepinephrine therapy in human septic shock. Crit Care Med 1987;15:134-37. 43. Grover R, Lopez A, Lorente J, et al. Multi-center, randomized, double blind, placebo-controlled, double bind study of nitric oxide inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 1999; 27(1):A33. 44. Driscoll W, Thutin S, Carrion V, et al. Effect of methylene blue on refractory neonatal hypotension. J Pediatr 1996;129(6):904-08. 45. Taylor K, Holtby H. Methylene blue revisited: Management of hypotension in a pediatric patient with bacterial endocarditis. Journal of Thoracic and Cardiovasc Surg 2005;130(2):566. 46. Tibby SM, Hatherill M, Marsh MJ, et al. Clinical validation of cardiac output measurement using femoral artery thermodilution with direct Fick in ventilated children and adults Intens Care Med 1997;23(9):987-91. 47. Rosenzweig EB, Starc TJ, Chen JM, et al. Intravenous arginine-vasopressin in children with vasodilatory shock after cardiac surgery. Circulation 1999;100(Suppl):II-182-II-186.

SEPTIC SHOCK 48. Klinzing S, Simon M, Reinhart K, Bredle DL, Meier-Hellmann A. High-dose vasopressin is not superior to norepinephrine in septic shock. Crit Care Med 2003;31(11):2646-50. 49. Delmas A, Leone M, Rousseau S, Albanese J, Martin C. Clinical review: Vasopressin and terlipressin in septic shock patients. Critical Care 2005;9(2):212-22. 50. Leibovitch L, Efrati O, Vardi A, Matok I, Barzilay Z, Paret G. Intractable hypotension in septic shock: Successful treatment with vasopressin in an infant. Israel Medical Association Journal 2003;5(8):596-98. 51. Matok I, Vard A, Efrati O, Rubinshtein M, Vishne T, Leibovitch L, Adam M, Barzilay Z, Paret G. Terlipressin as rescue therapy for intractable hypotension due to septic shock in children. Shock 2005;23(4):305-10. 52. Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano Y, Boyle WA 3rd. Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Critical Care Medicine 2001;29(3):48793. 53. Liedel JL, Meadow W, Nachman J, Koogler T, Kahana MD. Use of vasopressin in refractory hypotension in children with vasodilatory shock: Five cases and a review of the literature. Pediatr Crit Care Med 2002;3(1):1518. 54. Vasudevan A, Lodha R, Kabra SK. Vasopressin infusion in children with catecholamine-resistant septic shock. Acta Paediatrica 2005;94(3):380-83. 55. Rodriguez-Nunez A, Fernandez-Sanmartin M, Martinon-Torres F, Gonzalez-Alonso N, Martinon-Sanchez JM. Terlipressin for catecholamine-resistant septic shock in children. Intens Care Med 2004;30(3):477-80. 56. Matok I, Leibovitch L, Vardi A, Adam M, Rubinshtein M, Barzilay Z, Paret G. Terlipressin as rescue therapy for intractable hypotension during neonatal septic shock. Pediatr Crit Care Med 2004;5(2):116-18. 57. Peters MJ, Booth RA, Petros AJ. Terlipressin bolus induces systemic vasoconstriction in septic shock. Pediatr Crit Care Med 2004;5(2):188-89.

BIBLIOGRAPHY 1. Copper DJ, Russell JA, Walley KR, et al. E. Vasopressin and septic shock trial (VASST): Innovative features and performance. Am J Respir Crit Care Med. 2. Choong K, Menon K, Litalien C, Fraser. D, Joffe A, Gaboury I, et al. A study of the efficacy of Vasopressin in pediatric vasodilatory shock. http://www.controlled-trials.com/isrctn/trial/|/0/11597444.html 3. LeClerc F, Walter-Nicolet E, Leteutre S, Noizet O, Sadik A, Cremer R, Fourier C Admission plasma vasopressin levels in children with meningococcal septic shock Intens Care Med 2003;29(8):1339-44.

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21

Choice of Empiric Antibiotics in Severe Sepsis and Septic Shock

The balance of evidence unequivocally suggests that early administration of appropriate antibiotics reduces mortality in critically ill patients with bloodstream infections. Several studies have demonstrated significant reductions in mortality when appropriate antimicrobials are used early in patients with severe infections due to gram-negative and grampositive bacteria.1, 2 The choice of antibiotics is vital and should be guided by the susceptibility of likely pathogens in the community and the hospital, as well as any specific knowledge about the patient, including underlying disease and the clinical syndrome. The regimen should cover all likely pathogens since there is little margin for error in critically ill patients. The following table is a guide to aid in the selection of the most appropriate early antibiotic based on the suspected source; the eventual choice will also depend on prevalent pathogens and susceptibilities in the community and hospital. Although restricting the use of antibiotics, and particularly broad-spectrum antibiotics, is important for decreasing the development of antibiotic resistant pathogens, critically ill children with severe sepsis or septic shock warrant broad-spectrum therapy until the causative organism and its antibiotic susceptibilities are available. The antimicrobial regimen should always be reassessed after 48–72 hours on the basis of microbiological and clinical data with the aim of using a narrow-spectrum antibiotic to prevent the development of resistance, to reduce toxicity, and to reduce costs. Suggested empiric antibiotic regimen for severe sepsis based on suspected source 1.

Empiric antibiotic regimen for severe sepsis, source unclear, non-neutropenic host3,4

Age

Etiology

Primary drug regimen

Alternative regimen/ comments

0-3 months

Gp B streptococcus, E. coli, Cefotaxime 50 mg/kg/dose Q6H + Ceftriaxone contraindicated in Listeria monocytogenes ampicillin 50 mg/kg Q4-6H neonates Contd...

CHOICE OF EMPIRIC ANTIBIOTICS IN SEVERE SEPSIS AND SEPTIC SHOCK

Contd... Age

Etiology

Primary drug regimen

Alternative regimen/ comments

> 3 months Strep pneumoniae, Cefotaxime 50 mg/kg Q4-6H N. meningococcus, OR Ceftriaxone 50 mg/kg Q12H H. influenza (unvaccinated), Staphylococcus spp (MRSA, MSSA), aerobic gramnegative bacilli, Enterococci

Severe disease, ICU patient: Meropenem 20 mg/kg Q8H OR Imipenem 15-25 mg/kg/dose Q6H + either vancomycin 15 mg/kg/dose Q6H OR linezolid 10 mg/kg/dose Q12H

2. Empiric antibiotic regimen for severe sepsis and suspected intra-abdominal source3-5

Condition

Etiology

Primary drug regimen

Secondary drug regimen Comments

A. Primary peritonitis (spontaneous bacterial peritonitis)

Enterobacteriaceae, Strep .pneumoniae (commonest in nephrotics), enterococci, rarely anaerobes

Cefotaxime 50 mg/kg/ dose Q4-6H, OR Ceftriaxone 50 mg/kg/dose Q12H

B. Secondary peritonitis (Bowel perforation, ruptured appendix or divertculae)

Enterobacteriaceae, Bacteroides sp., enterococci, P. aeruginosa

Mild/ moderate disease, Severe disease, hospital in-patient: ICU patient: Piperacillin-tazobactam Meropenem 50-75 mg/kg/dose Q6H 20 mg/kg Q8H OR cefepime OR Imipenem 50 mg/kg/dose Q8H 15-25 mg/kg/dose + either metogyl Q6H 7.5 mg/dose Q12H OR clindamycin 10 mg/kg/dose Q8H

-Occurs especially in presence of nephrotic syndrome, ascitis, cirrhosis –Blood culture +ve in 30-40%, ascitic fluid culture +ve in 40-65%, culture of ascitic fluid in blood culture bottle +ve in 90%

3. Empiric antibiotic regimen for severe sepsis and community acquired pneumonia3,4,6

Age

Etiology

Primary drug regimen

1-3 months

C. trachomatis, RSV, other respiratory viruses, Strep pneumoniae, B.pertussis, Staphylococcus.

Afebrile: Consider staphylococcal etiology for Erythromycin 10 mg/kg Q6H severe multilobar disease with OR azithromycin 10 mg/kgx 1, effusions, postinfluenza/measles, then 5 mg/kgx 4 days developing countries: If febrile, add cefotaxime Add flucloxacillin 50 mg/kg Q24H 50 mg/kg/dose Q4-6H OR Ceftriaxone 50mg/kg/dose Q12H

Comments

4 months– 5 years

RSV, other respiratory Cefotaxime 50 mg/kg Q6H, viruses, Strep pneumoniae, OR Ceftriaxone 75 mg/kg Q24H H. influenza (unvaccinated), mycoplasma, staphylococcus

5–18 years

Strep pneumoniae, mycoplasma, respiratory viruses, staphylococcus, aerobic gram negative bacilli

Severe multilobar disease with effusions, postinfluenza/measles, developing countries: Add flucloxacillin 50 mg/kg Q24H

Ceftriaxone 50-75 mg/kg Q24H + Add anti-staph cover if evidence of azithromycin 10 mg/kgx1, lung necrosis: then 5 mg/kgx 4 days. Flucloxacillin 50 mg/kg Q24H

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PEDIATRIC INTENSIVE CARE 4. Empiric antibiotic regimen for severe sepsis and hospital acquired pneumonia1,2

Hospital acquired/ ventilator associated pneumonia

Etiology

Primary drug regimen

Wide spectrum depending on clinical setting: Strep pneumoniae (early VAP < 4 days), S. aureus, coliforms, P. aeruginosa, acinetobacter, anerobes

Cefepime 50 mg/kg/dose Meropenem 20 mg/kg Q8H Remember increasing Q8H OR high dose OR Imipenem 15-25 ESBL producing piperacillin-tazobactam mg/kg/dose Q6H enterobacteriaceae 50-75 mg/kg/dose Q6H. (If pseudomonas suspected or identified, add tobramycin) 2.5 mg/kg/day Q8H

Secondary drug regimen

Comments

5. Empiric antibiotic regimen for severe sepsis in the neutropenic host 3,4,7

Etiology Hospital or Any organism listed community under community acquired, and hospital acquired neutropenic + fungi (Aspergillus, host (ANC Candida spp) < 500/mm3 )

Primary drug regimen

Secondary drug regimen

Ceftazidime 50 mg/kg/dose Also consider Q6H OR cefepime pneumocystis, TB, CMV 50 mg/kg/dose Q8H OR piperacillin- tazobactam 50-75 mg/kg/dose Q6H + either vancomycin 15 mg/kg/dose Q6H OR linezolid 10 mg/kg/dose Q12H for MRSA

Comments Add anti-fungal (amphotericin or voriconazole) if not improving in 3 days.

6. Empiric antibiotic regimen for severe sepsis and suspected central nervous system infection 3,4,8

Age

Etiology

0-3 months Gp B streptococcus, E. coli, Listeria monocytogenes

Antibiotic regimen

Comments

Cefotaxime 50 mg/kg/dose Q6H + Ceftriaxone contraindicated in ampicillin 50 mg/kg/dose Q4-6H neonates

3 months Streptococcus pneumoniae, Cefotaxime 50 mg/kg/dose Q4-6H,–Consider adding vancomycin 15 mg/ to 15 years Neisseria meningitis, OR Ceftriaxone 50 mg/kg/dose kg/dose Q6H (max 500 mg) in areas H influenza ( rare if Q12H where penicillin resistant pneumococci vaccinated with Hib) common or patient deteriorating. –Add acyclovir empirically if CSF analysis not immediately possible

Adjunctive treatment: Dexamethasone 0.15 mg/kg/dose Q12H x 2-4 days to decrease hearing deficits and possibly other neurologic deficits. Administer first dose prior to or with the first dose of antibiotic. 7. Empiric antibiotic regimen for severe sepsis and suspected skin or soft tissue infections 3,4,9

Condition

Etiology

Antibiotic regimen

Cellulitis

Strep pyogenes, Staphylococcus aureus (MSSA)

Benzyl penicillin ( 50,000 units/kg/dose Q4-6H OR ceftriaxone 50 mg/kg/dose Q24H + Flucloxacillin 50 mg/kg/dose Q6H

Necrotizing β hemolytic Strep Ceftriaxone 50 mg/kg/dose Q12H fasciitis (NF) pyogenes, Staphylococcus OR meropenem 20 mg/kg/dose aureus (MSSA), gramQ8H+ negative bacilli, Clindamycin 10 mg/kg/dose Q8H polymicrobial flora

Comments

–Early extensive surgical debridement essential. –Clindamycin decreases toxin production

Adjunctive therapy for NF: Intravenous gammaglobulin associated with decreased sepsis–related organ failure. IVIG dose: 1gm/kg day1, then 0.5 gm/kg days 2 and 3. 8. Empiric antibiotic regimen for severe sepsis and bone and joint infections3,4

CHOICE OF EMPIRIC ANTIBIOTICS IN SEVERE SEPSIS AND SEPTIC SHOCK Age

Etiology

Antibiotic regimen

Comments

0-1 month

Staph aureus, Gp B streptococcus, gramnegative bacilli

Nafcillin or flucloxacillin 50 mg/kg/dose Q6H + Cefotaxime 50 mg/kg/dose Q6H

Seek early specialist advice, early debridement may be necessary

1 month5 years

Staph aureus, group A strep, H. influenza (in non-vaccinated)

Nafcillin or flucloxacillin 50 mg/kg/dose Q6H + Cefotaxime 50 mg/kg/dose Q6H

> 6 years

Staph aureus, group A strep, Strep pneumoniae

Nafcillin or flucloxacillin 50 mg/kg/dose Q6H + Cefotaxime 50 mg/kg/dose Q6H

9. Empiric antibiotic regimen for severe sepsis and urinary tract infections 3,4

Condition

Etiology

Antibiotic regimen

Hospitalized uncomplicated pyelonephritis

E. coli most common, then enterococci

Ceftriaxone 50 mg/kg/dose Q24H Gram-stain of uncentrifuged urine may OR gentamicin 8 mg/kg as a allow identification of gram-negative single daily dose IV/IM bacilli vs gram-positive cocci

Comments

Complicated UTI (Foley catheterrelated azotemia, obstruction, reflux, transplant)

Enterobacteriaceae, P. aeruginosa, enterococci ,

Piperacillin-tazobactam 50 mg/kg/dose Q6H OR Meropenem 20 mg/kg/dose Q8H OR Imipenem 15-25 mg/kg/dose Q6H

Rule out obstruction

REFERENCES 1. Kollef MH, Sherman G, Ward S, et al. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115:462–74. 2. Ibrahim EH, Sherman G, Ward S, et al. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118:146–55. 3. Bradley JS, Nelson JD. Nelson’s Pocket Book of Pediatric Antimicrobial Therapy, 2002-2003. 15th Ed., Philadelphia, Pa; Lippincott Williams and Wilkins 2002. 4. Gilbert DN, Moellering RC Jr, Sande MA, (Eds). The Sanford Guide® to Antimicrobial Therapy. 35th ed. Hyde Park, VT: Antimicrobial Therapy Inc 2005. 5. Solomkin JS, Mazuski JE, Baron EJ, et al. Guidelines for the Selection of Anti-infective Agents for Complicated Intra-abdominal Infections. Clin Inf Dis 2003;37:997–1005. 6. McIntosh K. Community acquired pneumonia in children. NEJM 2002;346;429-37. 7. Hughes WT, Armstrong D. 2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer. Clin Inf Dis 2002;34:730-51. 8. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice Guidelines for the Management of Bacterial Meningitis. Clin Inf Dis 2004;39:1267-84. 9. Stevens DL, Bisno Al, Chambers HF, et al. Practice Guidelines for the Diagnosis and Management of Skin and Soft-Tissue Infections. Clin Inf Dis 2005;41:1373-1406.

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Nitin Shah

Blood Components in Intensive Care Practice

INTRODUCTION Availability of blood components has improved the outcome of many children in Pediatric Intensive Care Units (PICU). Blood products are as often misused as used in the PICU. The child is not a miniature adult and so also a newborn is not a miniature child. There are major differences between an adult and a child in the etiology of cytopenias, the effect of cytopenia on homeostasis, the physiological responses by the body to cytopenia, the need of various blood components, the choice and the dose of the blood component used. This is even more so for a newborn. Accordingly, the guidelines for the use of blood components differ in children and newborns. Various recent publications are available which define these guidelines.1-9 Why not whole blood and why components? Each unit of whole blood has at least 4 basic components which include red blood cells, white blood cells, platelets and plasma. Each of these components has specialized function. All these functions are not deranged in all the patients and hence all the components are not required all the time. Blood is always in short supply and making components from one unit of whole blood will satisfy the needs of more than one patient from the same unit of blood. Besides, giving whole blood can lead to harmful effects like plasma overload; lymphocytes mediated toxicities or allosensitization. Some components can only be given effectively on their own, e.g. platelets, which are otherwise destroyed in refrigerated stored whole blood. Some components are better given as component, e.g. clotting factors, as one cannot achieve effective levels by using FFP alone.1-5 It is a social crime to use whole blood and waste this rare commodity! Which components? From one unit of unrefrigerated whole blood one can make packed red blood cells, platelet pack (random donor platelet), granulocytes and fresh plasma. Fresh plasma can be further frozen at

BLOOD COMPONENTS IN INTENSIVE CARE PRACTICE

–30° C and be used as FFP in future. Pooled plasma can be converted into further components like cryoprecipitate, albumin, gamma globulins, anti-D globulins, plasma proteins, etc. One can modify and manipulate these components and obtain neocyte red cells, frozen red cells, washed red cells or platelets, filtered red cells or platelets, UV light or gamma irradiated red cells or platelets. One can select a specific donor and get CMV negative blood components, HLA matched blood components or blood products from specific minor blood group compatible donor. Lastly, one can get stem cells from the umbilical cord blood of a newborn or peripheral blood of an older child for autologous or allogenic bone marrow transplant or rescue as the case may be. Storage and Shelf Life Whole blood is stored at 1-4° C. Shelf life will depend upon the type of anticoagulant and additive used. ACD is no more used. CPD or CP-2D blood can be kept for 21 days. CPDA1-A2 blood can be kept for 35 days. If one uses additives like Nutrisol or Adsol, one can keep the blood for 42 days. Packed red blood cell is stored at 1-4° C and should be used within 24 hrs if packed using an open system.1-5 Platelets are stored at 20-22° C on a constant agitator as resting platelets tend to aggregate. The shelf life is 3 to 7 days. Granulocytes are kept at room temperature and should be used within 24 hours of collection. FFP and cryoprecipitate have shelf life of one year and are stored at –30° C. Frozen red blood cells can be kept at –70° C and have shelf life of 5-7 years.

ABO and Rh Compatibility Tables 22.1 and 22.2 describe the choice of the ABO and Rh type of the donor blood component in various recipient ABO and Rh settings. Table 22.1: Choice of ABO blood group of donor components in childrenΔ

Patient’s ABO group O First Choice Second Choice A First Choice Second Choice B First Choice Second Choice AB First Choice Second Choice Third Choice

Red Cells

Donor ABO group Platelets

FFP Δ

O -

O A

O A or B or AB

A O*

A O*

A or AB

B O*

B# A or O*

B or AB

AB A or B O*

AB# A

AB A

* Group O component without high anti-A or anti-B titers should be selected. # Platelet concentrates of B or AB group may not be easily available. Δ Group O FFP should be given only to O group patients and no one else. AB group FFP may not be easily available.

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PEDIATRIC INTENSIVE CARE Table 22.2: Choice of Rh blood group of donor components in children

Patient’s Rh group Rh positive First Choice Second Choice Rh negative First Choice Second Choice * Δ

Red Cells

Donor Rh group Platelets

FFPΔ

Rh +ve Rh –ve

Rh +ve Rh –ve

Rh +ve Rh –ve

Rh –ve –

Rh –ve Rh +ve*

Rh –ve Rh +ve

If Rh +ve platelets are given to an Rh negative recipient, anti-D globulin in the dose of 250 mcg should be given to the recipient, which will cover upto 5 platelet transfusion for upto next 6 weeks. FFP usually are not labeled as Rh positive or negative.

Whole Blood Whole blood has all the components, but that is only in the first 6-8 hours and that too when stored at room temperature. The platelets are the first to disappear in the first 4-48 hours, the labile clotting factors V and VII are the next to disappear and the other clotting factors go down thereafter. On prolonged storage the potassium levels go up whereas the pH, the 2-3-DGP levels and the ATP levels fall. Hence for an exchange transfusion one prefers to use less than 7 days old blood. Whole blood is stored at 1-4° C and has a shelf life of 21 to 42 days as discussed before.

Indications Whole blood is used in the PICU only when massive transfusions are required like in exchange transfusion, massive blood loss with at least one volume blood transfused or during ECMO.1-5 One can use reconstituted whole blood and one should remember that there is nothing like ‘fresh’ blood! 10 cc/kg body weight of whole blood will raise hematocrit (HCT) by 5% and Hb by 1 to 1.5 gm%. Packed Red Blood Cells (PRBC) PRBCs are the backbone of any transfusion service as the help in improving both the oxygen carrying capacity as well as volume. Ideal HCT for PRBCs is 70-75% and it should not be too tightly packed. For newborns, while doing an exchange transfusion, HCT can be adjusted to 50-55% using additional FFP or albumin. Advantage of PRBC is that it is low volume as compared to whole blood and hence does not lead to circulatory overload. It has less plasma and hence has less citrate related toxicity. It is mainly used in patients with hemorrhage or anemia needing transfusions. As it contains significant amounts of plasma and leukocytes, it can lead to toxicities related to them like allergic reactions, NHFTR, allosensitization, GVHD, etc. Full cross-match for ABO and Rh and screening for abnormal antibody should be done before each transfusion. 10-cc/kg body weight of PRBCs will raise the HCT by 10% and Hb by 3-4 gm%.

Indications The ‘cut offs’ used in various indications are shown in Table 22.3.1-5 It is used for replacement of volume as well as oxygen carrying capacity. It is used in acute hemorrhage where more than 15-20% blood volume is lost, monitoring vitals, blood pressure and CVP. The commonest indication

BLOOD COMPONENTS IN INTENSIVE CARE PRACTICE Table 22.3: Indications of using PRBC in a > 4 mo old child 1. Acute blood loss of > 15-20% blood volume with hypovolemia 2. Hb < 8 gm% with a. Symptomatic peri-opertaive anemia b. Chronic congenital/acquired transfusion dependent anemia c. Emergency surgery with anticipated blood loss d. Uncorrectable pre-operative anemia e. Severe infections f. Associated severe pulmonary disease 3. Hb < 7.0 gm% with chronic transfusion dependent states e.g. a. Hemoglobinopathies other than thalassemia major b. Bone marrow failure syndrome including Fanconi’s anemia c. Congenital dyserythropoietic anemia d. Sideroblastic anemia e. Chronic hemolytic anemia like congenital spherocytosis, f. Chronic hemolytic anemia like hereditary non-spherocytic anemia 4. Pediatric Oncology a. Hb < 8 gm% with chemotherapy/Radiotherapy b. Hb < 10 gm% if i) Intensive chemotherapy planned ii) Presence of febrile neutropenia iii) Severe LRTI iv) Thrombocytopenic bleeding c. Hyperleucocytosis (Partial exchange preferred) 5. Patient on ventilatory support a. Hb < 11 gm% with significant ventilatory support b. Hb < 10 gm% with minimal ventilatory support

of PRBC is chronic transfusion dependent anemia as seen in Thalassemia, Sickle Cell Disease, Congenital Dyserythropoietic anemia, Diamond Blackfan Syndrome, Fanconi’s anemia, Aplastic anemia, Chronic Renal Failure, Cancer patients, Sideroblastic anemia etc.10 It is also useful in episodic transfusions for acute hemolysis like in G6PD deficiency, malaria, autoimmune hemolytic anemia, etc. It is rarely, if at all, used in nutritional anemia, if a patient has severe anemia with impending cardiac failure or has associated cardio-respiratory disease. Lastly it can be used before surgery, where a patient is anemic with Hb less than 7 gm% and where moderate blood loss is expected during surgery. In the PICU, it is also useful to maintain hemoglobin in a patient who is on ventilatory support as shown in Table 22.3. It is most often misused as “top-up” in patients with nutritional anemia, or during surgery to keep Hb above “10 gm%”. In such cases, it is counterproductive as it can lead to immune suppression of the recipient and delays healing. Red Blood cell cytapharesis can be done using cell separators like the Cobe Spectra machine in a case of falciparum malaria with a very high parasitic index. Though there is no cut off which is a gold standard, this can be done when the parasitic index is more than 20-40%. Very few studies are available on this and they have shown that the mortality is reduced by using red cell cytapheresis as compared to open exchange transfusion which is more hazardous with significant complications.1,2, 11 However this process needs sophisticated instruments and is fairly expensive and hence may not be available or affordable at many centers.

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Platelet Transfusions Whenever possible use ABO and Rh compatible platelets. Store the platelets at 22° C on a constant agitator. One can use a designated donor repeatedly to obtain single donor platelet using an apharesis machine. Transport the platelets quickly and infuse them in 20-30 minutes. Use plastic tubes and never use glassware as platelets will stick to glass surfaces and get activated.1-3 Remember, platelets should never be stored in a refrigerator!

Types of Platelets There are two types of platelets, random donor platelets (RDP) obtained by centrifugation of a unit of whole blood or single donor platelets (SDP) obtained by apharesis. One can use an HLA matched or CMV negative donor in specific situations. Use of WBC filters helps reduce allosensitization and febrile reactions.

RDP RDP are obtained by centrifugation of a unit of whole blood within 68 hours of collection, and it contains 5-6 × 1010 platelets in 50-60 ml. of plasma per pack. One unit/10 kg body weight will raise the platelet count by 20, 000 to 30, 000/cumm.2, 6, 12-14 RDP are less costly and easily available from the blood bank shelf, however are less efficacious than SDP as they contain 6-7 times less platelets. Hence patients needing repeated platelet transfusions may benefit by using SDP which will reduce the exposure to fewer donors.

SDP They are obtained from a designated single donor using an apharesis machine like Cobespectra cell separator. A compatible donor is selected and subjected to continuous or discontinuous apharesis and platelets collected over a 4-6 hr period. They contain 2-3 × 1011 platelets in 50-70 cc of plasma. Thus it has 6-7 times more platelets than RDP. The donor should be healthy, off medicines like aspirin and should have a platelet count of more than 1.5 lakhs/cumm. The same donor can be selected again after 2-3 weeks. A specific donor like CMV negative or HLA matched donor can be used in a given situation. But SDP is extremely costly and needs a sophisticated cell separator.

Criteria to Transfuse Platelet transfusions are usually given to those with thrombocytopenia due to decreased production rather than to those with increased destruction. Platelet transfusions are given when they have significant mucosal bleeds. Only skin bleeds do not warrant a platelet transfusion, but such patients should be closely monitored for any further mucosal bleeds. It is controversial as to when to give prophylactic platelet transfusions.2-6, 12-14 A child with thrombocytopenia usually does not bleed spontaneously unless the platelet count falls to less than 50, 000/cumm. The chances of spontaneous bleeds increase when the count drops to less than 10 - 20, 000/cumm. Hence the decision of when to transfuse platelets prophylactically is based on the basic disease, type of thrombocytopenia, platelet count, and the presence of associated coagulation abnormalities. A well child is a given prophylactic transfusion when the platelet count is less than 5, 000 - 10, 000/cumm. In patients with massive hemorrhage it should be given when the count

BLOOD COMPONENTS IN INTENSIVE CARE PRACTICE

is less than 50, 000/cumm as most of the circulating platelets are likely to be non-functional platelets of the infused stored blood. The ‘cut off’ used in various indications is shown in Table 22.4. Table 22.4: Indications of using platelets in a > 4 mo old child 1. Prophylactic platelets (without bleeding) a. < 5-10, 000/cumm in a non-sick child b. < 20, 000/cumm in a sick child with: i) Severe mucositis ii) DIC iii) Platelet likely to fall < 10, 000/cumm before next evaluation iv) Associated coagulopathy/anticoagulation c. Before surgery i) Bone marrow aspiration/biopsy can be without platelet support ii) Lumbar puncture < 30, 000/cumm iii) Other surgeries < 50, 000/cumm iv) Surgery at critical sites like CNS, eyes < 100, 000/cumm d. < 50, 000/cumm with acute bleeding, massive hemorrhage, head trauma, multiple trauma. 2. Chronic stable thrombocytopenia only in presence of significant mucosal bleeding 3. Platelet dysfunction only in presence of significant mucosal bleeding 4. Chronic stable DIC only in presence of significant mucosal bleeding

Indications Platelet transfusions are given for thrombocytopenia or for platelet dysfunction. 1. Decreased platelet production: This is seen when bone marrow failure occurs like in aplastic anemia, Fanconi’s anemia, TAR syndrome, and other constitutional hypoplastic anemia. It is also seen when the bone marrow is infiltrated e.g. in leukemia and other metastatic cancers or in presence of bone marrow suppression due to chemoradiotherapy or fulminant infections. Platelet transfusions have revolutionized the treatment and the outcome of pediatric cancers. The cause of mortality has shifted from bleeding to infections with better platelet support available now. 2. Increased consumption of platelets: It is indicated in DIC, NEC, and Kasalbach-Merritt syndrome. In these cases, there is good platelet recovery at one hour after transfusion, but not at 24 hr suggesting consumption. However it is contraindicated in TTP and HUS. 3. Increased platelet destruction: ITP is the commonest scenario in this category. It can occur due to immune or non-immune mechanisms. Immune destruction can occur in post-transfusion purpura, autoimmune diseases, ITP, and alloimmune disease of newborn. Platelet transfusions are generally not effective in this group of diseases, as they will be immediately destroyed after transfusion. However, in ITP with life-threatening bleeding like intracranial hemorrhage one may give platelet packs just to tide over a crisis till splenectomy is done or IVIG is administered. Nonimmune destruction can occur following drugs or infections. 4. Hypersplenism: Normally 1/3rd of platelets are pooled in the spleen. This proportion will increase in patients with hypersplenism due to any reason. Again platelet transfusions may not be effective in such cases, as they will be immediately removed from the circulation into the enlarged spleen.

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5. Dilutional: Dilutional thrombocytopenia can occur following massive transfusions in patients with massive hemorrhage or following exchange transfusions. Supplemental platelet transfusions may be required in such cases. 6. Platelet dysfunction: Various congenital and acquired platelet functional disorders may present with significant bleeding. If local measures fail to control bleeding, platelet transfusions will be required. One should use platelets sparingly in such cases as allosensitization may prevent good recovery in future after a number of transfusions are given. One can use HLA matched platelets in such cases.2, 6, 12, 13 Platelet transfusion efficacy: Clinically one can judge the efficacy by seeing the cessation of bleeding. One can look for the expected increments by calculating Corrected Count Increment (x 109/L) (CCI) as follows by doing platelet count at one hour and 24 hr after transfusion. Post-transfusion platelet count - Pre-transfusion platelet count CCI = ———————————————————————————— × BSA m2 Platelets infused × 1011

Normal CCI is > 7.5 × 109/L at one hour, and > 4.5 × 109/L at 20-24 hrs. If CCI is normal at one hour, but less at 24 hrs, it suggests consumption coagulopathy. If CCI is less at 1 hour itself, it suggests immune destruction.2, 6, 12-14 Granulocytes Though its use in infections may sound logical, granulocytes are rarely used in current clinical practice. People have tried giving granulocyte transfusion in patients with severe uncontrollable infection in the presence of congenital or acquired neutropenia or neutrophil dysfunction. It is usually reserved for neutropenic patients with fulminant sepsis not controlled by antibiotics and antifungal with ANC < 300 in newborn, ANC < 100 in infants and ANC < 500 in immune compromised host. It should always be used along with antibiotics and antifungals. As colony stimulating factors are now easily available and affordable, use of granulocytes has fallen in to disrepute.2 Buffy coat preparations are not very satisfactory as the cells tend to become non-functional. Packs obtained by apharesis are the best. They should be used within 24 hr of collection and stored at room temperature. Each pack has 1011 granulocytes in 200 cc of plasma. Dose recommended is 109 granulocytes/kg each time. It can be repeated every 12-24 hr for 4-6 days. It should be given obviously without using the WBC filter or without irradiation as both the procedures will inactivate the granulocytes. It leads to all the side-effect related to plasma and lymphocytes including high risk of TAGHHD and plasma borne infections. One should use ABO/Rh compatible donor. Leukodepleted Blood Components

Why Leukodepletion? Various side effects and toxicities are associated with the presence of significant number of donor lymphocytes in the unit of blood component transfused. These include non-hemolytic febrile transfusion reactions; allosensitization; increased chances of rejection of graft in candidates for future transplant; lymphocyte mediated lung toxicity like ARDS; transmission of viral infections like HIV, HTVL, EBV, CMV etc which are intracellular pathogens; transfusion associated graft Vs host disease (TAGVHD) in immune compromised patients and in transfusion from first degree relatives; and

BLOOD COMPONENTS IN INTENSIVE CARE PRACTICE

immune suppression of the recipient especially in surgical patients. These donor lymphocytes ordinarily do not serve any beneficial effects and hence should be removed or depleted from the unit transfused to eliminate or reduce the chances of these side effects and toxicities.2, 15, 16 NHFTR occur when > 5 × 106 lymphocytes are present in the unit, whereas for TAGVHD it is > 107 cells/kg body weight. One pack of PRBC has 109 WBC, RDP has 4-6 × 107 WBC, SDP has 2-4 × 108 WBC and granulocyte pack has 1011 WBC. Ideally all transfusions should be leukodepleted especially in patients needing recurrent transfusions and in immune-compromised hosts.2, 15, 16 Methods of leukodepletion: There are various ways of leukodepletion. Each method has its own merits and demerits and efficacy.2, 15, 16 1. WBC filter: 3rd generation WBC filters are 99.5 % efficient in removing the donor lymphocytes. Activated lymphocytes can release cytokines like IL2, TNF-α during storage and hence it is best to remove the lymphocytes while collecting blood from the donor using in-line WBC filter, rather than using the WBC filter at bedside while giving the transfusion to the recipient. The advantage of WBC filter is its high efficacy and simplicity to use. The disadvantages include its high cost and inability to prevent TAGVHD. Each filter costs Rs. 400 - 500/- and is not re-usable. Ideally all transfusions should be given using filters especially if patient needs recurrent transfusions and develops NHFTR. 2. Washed cells: 90% of lymphocytes and 99% of plasma are removed by washing the PRBC with saline or blood processor. This will help reduce NHFTR, allosensitization and other toxicities related to WBC as well as allergic reactions to plasma proteins. It is a simple technique and needs a cold centrifuge but is not as effective as the WBC filter for leukodepletion. One can combine washing and use of WBC filter where the patient is prone to severe allergic reactions. Washing does not prevent TAGVHD. Lastly, washed platelets from the mother are given to a baby suffering from alloimmune thrombocytopenia. 3. Gamma irradiation: TAGVHD can be only prevented by gamma irradiating the blood. A dosage of 2500 - 3500 cGy is used to irradiate the components. The only disadvantages are the need for a sophisticated and expensive irradiator. There are chances of a membrane leak from the irradiated cells which can result in increased potassium levels. Hence blood should be irradiated just before infusion or the supernatant plasma should be removed before transfusion. Ideally all blood should be irradiated where there is risk of TAGVHD. This includes transfusions given to newborns especially preterms < 1200 gm, intra-uterine transfusions, patient with primary or secondary immunodeficiency, cancer patients, organ transplant recipients and transfusion given to normal person from a first degree relative donor.2, 15, 16 4. Frozen Red Cells: This is routinely available in the west but is rarely available in India.1, 2 RBC frozen at - 70° C have a shelf life of 5-7 yrs. While freezing, deglycerolisation is done to prevent intracellular ice formation. The unit should be thawed gradually and once thawed should be used within 24 hours. The efficacy for leukodepletion is 90% and plasma depletion is 99%. Hence it reduces toxicities related to both lymphocytes and plasma. The advantage of frozen cells is its availability in an emergency where one can use O -ve frozen cells in AB negative plasma. Blood from CMV negative donors; HLA matched donor or rare blood group donor can be collected and frozen for future use. Lastly autologous blood collected for surgery can be frozen and used in future if surgery gets postponed. The disadvantages of frozen cells are that they need

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sophisticated instruments to prepare and store it and are extremely costly. TAGVHD cannot be prevented by using frozen red cells. Fresh Frozen Plasma (FFP) FFP is made by freezing the plasma obtained at the end of centrifugation of the whole blood unit and is stored at < - 30° C. The shelf life of FFP is one year when properly stored. It should be thawed at 37° C over 30 minutes in a water bath. Thawed FFP should be used within 4 hours if used for hemophilia A or used within 24 hours if used for other conditions provided it is stored properly.2,7,9 FFP contains all the plasma proteins including albumin, gamma globulins and most importantly clotting factors. As labile factor V and VIII tend to decrease on storage, freezing of the plasma should be done within 4-6 hours of collection to prevent loss of these factors. One unit of FFP has 200250 ml of plasma and 1 ml of plasma contains approximately 1 unit of each clotting factor. As the maximum tolerated dose of FFP is 10-15 cc/kg every 12 hr, one can not achieve very high plasma level of the missing clotting factors without volume overloading the patient. FFP is often misused as a volume expander. As FFP can lead to allergic reactions, anaphylaxis in Ig A deficient patient and can transmit plasma borne infections; albumin which is much safer should be used instead. Similarly albumin and not FFP should be used to replace proteins or albumin. If a patient needs both volume expansion as well as clotting factors like in DIC, sepsis, NEC etc., FFP can be used. However FFP should not be used in a case of DIC without clinical bleeding. FFP should also not be used prophylactically to prevent intracranial bleeding in newborns. . Table 22.5 summarizes the indications for using FFP in clinical practice.2, 7, 9 FFP is mainly used to replace clotting factors. It can be given when the patient presents with bleeding for the first time where the diagnosis is uncertain as to which factor is deficient. In known cases of hemophilia, it is better to use factor concentrates, as they are more efficient and safe. FFP is used for deficiencies of other factors like factor V, VII etc. where factor concentrates are not available. It is also used where multiple factors need to be replaced as in case of hemorrhagic disease of newborn, liver disease, preterm with liver dysfunction, DIC, etc. FFP also contains Anti-thrombin III, Protein C and Protein S and hence is useful in the deficiency of these factors too like in the treatment of purpura fulminans; however in the West activated protein C concentrates are easily available. FFP is used for plasma exchange in patients with TTP or HUS. It can be used to reconstitute whole blood along with PRBC Table 22.5: Indications of using FFP considered as appropriate 1. Inherited factor deficiency a. Patient with unknown clotting factor deficiency presenting for the first time b. Single clotting factor where factor concentrate is not available like factor V or XI c. Multiple clotting factor deficiency 2. DIC with clinical bleeding 3. Hemorrhagic disease of newborn 4. Liver disease with coagulopathy for prevention and control of bleeding 5. Dilutional coagulopathy as seen after massive transfusion (surgical patients) to maintain PT, aPTT to < 1.5 time the control 6. Plasma exchange for TTP/HUS 7. Sick newborn with coagulopathy and bleeding

BLOOD COMPONENTS IN INTENSIVE CARE PRACTICE

or to adjust HCT of PRBC for exchange transfusion in newborns. Lastly, FFP is useful to prevent and treat coagulopathy due to L-asperginase in cancer patients. FFP leads to all the side effects related to plasma like allergic reactions like urticaria, anaphylaxis, especially in IgA deficient patient and transmission of plasma borne infections to the recipient. In small babies, it can lead to hemolysis if it contains high levels of antibodies against recipient’s blood group antigens. FFP has also been associated with rare but significant toxicities like Transfusion Related Acute Lung Injury (TRALI). Cryoprecipitate Cryoprecipitate is prepared from FFP by thawing it at 4°C when a white precipitate occurs at the bottom leaving supernatant cryo-poor plasma. Cryo-poor supernatant plasma is further used to prepare other products like IVIg and albumin. The precipitate thus obtained is resuspended in plasma to make a volume of 25-30 ml. It is then frozen and stored at -18°C which has a shelf life of about 1 year. It is thawed at 37°C using a water bath just before its use. It is injected over 15 minutes. Cryoprecipitate is rich in factor VIII, fibrinogen, von Willebrand factor, factor XIII and fibrinectin. Each bag contains approximately 80-120 units of factor VIII, 150-400 mg of fibrinogen, 80 units of vWF and 40-60 units of factor XIII.2, 7, 9 The indications of using cryoprecipitate are given in Table 22.6. Cryoprecipitate is the backbone of treating Hemophilia A when the patient cannot afford or has no access to factor VIII concentrates where as cryoprecipitate may be easily available from nearby blood bank. However, the amount of factor present is not standard and varies a lot from bag to bag. Cryoprecipitate is also useful along with FFP and platelet in the management of DIC and massive transfusions in the PICU. Lastly it can be used for von Willebrand’s disease and factor XIII disease as replacement therapy. Usually 1-2 bag per 10 kg body weight per dose are used. Table 22.6: Indications for using cryoprecipitate 1. Hemophilia A 2. Low fibrinogen levels as seen in: a. a/hypo/dys fibrinogenemia b. DIC c. Massive transfusion 3. von Willebrand’s Disease 4. Factor XIII deficiency

Massive transfusion and guidelines for use of blood components: In PICU one will often face the challenge of managing the complications of major blood loss and massive transfusion which may jeopardize the survival of the patient and strain the transfusion services of the institute. Massive blood loss is defined as loss of one blood volume in a 24 hours period, or 50% blood volume within 3 hours. Management of such patient is often complicated with presence of thrombocytopenia (dilutional), coagulopathy (dilutional) or DIC (due to shock). Management principles include initial resuscitation with volume expanders, measures to arrest bleeding, hematological laboratory investigations which include CBC, PT, aPTT, platelet count, fibrinogen level and D-dimer estimation at the time of admission and every 4 hours thereafter, and use of blood components including PRBCs, platelets, FFP and cryoprecipitate.2, 17

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PRBC: In emergency one can use O –ve PRBC till group and cross match reports are available. Thereafter one should use compatible blood group donors. Remember that HB and HCT may not fall immediately after bleeding starts and hence one should repeat these tests after 4 hours to know the exact impact of bleeding and the initial management. Platelets: Platelet counts will fall to < 50, 000/cumm once two blood volumes have been replaced. This is because of the dilutional effect which occurs due to massive infusion of volume expanders and platelet poor PRBCs/FFP. Platelets are given to keep the platelet count > 50, 000/cumm in ordinary circumstances and > 100, 000/cumm in presence of CNS injury.2, 17 FFP and cryoprecipitate: Coagulopathy even without DIC is common due to dilutional effect caused by replacement of massive amount of volume expanders and plasma poor PRBCs. The clotting factor levels fall to around 25% after 2 volumes have been replaced. Fibrinogen decreases to < 1 gm/l when 1.5 volumes have been replaced. The aim is to give 15 cc/Kg weight of FFP 12-24 hourly to keep PT/aPTT within 1.5 times the normal range. Additional infusion of cryopripitate is warranted if the fibrinogen levels do not come up > 1 gm/l in spite of the infusion of enough FFP.2, 17 BIBLIOGRAPHY 1. American Association of Blood Banks. Pediatric Transfusion: A Physician’s Handbook; 1st Edition. Edited by Roseff SD 2003. 2. Beulter E. Platelet transfusion: The 20000/L trigger. Blood 1993;81:1411-13. 3. Consensus Conference on Platelet Transfusion. Br J Cancer 1998;78:290-91. 4. Deshpande A, Kalgutkar S, Udani S. Red cell exchange using cell separator (erythrocytapheresis) in two children with acute severe malaria. J Assoc Physicians India 2003;51:925-26. 5. Ennio CR. Red cell Transfusion Therapy in Chronic anemia. Hemat Oncol Clin North Am 1994;8:1045-52. 6. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Brit J Hematol 2004;126: 11-28. 7. Guidelines for the use of platelet transfusions. Brit J Hematol 2003;122:10-23. 8. Indian Academy of Pediatrics transfusion guidelines for neonates and older children (under publication). 9. Miller JP, Mintz PD. The use of Leucocyte- Reduced Blood Components. Hemat Oncol Clin North Am 1995; 9:69- 90. 10. Rentels PB, Kenney RM, Crowley JP. Therapeutic support of the patient with Thrombocytopenia. Hemat Oncol Clin North Am 1994;8:1131-51. 11. Roseff SD, Luban NL, Manno CS. Guidelines for assessing appropriateness of pediatric transfusion. Trans 2002;42:1398-1413. 12. Rosen NR, Weidner JG, Boltd HD et al. Prevention of Transfusion associated graft-versus-host disease: Selection of sufficient dose of gamma irradiation. Transfusion 1993;33:125. 13. Shah Nitin, Lokeshwar MR. Blood components in pediatric practice. Proceedings of South. Pedicon 2000:5568. 14. Stainsby D, MacLennan S, Hamilton PJ. Management of massive blood loss: A template guideline. Br J Anesth 2000;85:487-91. 15. Strauss RG, Levy GJ, Sotelo-Avila c et al. National survey of Neonatal Transfusion Practices: II. Blood Component therapy. Pediatrics 1993;91:530-36. 16. Transfusion guidelines for neonates and older children. Brit J Hematol 2004;124:433-53. 17. Voak D, Cann R, Finney RD et al. Guidelines for administration of blood product transfusion of infants and neonates. British Committee for Standards in Hematology Blood Transfusion Task Force. Transfusion M.

Veena EVALUATION Kalra, Bidisha Banerjee OF A COMATOSE CHILD 265

23

Evaluation of a Comatose Child

INTRODUCTION Evaluation of a comatose child involves assessment of the severity of coma, elucidation of the etiology from the plethora of causes that can impair consciousness. Providing care to maintain life/vital signs, prevent acute complications from dysmetabolic state raised intracranial pressure, seizures, etc. takes precedence over investigations. Careful monitoring to determine progress and identification of complications is crucial. The treatable etiologies should be addressed even on suspicion and constant parent counseling be maintained. PATHOPHYSIOLOGY OF COMA Consciousness requires interplay between cerebral cortex and subcortical structures, viz. diencephalon, midbrain, upper pons. Anatomic substrate for arousal is the ascending reticular activating system which receives afferents from somatic and special sensory pathway; prominent are spinothalamic tracts and sensory components of trigeminal nerves. Efferents pass to each cerebral cortex directly or via thalamus and hypothalamus.1 Thus structural lesions within brainstem or cerebral hemispheres or both result in coma. Metabolic or toxic causes lead to a decrease in the cerebral metabolic rate and oxidative processes required for neurotransmission and synthetic processes. Intracranial hypertension further compounds the problem by mechanical displacement of structures and reduced cerebral perfusion pressure. Factors that precipitate coma may be shock, hypoxia and raised intracranial pressure (ICP) through acute herniation. Herniation syndromes arise as a result of differential intracranial pressure between various brain compartments; may be uncal, diencephalic or brainstem. Herniation often compromises intact survival if unrecognized.2 Clinical Evaluation of a Comatose Child • Vitals assessment and stabilization • History

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• Coma scale • Brainstem function assessment • Elucidation of etiology. HISTORY Onset and tempo of illness progression. Acute onset–think of inflammation, trauma, seizures, intracranial bleed. Gradually progressive sensorial alteration and evolving neurodeficits–metabolic including neurometabolic diseases. History of fever in the recent past, accompanying, focus of infection, ear discharge may point to a central nervous system infections or parainfectious process. History suggestive of seizures, trauma–accidental or non-accidental, possible drug overdose, or other organ system diseases (hepatic, renal, hematologic, connective tissue disorder) need to be enquired. Past history of such episodes, abnormal odor of breath or urine and/or family history should make one consider inborn errors of metabolism. Examination

1. Vitals-to look Temperature-raised in infections/hypothalamic dysfunction, low in septic shock. Pulse rate, capillary refill time, colour; Tachycardia–Early identification of shock and treatment. Bradycardia in raised ICP, hypothermia, hypoxemia, myocardial injury. Blood pressure–Low in septic shock, high-feature of raised ICP especially systolic HT, if raised diastolic BP + fundus changes consider hypertensive encephalopathy. Respiration – as in Table 23.1.

2. General physical examination Pallor–intracranial bleed, Jaundice–hepatic encephalopathy, Scalp bruise, ear/nose bleed–head injury. Skin rashes–meningococcemia/viral exanthems. Odor of breath–sweet in diabetic ketoacidosis, musty in hepatic, ‘Urine like’in uremic.

3. ‘Coma’ scales Identifying coma and grading it on a scale is essential to have inter and intra-observer consistency in assessing daily progress. States of impairment of consciousness with reduced mental state (Plum and Posner) include: Obtundation-reduced alertness or interest in surroundings; Stupor-arousable sensorial depression. Coma-state of deep, unarousable, sustained pathologic unconsciousness. The period of unconsciousness should persist for at least 1 hour to distinguish from syncope, concussion, etc. Related states: Vegetative state–retained wakefulness but lack of awareness. Minimally conscious state–state of severely altered consciousness in which the person demonstrates minimal but definitive behavioral evidence of self or environmental awareness, viz. follow simple commands, gesture or verbal yes or no responses regardless of accuracy, movements or affective behaviors not attributable to reflexive activity.3

EVALUATION OF A COMATOSE CHILD

Various coma scales commonly used are: • Glasgow coma scale (GCS) • Glasgow coma scale modified for children3 • Pediatric coma scale/Adelaide scale (Simpson and Reilly)3 It is important to use a scale which is familiar to all care-givers and is objective. GCS (Table 23.1) Initially designed for monitoring traumatic brain injury. There are only few studies in children with non-traumatic coma. It does not take into account some important brainstem reflexes. It is not useful in paralyzed and sedated patients and cannot be used in young children or infants. Fundus–to look for papilledema, retinal hemorrhages, changes of hypertensive retinopathy. Table 23.1: Modified GCS3

Best motor response

Eye opening

Best verbal response

Spontaneous movement/obeys verbal command-6

Spontaneous-4

Smiles, oriented to sound, follows object, interacts-5

Localizes to supraocular pain-5 (>9 months)

Reaction to speech-3

Consolable cry-4

Withdraws from nailbed pressure-4 Reaction to pain-2

Inconsistently consolable cry -3

Abnormal flexion to supraocular pain-3

Inconsolable cry, restless, agitated, unaware of environment or parents-2

No response-1

Abnormal extension to supraocular pain-2

No response-1

No response-1 Grading: 13 to14-mild, 9 to 12-moderate, < 8 = severe

Anatomical and Etiological Localization (Tables 23.2 and 23.3) Supratentorial destructive or mass lesions • Initial signs focal; combination of focal motor and cranial nerve deficits help in determining probable site of lesion • Rostral-caudal progression. Infratentorial destructive or mass lesions • Preceding brainstem dysfunction • Sudden onset of coma • Cranial nerve palsies • Early respiratory disturbances. Toxic, metabolic or infectious disease • Confusion or stupor precedes motor signs • Motor signs symmetric • Pupillary reactions preserved till late • Asterixis, myoclonus, tremor or seizures • Hyper/hypoventilation.

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INVESTIGATIONS 1. Blood sugar, electrolytes, blood gas arterial lactate, ammonia (elevated in hepatic dysfunction, Reye’s syndrome, urea cycle defect, organic acidemias).Counts and cultures. Malarial parasite in peripheral blood film and by QBC. 2. Lumbar puncture: To be done if meningitis suspected. Contraindicated if- Overt raised ICP, herniation syndromes, GCS70. Rarely, the CPP may go above 110 and ICP >20. The cerebral vasoconstriction that occurs in response to the high CPP in combination with the high ICP would cause cerebral ischemia and further secondary neuronal damage. Here the MAP would need to be brought down by using short acting agents like labetalol or nitroprusside. However, nitroprusside may also dilate the intracranial vessels and is best avoided. The critical threshold for CPP in adults seems to be 55 cm H2O but there are no clear values for children. Hence we should attempt to keep the CPP in children in the same range till we know better.6 The entire discussion and treatment based on the concept of ICP/CPP requires invasive monitoring of ICP arterial BP and if possible SjvO2, etc. While the next chapter on STBI will discuss the detailed management of the brain injured child, some of these aspects of monitoring will be discussed here. Indications for invasive monitoring: When all 3 of the following criteria are met: (i) The patient is suspected to be at risk for elevated ICP (ii) The GC Scale is 9 months)

2 To pain

4 Withdraws from nail bed pressure

1 None

3 Flexion to supraocular pain 2 Extension to supraocular pain 1 No response to supraocular pain

Verbal 5 Orientated Alert, babbles, coos, words or sentences normal 4 Confused Less than usual ability, irritable cry 3 Inappropriate words

Cries to pain

2 Incomprehensible sounds

Moans to pain

1 No response to pain Fig. 25.2: Modified Glasgow coma scale (James) for 3 at some point subsequent to injury v) Secondary clinical deterioration vi) Evolving cerebral herniation syndrome Aggressive treatment of seizures: Seizure activity, even if not overt, is known to increase the cerebral metabolic demand result in relative ischemia. Most units administer phenytoin prophylactically, especially if the patient is to be sedated and paralysed. If there is suspected activity as seen by nystagmoid eye movements, subtle twitches or fluctuations in consciousness, an EEG will identify true seizures. Table 25.5: Some specific injuries

Injury

Features

Treatment

Sub galeal hematomas

Collection of blood above periosteum

No needling. Watch hematocrit

Cephalhematoma

Subperiosteal. Limited by suture line

No treatment required

Skull fractures

Linear, diastatic or depressed

Only depressed may require urgent elevation

Basilar skull fractures

CSF otorrhea or rhinorrhea (β 2 transferrin distinguishes CSF from snot)

Expectant management. NO packing of ear, NO prophylactic antibiotics. 85% spontaneously seal. 4% meningitis. If leak persists ENT repair17

Epiduaral hematoma

Lucid interval in only 33%

Urgent evacuation if mass effect

Subdural hematoma

Underlying brain injury common Cortical bridging vein tear. If chronic think of child abuse.

Evacuate if large or causing mass effect

Intraparenchymal injury

Focal contusions, DAI, hematomas

Neurosurgical intervention usually not helpful. Decompressive cariotomy with or without lesionectomy

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The Columbia Stepwise Protocol for ICP Management21 (Modified) 8. Decompressive craniectomy 7. Hypothermia 6. Pentobarbital Coma 5. Hyperventilation 4. Osmotherapy—mannitol/ hypertonic sal 3. CPP Optimization 2. Sedation ventilation 1. Surgical removal of amenable lesion

Post-traumatic Seizures These may follow even minor trauma. Immediate seizure may occur immediately on impact or within the first 24 hours. Most appear within the first 3 hours, are short-lived, generalized and not associated with any CT scan findings. They do not predict future epilepsy, require no treatment and bear a good prognosis for future outcome. If the nature of the seizure is complex, prolonged or focal; further observation and treatment may be warranted.22 Postconcussive syndromes: This is another aspect of head injury that the ER physician may have to deal with and triage to a ward, ICU or watch and discharge home. Delayed lethargy, irritability and behavioral changes may be seen after head injury. This happens in a child where the scan shows nothing and neurological examination is normal, after about 10-30 minutes. Vomiting, sweating and progressive drowsiness may be seen. If a CT has not already been done, it should be done to rule out an expanding hematoma. Recovery occurs over the next 2-24 hours. No specific treatment is warranted. Other transient phenomena: Vomiting, migraine and cortical blindness can occur. Recovery is the hallmark of postconcussive syndromes.23 SUMMARY OF RECOMMENDED PRACTICES Decrease Intracranial Pressure • Evacuate mass occupying hemorrhages • Consider draining CSF with ventriculostomy when possible • Hyperosmolar therapy, +/– diuresis (cautious use to avoid hypovolemia and decreased BP) • Be mindful of keeping a good CPP • Mid-line neck, elevated head of bead (some research supports elevation not > 30 degrees) • Treat pain and agitation - consider pre-medication for nursing activities, +/– neuromuscular blockade (only when needed) • Careful monitoring of ICP during nursing care, cluster nursing activities and limit handling when possible • Suction only as needed, limit passes, preoxygenate/+/– pre-hyperventilate (PaCO2 not < 30)/ use lidocaine IV or IT when possible • After careful preparation of visitors, allow calm contact

HEAD INJURY IN CHILDREN

Supportive Measures • • • • •

Periodic reevaluation with GCS and papillary response plus neurological examination Attention to ABC and hemodynamics Careful nursing with minimal handling Liaison with neurosurgeon regularly Any transport undertaken with same car as in the unit.

Decrease Cerebral Metabolic Rate • • • •

Prevent seizures Reserve pentobarbital for refractory conditions Avoid hyperthermia, +/– hypothermia Avoid hyperglycemia (early).

REFERENCES 1. Tullous M, Walker ML, Wright LC. Evaluation and treatment of head injuries in children. In: Furhman BP, Zimmerman JJ, editors. Pediatric Critical Care. St Louis: Mosby; 1992;1165-82. 2. Luerssen TG, Klauber MR, Marshall LF Outcome from head injury related to patient’s age. J Neurosurg 1988;68:409-16. 3. McHugh GS, Engel DC, Butcher I, Steyerberg EW, Lu J, Mushkudiani N, Hernández AV, Marmarou A, Maas AI, Murray GD. J Neurotrauma. Prognostic value of secondary insults in traumatic brain injury: results from the IMPACT study 2007;24(2):287-93. 4. Tatman A, Warren A, Williams A, et al. Development of a modified paediatric coma scale in intensive care practice. Arch Dis Child 1997;77:519-21. 5. Hahn YS, McLone DG. Risk factors in the outcome of children with minor head injury. Ped Neurosurg 1993;19:135-42. 6. Mayer T, Walker ML, Metlak ME. Causes of morbidity and mortality in severe pediatric head trauma. JAMA 1981;245:719-22. 7. Gentleman D, Jennet B. Hazards of inter-hospital transfer of comatose head-injured patients. Lancet 1981; 17;2(8251):853-4. 8. Adelson PD, Bratton SL, Carney NA, et al. Guidelines for the acute medical management of severe traumatic brain injury in infants, children and adolescents. Ped Cit Care Med 2003;4 (3 Suppl):S1-75. 9. Muizelaar JP, Marmarou A, Ward JD. Adverse effects of prolonged hyperventilation in patients with severe head injury: A randomized control trial. J Neurosurg 1991;75:731-9. 10. Chestnut RM, Marshall LF. Treatment of abnormal intracranial pressure. Neurosurg Clin N Am 1991;22(2):26784. 11. Slavik R, Rhoney D, Indomethacin. A reviw of its cerebral blood flow effects and potential use in controlling ICP in traumatic brain injury. Neurology Research 1999;21:491-499. 12. Burke AM, Quest DO, Chien S, et al. The effect of mannitol on blood viscosity. J Neurosurg 1981;55: 550-3. 13. Muizelaar JP, wei EP, Kontos HA. Mannitol causes compensatory vasoconstriction and vasodilation in response to blood viscosity changes. J Neurosurg1983;59:828. 14. Marshall LF, Smith RW, Raushner LA, et al. Mannitol dose requirements in brain injuryed patients. J Neurosurg 1978;48:169-72. 15. Qureshi AL, Suarez JL, Bhardwaj A, Mirski M, Schnitzer MS, et al. Use of hypertonic (3%) saline/acetate infusion in the treatment of cerebral edema. Effect on intracranial pressure and lateral displacement of the brain. Crit Care Med 1998;26(3):440-6. 16. Taylor G, Myers S, Kurth CD, et al. Hypertonic saline improves brain resuscitation in a pediatric model of head injury and hemorrhagic shock. J Pediatr Surg 1996;31(1):65-70. 17. Lang EW, Chestnut RM. Intracranial pressure monitoring and management. Neurosur Clin N Am 1994;5(4):573605. 18. Levy DI, Rekate HL, Cherney WB, et al. Controlled lumbar drainage in pediatric head injury. J Neurosurg 1995;83:453-60.

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PEDIATRIC INTENSIVE CARE 19. Sahuquillo J, Vilalta A. Cooling the injured brain: how does moderate hypothermia influence the pathophysiology of traumatic brain injury. Curr Pharm Des 2007;13(22):2310-22. 20. Qiu W, Zhang Y, Sheng H, Zhang J, Wang W, Liu W, Chen K, Zhou J, Xu Z. Effects of therapeutic mild hypothermia on patients with severe traumatic brain injury after craniotomy. J Crit Care J Crit Care 2007;22 (3):229-35. Epub 2007 Jan 31. 21. McKinley B, Parmley C, Tonneson A. Standardardized management of raised intracranial pressure:a preliminary clinical trial. J Trauma 1999;46:271-279. 22. Dias MS, Carnevale F, Li V. Immediate post traumatic seizures: is routine hospitalization necessary? Ped Neurosurg 1999;30:232-8. 23. Dias MS. Traumatic brain and spinal cord injury PCNA51 2004;271-303.

Lalitha Janakiraman THE NEUROMUSCULAR DISEASES IN CRITICALLY ILL CHILDREN 291

26

The Neuromuscular Diseases in Critically Ill Children

INTRODUCTION Neuromuscular diseases, which encompass the entire motor unit, can present as an acute or a chronic problem. The motor unit consists of the anterior horn cell, the axon of the anterior horn cell with its myelin sheath, the neuromuscular junction and the muscle fibers innervated by the nerve. Any disruption of function in this pathway leads to weakness of varying degree. Recently, neuromuscular disorders are increasingly being recognized as a complication in patients in intensive care unit (ICU) and represent one of the common causes of prolonged ventilatory dependency. In many cases timely evaluation and therapy can prevent or reduce both morbidity and mortality from many neuromuscular disorders. The management requires simultaneous performance of many tasks like stabilization of vital functions, assessment of systemic and etiological factors, thorough physical examination, performance of diagnostic studies that help in localization of the neurological insult and specific therapeutic intervention. A variety of neuromuscular diseases exist and this chapter deals with the common diseases presenting to the Pediatric Intensive Care Unit (PICU) and the same are listed in Table 26.1 and the differentiating clinical features of the various components of the motor unit is shown in Table 26.2. PATHOPHYSIOLOGY Neuromuscular diseases involve the muscles of inspiration and expiration to a varying degree and the clinical manifestations reflect the compromise of both the muscle groups. Inspiratory muscle weakness: Weakness of the muscles of inspiration results in alveolar hypoventilation and impaired CO2 exchange. The initial effect is loss of the ability to increase minute ventilation in response to the increased ventilatory demands and as muscle weakness progresses and/or ventilatory demands remain excessive, the inspiratory muscles fatigue. Tachypnea is the usual response to unmet ventilatory demands and tachypnea enhances the work of breathing (by

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Anterior horn cell dysfunction Acute

Peripheral nerve involvement

Neuromuscular Junction Acute

Muscle

Poliomyelitis

Guillain–Barre Synd.

Botulism

Infantile Myotonic dystrophy

Toxins Clostridium tetani Strychnine

Diphtheritic neuropathy

Organophosphates

Congenital Muscular Dystrophy

Metabolic and toxic neuropathies

Tick paralysis

Chronic

Acute intermittent Porphyria

Chronic

Chronic

SMA

Critical illness neuropathy

Myasthenia Gravis

DMD Dermatomyositis, Polymyositis Periodic Paralysis

Acute

Table 26.2: Differentiating features

Reflexes Muscle bulk Fasciculations Tone Power Sensation - Absent + Present

Motor Neuron

Muscle

– ↓ + ↓ ↓ WNL

– ↓ + ↓ ↓ ↓

NMJ – ↓ – ↓ ↓ Variable

Nerve – ↓ – ↓ ↓ ↓

↓ Decreased

increasing dead-space ventilation) and, by increasing the relative time spent in inspiration, compromises blood flow to respiratory muscles (which occurs primarily during expiration). Inspiratory muscle weakness also predisposes to atelectasis by reducing vital capacity, tidal volume, and the volume of sighs. Expiratory muscle weakness: Weakness of the expiratory muscles has less impact on respiratory mechanical and ventilatory function, as the elastic recoil of the stretched thoracic and lung tissues provide the principal driving pressure for expiratory airflow. However, expiratory muscles are essential for generation of an effective cough and the clearance of respiratory secretions. The pathophysiology of neuromuscular respiratory failure is shown in Figure 26.1. CLINICAL FEATURES Assessment of a patient with neuromuscular disease should focus on the evaluation of both respiratory muscle (intercostals and diaphragm) and bulbar function separately. The clinical manifestations of respiratory muscle weakness include • Tachypnea

é

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293

Fig. 26.1: Pathophysiology of neuromuscular respiratory failure

• Reduced tidal Volume • Paradoxical breathing • Nasal speech, difficulty in swallowing and pooling of secretions due to bulbar weakness and an increased risk of aspiration. Respiratory muscle weakness may progress more rapidly than the underlying process. Therefore close and careful assessment of upper airway integrity, ventilatory function, oxygenation and chest radiographs are essential in determining the need for ventilatory assistance. The changes in these parameters over time are more important than single, isolated determinations. FEATURES OF COMMON DISEASES THAT PRESENT WITH NEUROMUSCULAR WEAKNESS TO THE PICU Guillain Barré Syndrome (GBS) One of the most common cause of acute neuromuscular diseases that present to the intensive care unit is GBS and the incidence of typical GBS has been reported to be relatively uniform between 0.6 and 4 cases/100000 per year throughout the world. A prodromal respiratory or gastrointestinal illness is commonly found in the history. The prodromal illness may include Campylobacter jejuni,

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cytomegalovirus, Epstein-Barr virus and Mycoplasma pneumoniae infection which elicits an immune response that cross reacts with axolemmal or Schwann cell antigens and thereby damage the peripheral nerves. The recognized forms of GBS are AIDP (acute inflammatory demyelinating polyneuropathy), AMA (acute motor sensory axonal neuropathy) and MFS (Miller Fisher variant). The neurological symptoms typically present with progressive paralysis that is symmetrical and may evolve to all extremities. Other features include varying degree of hyporeflexia or areflexia or even respiratory embarrassment. Asbury and Cornblath have established criteria for the diagnosis of GBS and as per their criteria the features that are required for the diagnosis include- progressive motor weakness of more than one limb and areflexia. Features that are strongly supportive of GBS include –relative symmetry of symptoms, cranial nerve involvement, autonomic symptoms and recovery that begins 2 to 4 weeks after symptom progression discontinues. Sphincter disturbance is rare, occurring early in the course of GBS and is usually transient. Diagnostic studies include CSF examination and neuropsychological studies. The neuropsychological studies play an important role in diagnosis, subtype classification and confirmation that the disease is a peripheral neuropathy. Typical features include reduced motor and sensory conduction velocities, prolonged F wave and abnormal temporal dispersion. After the first week of the symptoms, analysis of cerebrospinal fluid (CSF) typically reveals normal glucose, few cells ( 50 mg /dl). Even before initiating specific therapy, the problems are when and whether to admit to the PICU and when to consider mechanical ventilation. It has been reported that 20 to 30 % of patients with GBS develop neuromuscular failure and require mechanical ventilation. The 20/30/40 rule i.e. patients with vital capacity 40 cm H2O progress to require mechanical ventilation; Patients with rapid progression (< 7 days), inability to raise their head against gravity, bulbar dysfunction, bilateral facial weakness and autonomic dysfunction need PICU care. The main modalities of treatment of GBS include intravenous immunoglobulins and plasmapheresis. Plasmapheresis: Plasmapheresis became the accepted gold standard of treatment of GBS 20 years ago. Evidence to support this practice has accumulated from 6 trials. Treatment with plasma exchange was beneficial during the first 4 weeks but its benefit was greater when treatment was given early. Increased muscle strength, earlier improvement and a lower requirement for mechanical ventilation have been demonstrated with plasmapheresis. The usual regimen is a total exchange of about 5-plasma volume (200 to 250 ml/kg) over 1-2 weeks. IVIG (Intravenous immunoglobulin) IVIG appears to be as effective as plasma exchange for the treatment of GBS. This conclusion was reached by the American Academy of Neurology (AAN) practice parameter as immunotherapy for GBS published in 2003. The standard immunoglobulin dose is 2 gm/kg (0.4 gm/ kg/ day for 5 days or 1 gm/kg /day for 2 days or 2 gm/kg/day for 1 day). The AAN practice parameters on immunotherapy published in 2003 has made the following observations:

THE NEUROMUSCULAR DISEASES IN CRITICALLY ILL CHILDREN

a. b. c. d.

Treatment with plasma exchange (or) IVIG hastens recovery from GBS The effects of plasma exchange and IVIG are equivalent Combining the two treatments is not beneficial Steroid treatment alone is not beneficial. The other treatment options for GBS are interferon Beta and immunoadsorption. The supportive treatment include–monitoring of respiratory function (PFT) ventilatory support, tracheostomy care and physiotherapy. Most patients with GBS either recover completely (15%) or are left with only minor deficits that do not interfere with activities of daily life (65%). Only 5 to 10 % of patients suffer from permanent disabling weakness and 3 to 8 % die despite of intensive care. The causes of death in GBS are due to acute respiratory distress syndrome, sepsis, pulmonary embolism and unexplained cardiac arrest. Spinal Muscular Dystrophy (SMA) SMA is a disease of the anterior horn cell and is inherited in an autosomal recessive manner. There are three types of SMA with onset of symptoms ranging from birth to 2 years of age. The general presentation is progressive proximal muscle weakness that is accompanied by hypotonia. Lower cranial nerve involvement occurs early leading to feeding difficulties and changes in the quality of the cry. The respiratory complications are the most concerning aspect of this disease and include aspiration pneumonia and respiratory failure. Respiratory failure may even be the presenting symptom in SMA. Respiratory muscle weakness results in restrictive lung disease with a weak cough and hypoventilation. Hypercapnea is also a consequence of restrictive lung disease; so supplemental O2 may have devastating consequences including apnea and death. If supplemental O2 is needed, conventional ventilation or noninvasive ventilation should be instituted. Management is supportive and includes meticulous chest and limb physiotherapy and genetic counseling with prenatal diagnosis for future pregnancy. Myasthenia Gravis It is a disease process involving the neuromuscular junction with abnormal transmission of acetylcholine across the synaptic membrane to its receptors. The common heralding symptoms include waxing and waning ptosis and diplopia and the weakness may generalize to involve the extremities. The most troublesome symptoms seen in generalized myasthenia are due to involvement of bulbar and respiratory muscles thereby causing swallowing dysfunction and respiratory failure warranting ICU admission. Treatment includes use of cholinesterase inhibitors like neostigmine, which can be given orally in a dose of 0.4 mg/kg every 4 to 6 hours. Myasthenic crisis is an exacerbation of myasthenia requiring ventilatory assistance. Improvement with edrophonium helps to differentiate myasthenic crisis from cholinergic crises, which is due to overdose of anticholinesterase drugs. Acute Poliomyelitis A few patients with poliomyelitis progress to complete loss of motor function asymmetrically in one or more extremities. Weakness is classically proximal and involves the lower extremities without any sensory loss. The disease can affect the phrenic nerve nuclei leading to diaphragmatic paresis and resultant respiratory failure. The infection may also affect the cranial nerve nuclei progressing to bulbar involvement needing early assisted ventilation.

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Diphtheria This disorder is uncommon in the present era of vaccination. When there is severe disease, neuropathy is seen in approximately three fourths of the patient’s .The axonal and demyelinating neuropathies are based on circulating toxins and range from motor weakness to sensory abnormalities in a stocking glove distribution. The symmetrical polyneuropathy has a varied onset from 10 days to 3 months following an oropharyngeal infection. Local paralysis of the palate followed by weakness of pharyngeal, facial and ocular nerves may occur. Airway complications should be anticipated and tackled appropriately. Toxic myocarditis may occur in 10-25% of patients and accounts for significant mortality. Early administration of antitoxin reduces mortality. Antimicrobial therapy with penicillin is essential. Organophosphates Organophosphates (which are used as insecticides) exposure is a classical example of NMJ dysfunction. They inhibit cholinesterase activity and hence clinical symptoms of muscarinic effects occur. The depolarizing blockade results in diffuse weakness and fasciculation. In addition to the specific antidotes (atropine and pralidoxime), the main stay of treatment is supportive. Atropine is an antidote for muscarinic symptoms but does not reverse nicotinic symptoms such as muscle weakness and respiratory failure. Pralidoxime, a cholinesterase reactivator is an antidote for nicotinic symptoms. Frequent suctioning and ventilation should be provided until the patient regains respiratory strength. Cardiac monitoring to recognize arrhythmias is also important. Botulism Toxin of Clostridium Botulinum produces paralysis by binding to the presynaptic segment of NMJ thereby preventing the release of acetylcholine at the myoneural junction and causing neuromuscular weakness. The most common symptoms include weakness, poor suck and feed, decreased tone and reflexes, weakness in descending pattern, constipation and autonomic symptoms (tachycardia, hypotension, urinary retention, decreased tears). The most concerning consequence of botulism is respiratory embarrassment. The management of patients with botulism is supportive until axonal sprouting reestablishes at the neuromuscular junction. In respiratory compromise, mechanical ventilation should be instituted until the patient regains protective reflexes and respiratory strength. If the patients are unable to tolerate oral feeds, nasogastric/ nasojejunal feeds should be initiated. The resolution of symptoms occurs in the reverse pattern of presentation with return of head control appearing to be a reliable measure of improving muscle function. Axonal Neuropathy Causes of this are numerous. Most metabolic or toxic neuropathies preferentially attack axons and are usually chronic, sensory more than motor with a distal predilection more than proximal. Because of these they rarely need ICU admission. Heavy metal poisoning from lead, arsenic or thallium and organic compounds have been reported to cause axonal damage. Acute Intermittent Porphyria (AIP) An acute neuropathy is seen in approximately 40 % of acute AIP attacks. Rapid progression of weakness leads to a flaccid involvement of all four extremities and respiratory compromise. It is

THE NEUROMUSCULAR DISEASES IN CRITICALLY ILL CHILDREN

often associated with abdominal pain. Recommended treatment modalities include carbohydrate loading and administration of heme. Prophylaxis consists of adequate nutritional intake, avoidance of drugs known to exacerbate porphyria and prompt treatment of intercurrent diseases or infections. Tick Paralysis Toxin of tick inhibits the release of acetylcholine at the presynaptic terminal and causes ascending paralysis which progresses rapidly to the bulbar area and rapid improvement occurs with removal of the tick. Diseases of Muscle These conditions present for intensive management in specialized situations of neonatal and infantile onset, requiring both diagnosis and management, or in the situation where the diagnosis is known but natural history or iatrogenic complications supervene. In the neonatal period the presentation of muscle disease is usually either respiratory compromise or poor feeding. The common disorders are infantile myotonic dystrophy and congenital muscular dystrophy. Benign congenital myopathies present with hypotonia in childhood.

Muscular Dystrophy Most of these patients would already have been diagnosed and present to the ICU in the pre terminal stages of chronic respiratory failure because of progressive muscle weakness. Recurrent pneumonia adds to the problem. The most common is Duchenne’s muscular dystrophy.

Periodic Paralysis Rare illness that results in episodes of severe weakness associated with an abnormality of circulating potassium during attacks. Two major forms are described: Hypokalemic Periodic Paralysis It is the most common form of periodic paralysis. The weakness may progress to flaccid paralysis of all limbs with areflexia and normal sensation. Cranial nerve functions remain normal. The paralytic attack may be reversed with normalization of potassium levels. It does not cause respiratory compromise despite the presence of dramatic limb paralysis. Hyperkalemic Periodic Paralysis Occurs while resting after severe exercise. Light exercise can prevent an attack and an acute attack can be relieved by intake of glucose. Cardiac monitoring may be needed as cardiac arrhythmias may occur.

Dermatomyositis and Polylmyositis Both these conditions can present with acute weakness to the ICU. Erythema and edema of periorbital area and extensor surfaces may be seen in dermatomyositis. Typical EMG abnormalities, elevation of creatinine kinase, antinuclear antibodies supports the diagnosis. Immunotherapy is with high dose corticosteroids. Other complications needing ICU care are due to chronic interstitial pulmonary fibrosis, pneumothorax, pericarditis and arrhythmias.

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Critical Illness Neuromuscular Disease Some children in ICU may develop weakness or paralysis during the course of sepsis and multiorgan failure or when they are exposed to steroids or neuromuscular blocking agents. These include critical illness polyneuropathy, acute myopathy or both and manifest as prolonged ventilatory dependency. 1. Critical illness polyneuropathy is characterized by development of neuropathy during a severe illness requiring intensive care. The pathophysiology is not known but mediators of systemic inflammatory response like tumor necrosis factor (TNF α) that can damage myelin may play a role. Recovery is gradual over a period of several months. 2. Acute myopathy in ICU is of two types: i. Acute necrotizing myopathy in sepsis or trauma presents as a sudden onset of generalized muscle weakness, high blood creatinine kinase and myoglobinuria. Biopsy shows pan fascicular necrosis and recovery is rapid. ii. Myopathy associated with corticosteroids and curare. Muscle biopsy shows changes ranging from isolated type II fiber atrophy to severe necrosis of all fiber types. MANAGEMENT OF RESPIRATORY FAILURE IN CHILDREN WITH NEUROMUSCULAR DISORDERS Disorders of the motor unit may produce either acute or chronic respiratory failure, which may be accompanied by airway compromise, which may be due to the involvement of respiratory muscles or abnormal control of breathing. The management strategies in neuromuscular respiratory failure include: Respiratory Management Careful assessment of the upper airway and the patients ability to protect his/her airway is essential. Ventilatory function (PFT), laboratory measures, and chest radiographs are helpful but not essential in determining the need for ventilatory assistance. None of these can replace clinical observation and judgment in this cohort of patients. The ABG, rise in CO2, fall in O2 and falling SpO2 are all very late signs of respiratory failure. More important is a clinical and constant watch on the patients effort, air entry, pattern of breathing- abdomino-thoracic, loss of diaphragmatic movement etc; use of accessory muscles, diaphoresis, restlessness or drowsiness. Administration of O2 to keep up a falling saturation is foolhardy as it only saves to mask hypoventilation and delay proper intervention. As the lungs are usually normal, a small amount of O2 will cause a quick and steep rise in SpO2 and PaO2 and this will give a false sense of security. Peak flow meters and single breath counts are good bed side tools in the co-operative patient. Although ventilatory support is clearly indicated in the setting of frank respiratory failure, particularly when there is cardiovascular instability, ideally it should be initiated in the setting of emerging respiratory failure when there has been a clear downward trend in respiratory function. The options for ventilatory support include endotracheal intubation, noninvasive positive pressure ventilation and tracheostomy, which are discussed below. a. Endotracheal intubation — Endotracheal intubation with positive pressure mechanical ventilation

THE NEUROMUSCULAR DISEASES IN CRITICALLY ILL CHILDREN

remains the traditional form of ventilatory support in these patients. It has generally been initiated when the underlying disease process is new or uncontrolled and the patient manifests evidence of emerging respiratory failure. b. Noninvasive positive pressure ventilation —An alternative to elective intubation in selected patients involves the use of noninvasive positive pressure ventilation. This modality may be tried in patients who present with early acute respiratory failure, are cooperative, can protect their airway with intact brain stem and lower cranial nerve function, have adequate upper airway function, have minimal secretions, and remain hemodynamically stable. This modality is more suited to the chronic patient such as the Duchenne or spinal muscular atrophy patient and not for the acute patient whose disease progression is unknown. Once the child has been intubated and is comfortable, minimal analgesia and sedation is usually needed. Patient triggered modes can be used and the trigger should be carefully adjusted to the level of strength/weakness of the patient’s respiratory muscles. If there has been any atelectasis or collection of secretions for a long time prior to intubation, settings may need to be higher with additional PEEP. This phase may require extra sedation. As the intercostals and diaphragm are weak, there is a strong tendency to airway collapse and tidal volumes need to be physiological and higher than what is used for the ARDS “baby” lung. Every effort should be made to keep the wave form, cycle times and pressures as physiological as possible. NO relaxants should be used unless required for other reasons. Limb and chest physiotherapy should be actively undertaken daily. c. Tracheostomy — In patients with acute neuromuscular respiratory failure, tracheostomy is an important decision when the need for mechanical ventilation appears prolonged in order to minimize the well described problems associated with prolonged nasotracheal or orotracheal intubation. However, the indications for tracheostomy and the timing will vary with the individual patient and the underlying disease process. d. Discontinuation of ventilatory support —Although the initial strategy for weaning depends on the individual patient, weaning is often initiated in the pressure support mode. As the patient would be on a trigger, it is easy to see the effort that the muscles are capable off producing. Gradually the trigger sensitivity can be decreased. As the patient gets stronger, the levels of support are reduced and the tidal volumes generated are closely watched. When the patient can mange adequate tidal volumes on minimal support of about 5-8 cm H2O over about 5 cm H2O PEEP, it may be time for a spontaneous trial of breathing on a T-piece if the child is old enough- above 4-5 years or a CPAP trial in a younger child. In older children who have had a long recovery period on the ventilator, there is often a great deal of anxiety associated with extubation and psychological dependence on the ventilator. Daily counseling and encouragement is needed and the child should never be forced as excessive anxiety will cause failure of extubation. As the recovery of the upper airway protective muscles might lag behind the recovery of the ventilatory musculature, the integrity and function of the upper airway musculature should be closely monitored following extubation. Other Considerations A variety of other considerations are important in the overall management of patients with acute respiratory failure from peripheral neuromuscular disease. They include:

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i. Nutritional support — The goals of nutritional support for patients with neuromuscular respiratory failure are similar to those for other critically ill patients and include: • Maintenance of fluid and electrolyte balance, skin integrity, and immune competence. • Prevention of starvation-induced muscle wasting. • Avoidance of overfeeding and thereby resultant increase in CO2 generation and ventilatory requirements. Failure to optimize the nutritional support increases the risk of infectious complications and compromises weaning from mechanical ventilation. ii. Infection — Intercurrent infection may be associated with increased weakness, particularly in patients with myasthenia gravis. Hence there should be a careful search for an infectious process in the deteriorating patient, especially in the setting of immunosuppressive therapy and appropriate antibiotics are to be administered depending on the clinical situation. iii. Psychologic and emotional well-being — As the patient’s stay in the intensive care unit often extends over weeks or months, it is common for feelings of helplessness, anger, fear, isolation, hopelessness, and/or anxiety to emerge. The din and often-incessant activity of the intensive care unit as well as the multiple and changing faces of the caregivers contribute to the patient’s disorientation and often amplify these feelings. These reactions are not only emotionally debilitating but may interfere with the patient’s care and may slow recovery. Consequently, liberal psychologic support, structuring care and testing to optimize rest and privacy, and creating familiar and friendly rooms and effective communication with the patient are all essential to a patient’s emotional well-being iv. Prevention of disability — Efforts should be directed toward preventing pressure sores, compression neuropathies, tendon shortening, and joint malalignment. Important measures in this regard include frequent repositioning, careful attention to skin care, molded ankle and wrists splints, and passive range of motion exercises (physiotherapy and occupational therapy). SUMMARY Neuromuscular diseases can present at anytime from the neonatal period to adolescence. The presentation to the intensivist can either be as an acute unknown catastrophic illness or an exacerbation of a previously diagnosed chronic process. A multidisciplinary approach will aid in optimizing the outcome. BIBLIOGRAPHY 1. Ahlawat S, Sachdev A. Hypokalemic paralysis. Postgrad Med J 1997;75:193-197. 2. Asbury A, Comblath D. Assessment of current diagnostic criteria for Guillian Barre syndrome. Ann Neuro 1990;27(Suppl):521-524. 3. B Tabarki, A Coffinieres, P Van den Bergh, G Huault, P Landrieu, G Sebire. Arch Dis Child 2002;86:10307. 4. Campbell JP, Alwarez JA. Acute arsenic intoxication. Am Fam Physician 1989;40:93. 5. Elder GH, Hift RJ. Treatment of Acute Porphyria, Hos Med 2001;62:422-425. 6. Fink M. Treatment of the critically ill patient with Myasthenia Gravis. In: RopperA (Ed). Neurological and Neurosurgical Intensive Care, New York 1993, Raven Press. 7. Grattan-Smith P, Morris J, Johnston H, et al. Clinical and neurophysiological features of tick paralysis. Brain 1997;120:1975-1987. 8. Horace M DeLisser. Respiratory failure from peripheral neuromuscular disease. Available from URL :http:/

THE NEUROMUSCULAR DISEASES IN CRITICALLY ILL CHILDREN /gslbpatients.uptodate.com/topic.asp?file=muscle/14278.Accessed September 2007. 9. Hughes RAC, Comblath DR. Guillian Barre Syndrome. Lancet 2005;366:1653-61. 10. Joanne M Decker. Weakness./Flaccid Paralysis, In: GR Fleisher, S Ludwig (Eds).Textbook of Pediatric Emergency Medicine (4th edn). Lippincot Williams and Wilkins, Philadelphia 2000;635-41. 11. Lisak R, Lebeau J, Tucker S, et al. Hyperkalemic periodic paralysis and cardiac arrhythmia. Neurology 1972;22:810-815. 12. MacDuff A, Grant IS. Critical care management of neuromuscular disease, including long term ventilation. Curr Opin Crit Care 2003;9:106. 13. Maria B Weimer, Ann Henderson Tilton. Acute Neuromuscular Diseases and Disorders. In: Fuhrman BP, Zimmerman JJ (Eds). Pediatric Critical Care (2nd edn). St.Louis, Mosby 1998;877-88. 14. Mortensen M. Management of acute childhood poisonings caused by certain Insecticides and herbicides. Pediatr Clin North Am 1986;33:421-445. 15. Overturf GD, Corynebacterium Diphtheria. In: Long SS, Pickering LK, Prober CG (Eds). Principles and practice of pediatric infectious diseases, New York, Church Livingstone, 2003. 16. Perrin C, Unterborn JN, Ambrosio CD, Hill. Pulmonary complications of chronic neuromuscular diseases and their management. Muscle Nerve 2004;29:5. 17. Schreiner M, Field E, Ruddy R. Infant botulism: A review of 12 year’s experience at the Children’s Hospital of Philadelphia, Pediatrics 1991;87:159-165. 18. Spiro A. Childhood dermatomyositis and polymyositis. Pediatri Rev 1984;6:163-172. 19. Unterborn JN, Hill NS. Options for mechanical ventilation in neuromuscular diseases. Clin Chest Med 1994; 15:765. 20. Wermer MB, Tilton AH. Acute neuromuscular diseases and disorder. In Fuhrman BP, Zimmerman J Eds. Pediatric Critical Care 3rd edn, Mosby Elsevier, Phildelphia 2006;876-90.

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27

Trauma in Children

MANAGEMENT OF A SEVERELY INJURED CHILD Injuries surpass all major diseases in children and young adults making it the most serious health care issue for this population cohort (ATLS 1997).1 Severely injured children have improved outcomes if managed in designated trauma centers with well organized, skilled pediatric multidisciplinary teams.2 Falls and road traffic accidents account for upto 80% of pediatric injuries although distressingly the number of penetrating injuries is on the rise. Particularly in an Indian scenario where road safety rules are flouted openly, with lack of designated areas for children to cross roads near educational institution, our pediatric population is at a far greater risk than our western counter part. Multisystem injury is a rule rather than exception and therefore all organ systems must be assumed to be injured until proved otherwise. Children with multisystem injuries can deteriorate rapidly and hence should be transferred to a facility capable of managing the child with multisystem injuries which is unfortunately not many in our country. In 1979, Dr Cowley was 1st to describe the importance of 1st hour after injury calling it the “Golden Hour”. The greater the delay in definitive treatment from the time of initial injury, the greater the likelihood of poorer outcome. It is difficult to overstate the importance of the prehospital phase of treatment for indeed the “golden hour” for small children and infants may be more accurately described as the “Platinum half hour”.3 Children are remarkably resilient, however the initial period of “metastability” has been shown to be significantly shorter as age decreases. 4 The order and priorities of assessment and management of injured children are as per the ATLS protocol.1,4 Each critical area of this standardized approach is supplemented with specific points relevant to care of the injured child. The unique anatomic characteristics of the pediatric population require special consideration in the assessment and management of pediatric trauma victim.

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Size and Shape 1. Smaller body mass and hence greater distribution of force per unit body area. 2. Energy is transferred to a body that has less fat, less elastic connective tissue and close proximity of multiple organs resulting in multiple organ injuries. 3. Large surface area relative to volume predisposes children to insensible fluid and heat loss resulting in hypothermia. Skeleton 1. More pliable skeleton due to incomplete calcification. 2. Resulting in serious organ injury without overlying skeletal fracture. 3. Spinal injuries are rare but can occur without osseous trauma visible on radiographs. 4. If rib fractures identified anticipate serious organ injury as the force may have been great. 5. Multiple active bone growth centers resulting in unique fractures with potential growth arrest or abnormality. The dimensions of the child’s torso leads to increased vulnerability of intra-abdominal organs. Superiorly the very pliable ribs can lead to solid organ injuries to liver and spleen and inferiorly the pelvis fails to protect the bladder leading to genito-urinary injury. As a result of the sum of these important differences the surgeon treating an injured child must have resources immediately available to him to treat these injuries effectively. The resources include the specific differences between children and adults and the appropriate equipment essential care of injured children. Immediately available equipment of the appropriate size is essential for successful management of injured child (Table 27.1). A “Broselow Pediatric Resuscitation measuring Tape” is an essential adjunct for the rapid determination of weight based on length for appropriate drug doses and equipment size (Figs 27.1A and B).

Figs 27.1A and B: Broselow pediatric resuscitation measuring tape (Fig. 27.1A For color version see Plate 1)

PED

PED

Adult

1-3 yrs. 10-12 kg

4-7 yrs. 16-18 kg

8-10 yrs. 24-30 kg Large

Medium

Medium

Medium

Small

PED

6-12 mos 7 kg

Infant

Infant

Small

NB

Newborn

Preterm

O2 Mask

Oral Airways

Newborn 0-6 mos 3.5 kg

Preterm 3 kg

Age Weight (kg)

Adult

PED

PED

PED

PED

Infant

Infant

BagValve Mask

4.0-4.5 Uncuffed

3.5-4.5 Uncuffed

3.0-3.5 Uncuffed

2.5-3.0 Uncuffed

ET Tubes

2-3 Straight or Curved 5.5-6.5 Cuffed

2 5.0-5.5 Straight Uncuffed or Curved

1 Straight

1 Straight

1 Straight

0 Straight

Laryngoscope Blades

Airway/Breathing

14 Fr

14 Fr

6 Fr

6 Fr

6 Fr

6 Fr

Stylet

14 Fr

14 Fr

10 Fr

8-10 Fr

8 Fr

6-8 Fr

Suction

Adult

Child

Child

Child

Child

Infant

Infant

Newborn

Newborn

Preterm

BP Cuff

18-20 Gauge

20 Gauge

20-22 Gauge

22 Gauge

22 Gauge

22 Gauge

IV Catheter

Circulation

Table 27.1: Pediatric equipment

12 Fr

12 Fr

12 Fr

12 Fr

12 Fr

12 Fr

NG Tubes

10 Fr

8 Fr

5-8 Fr Feeding

5 Fr Feeding

Urinary Catheter

28-38 Fr

12 Fr

20-32 Fr 10-12 Fr

14-24 Fr

14-20 Fr

12-18 Fr

10-14 Fr

Chest Tubes

Supplemental Equipment

Medium

Small

Small

Small

-

-

C-collar

304 PEDIATRIC INTENSIVE CARE

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The initial treatment of life-threatening injuries is surgical and hence it is imperative that the leader of initial resuscitation and treatment is a surgeon who is qualified and comfortable making surgical decisions. The primary survey in the ATLS protocol follows the ‘ABCDE’ sequence that are same for adults and children. A. Airway with cervical spine control. B. Breathing with ventilation management. C. Circulation with hemorrhage control. D. Disability or neurologic status. E. Exposure (undress) with environment control (avoid hypothermia). The primary goal of initial assessment and management of a multiple injured child is to restore and or maintain adequate tissue oxygenation. The inability to establish and maintain a patent airway leads to hypoxia and inadequate ventilation which is the most common cause of cardiorespiratory arrest in a child. Thus control of pediatric airway requires an undertaking of and familiarity with pediatric airway with an organized approach to intubation. AIRWAY MANAGEMENT The child’s airway is the first priority as assessment. Anatomic Peculiarities in Child 1. Smaller the child greater disproportion between the size of the head and the midface, producing a passive flexion of the cervical spine due to the relatively large occiput producing posterior phalangeal wall to buckle. 2. Child’s airway is protected by a slightly anterior and superior position of midface. 3. Soft tissue in the oropharynx (tongue/tonsils) relatively larger making visualization of larynx relatively difficult. 4. Child’s larynx has a more anterocaudal angle and is frequently more difficult to visualize for intubation due to the slightly head flexed position in a supine child. 5. Infants trachea is 5 cms in length and grows to 7 cms by 18 months failure to appreciate this short length may result in intubation of the right main bronchus, inadequate ventilation and mechanical injury to the delicate bronchial tree. Management In a spontaneously breathing child airway should be secured by chin lift maneuver. After the mouth and oropharynx have been cleared of debris supplemental oxygen should be administered. In an unconscious child mechanical methods of maintaining the airway may be necessary. “Before attempts are made to mechanically establish an airway the child should be oxygenated.” Endotracheal intubation is the most reliable means of ventilating a child with airway compromise. Uncuffed tubes of correct size (Table 27.1) should be used to avoid subglottic edema, ulceration and disruption of infants fragile airway. The smallest area of the child’s airway is at the cricoid which forms a natural seal around the endotracheal tube. A simple technique to gauge the size of the tube is to approximate the diameter of the external nares or the child’s little finger with the tube.

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“Nasotracheal intubation should not be performed in children” due to the anterocaudal position of larynx. “Orotracheal intubation under direct vision with adequate immobilization and protection of cervical spine is the preferred method of obtaining initial airway control”.4 Each hospital managing injured children must establish a protocol for emergency intubation referred to as a “Rapid Sequence Intubation (RSI)”. The ATLS algorithm for RSI of an injured child.1 1. Children should be pre-oxygenated using a ventilating mask and receive atropine sulphate (0.1 – 0.5 mg) to ensure heart rate remains high during intubation. The cardiac output of a child is rate dependent as small infants have limited ability to increase stroke volume. 2. The child should be sedated using thiopental sodium (5 mg/kg) if volume status is normal or midazolam (0.1 mg/kg/ 5 mg maximum dose) if the child is hypovolemic. 3. Cricoid pressure must be maintained and a paralysing agent is selected appropriate to resuscitation activities succinyl choline chloride (1 mg/kg) as short acting agent, vecuronium bromide (0.1 mg/kg) may be used if a longer period of paralysis is needed as in imaging or surgical intervention. 4. The position of the endotracheal tube must be carefully assessed after intubation by auscilating both hemithoracis in the axilla. Multiple studies have shown that hypoventilation is the most common cause for cardiac arrest in children. Pre-arrest respiratory acidosis must be treated with adequate ventilation and perfusion. Sodium bicarbonate must not be used in this situation until adequate ventilation and perfusion is achieved. 5. An intubated child must be monitored continuously with pulse oxymeter and where facilities are available with endtidal CO2. Children should be ventilated at 20 breath/min while infants require 40 breaths/min. VENOUS ACCESS Obtaining a venous access is often the most difficult problem in the casualty. Seriously injured children are often hypotensive with decreased circulating volume, obscuring venous landmarks making IV cannula placement difficult. Two attempts should be made to place large bore peripheral IV’s in the uninjured upper extremities. If unsuccessful an IO (intraosseous line) should be placed in a child less than six years of age (Fig. 27.2).

Fig. 27.2: Intraosseous access (For color version see Plate 1)

TRAUMA IN CHILDREN

If over six year of age, a venous cutdown should be performed at the ankle or in the hands by an adequately trained doctor at percutaneous femoral line. The IO line should be placed one finger breadth below tibial tuberosity but should not be placed in an extremity with fracture. Bone marrow needles can be used if IO needles are not available. The most common site recommended for insertion is the proximal tibia. The tibial tuberosity, just below the knee, is first identified by palpation. Locate a consistent flat area of bone 2 cm distal and slightly medial to the tibial tuberosity. Identifying these landmarks also helps in avoiding the growth plate. If time permits, the area should be cleansed with an iodine solution and draped. Perform insertion using sterile gloves and technique. Local anesthesia with 1% lidocaine should be injected in the skin, subcutaneous tissue, and over the periosteum, especially if the patient is awake. The IO needle is easily inserted through the skin and subcutaneous tissue. Upon reaching the bone, hold the needle with the index finger and thumb as close to the entry point as possible and, with constant pressure on the needle with the palm of the same hand, use a twisting motion to advance the needle through the cortex until reaching the marrow. A 10-15° caudal angulation may be used to further decrease chances of hitting the growth plate, but direct entry parallel to the bone is acceptable. When the needle advances from the cortex into the marrow space, a popping sensation or lack of resistance is felt. At this point, discontinue any further advancement. The first indication of proper placement occurs when the needle stands up on its own. Remove the inner trocar, attach a syringe to the needle, and aspirate bone marrow. Obtaining marrow confirms placement. If marrow is not aspirated, a 5 to 10 mL bolus of isotonic sodium chloride solution is pushed. Resistance to flow should be minimal, and extravasation should not be evident. Observing the calf area is important. If flow is good and extravasation is not evident, the IV line is connected with a 3-way stopcock at the needle and the needle is secured with gauze pads. Although fluid may run from the IV by gravity, the rate is too slow for resuscitation. More rapid rates of infusion occur by drawing up 30 to 60 mL from the IV bag and administering manual fluid boluses via the stopcock. Administering medications this way is much easier as well, and it provides more accurate administration of fluid to small infants. As an alternative for larger boluses, an IV pump or pressure bag can be used to increase flow. The IO line is a temporary maneuver for initial resuscitation and no child should leave casualty without removing the IO line and replacing it with an appropriate IV line. Hypotension in a child indicates a state of uncompensated shock and indicates severe blood lost and inadequate resuscitation changes in vital organ function (Table 27.2). Early compensated shock may present with normal vital signs Table 27.3. As a rule a child’s blood pressure should be 80 mm of Hg plus twice the age in years and diastolic should be two third of systolic blood pressure. When shock is suspected a fluid bolus of 20 ml/kg of warmed crystalloid solution (Ringer’s Lactate-RL) is given. This may be repeated one more time based on response (Fig. 27.3). The injured child is monitored carefully. The following indicators indicate improving hemodynamic stability. 1. Slowing of the heart rate (< 130 beats/min). 2. Increased pulse pressure (> 20 mm Hg). 3. Return of normal skin color.

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PEDIATRIC INTENSIVE CARE Table 27.2: Systemic responses to blood loss in the pediatric patient4

< 25% Blood Volume Loss

25% - 45% Blood Volume Loss

> 45% Blood Volume Loss

Cardiac

Weak, thready pulse; increased heart rate

Increased heart rate

Hypotension, tachycardia to bradycardia

CNS

Lethargic, irritable,

Change in level of consciousness, dulled response to pain

Comatose

Skin

Cool, clammy

Cyanotic, decreased Capillary refill, Cold extremities

Pale, cold

Kidneys

Decreased urinary output; increased Specific gravity

minimal urine output

No urinary output

Table 27.3: Vital functions

Age 0-6 mths. < 2 years 2 – 4 yrs. > 12 yrs.

Wt/kg

HR

SBP

RB

MI/kg/hr

3–6 ≤ =15 15 – 35 > 35

180–160 160 120 100

60–80 80 90 100

60 40 30 22

2 1.5 1 0.5

Fig. 27.3: Management of shock, if suspected in a child

TRAUMA IN CHILDREN

4. 5. 6. 7.

Increased warmth in extremities. Clearing of sensorium (improved Glasgow coma score). Increased systolic blood pressure (>80 mm of Hg). Urine output 2cc/kg/hr in infants and 1cc/kg/hr in adolescents. The resuscitation flow diagram is a useful guide in the initial management of a severely injured child. The injured child should be completely undressed for a thorough examination and identification of injuries at the same time preserving the child’s core body temperature by using warmers. RESUSCITATION PHASE Once the ABC’s are completed adjuncts to the primary survey and resuscitation is started. These include ECG monitoring and placement of urinary and Naso-Gastric (NG) catheters. A quick examination for midface fractures, involving the cribriform plate needs to be done prior to NG catheterization. If needed gastric decompression should be done through the oral NG catheter. Similarly the perineum must be assessed prior to Foleys catheter insertion. Look for scrotal ecchymosis or blood at the meatus and rectal examination may reveal a swollen or elevated prostate indicating a urethral injury. A urinary catheterization is contraindicated in case of suspected urethral injury. A uretheral injury could be an indicator of a severe pelvic injury. A suprapubic catheterization may need to be considered in a suspected case of urethral injury. Multiple studies have shown that initial laboratory studies can be limited to hemoglobin, arterial blood gas, group and cross matching for possible transfusion and urine analysis for occult blood. The use of a battery of lab test without considering the traumatic circumstances is to be discouraged.5 SECONDARY ASSESSMENT After completion of the primary survey and the resuscitation phase the secondary survey is performed. Revaluation of the initial resuscitation (ABC’s) is an integral part of ongoing resuscitation. CHEST TRAUMA Thoracic injuries are the second most common cause of death following CNS injuries (ATLS). Few of these injuries (10%) will require a thoracotomy, and most can be diagnosed with a chest radiograph and treated with relatively simple measures including intercostal tube drains, supplemental oxygen and analgesia. Approximately 20% of children with chest injuries will require intubation usually for management of closed head injury.6 Life threatening injuries viz airway obstruction, tension pneumothorax, massive hemothorax and cardiac tamponade must be recognized and treated in primary survey. Anatomical differences between child and adults airways can complicate resuscitation and has already been discussed in airway management earlier. The mobile mediastinum will shift with increased intrathoracic pressure from tension pneumothorax or hemothorax compromising ventilation and decreasing venous return, causing hypoxia and hypertension. The pliable chest wall in children allows energy to be transmitted to thoracic content resulting in lung contusions and hemothorax. The presence of rib fractures in young children is an indicator

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of severity of trauma and a poorer prognosis. Recognition of thoracic injury may be difficult, more than two thirds of children with significant thoracic injuries present with stable vital signs.7 Thus chest injuries must be searched for carefully with a complete physical examination. Salient Points in Chest Trauma 1. Indications for thoracotomy: Massive bleeding, massive air leak, cardiac tamponade. 2. Management of hemothorax is tube inter costal drain with thoracotomy indicated for a. Initial drainage greater than 20 cc/kg or b. Continuous drainage greater than 2 cc/kg for more than two hours. Remember occasional massive hemorrhage from chest may be due to abdominal bleeding with an occult diaphragmatic injury. 3. Subcutaneous emphysema, dyspnea and hemoptysis may be signs of tracheobronchial laceration. Persistent air leak after placement of intercostal drain or cardiopulmonary collapse with institution of positive pressure ventilation confirm the injury. Advancement of endotracheal tube beyond the site of injury or selective intubation into the contralateral bronchi may allow adequate ventilation until the patient can be taken for repair. 4. Beck’s triad of hypotension, jugular venous distension, and muffled heart tones is not frequently seen in children and therefore cardiac tamponade should be suspected in all cases of unexplained hypotension. When available an echocardiography is sensitive and specific when confirmed thoracotomy is indicated. 5. Pulmonary contusion is very common and should be monitored in paediatric intensive care unit (PICU) with continuous SaO2 monitoring. Serial chest radiographs to be obtained to identify associated pneumohemothorax, pleural effusion. 6. Aortic injuries are uncommon in children. The Plain chest radiograph signs of aortic injuries in children are widened mediastinum (Mediastinal to chest ratio of > 0.25 on upright chest Xray), loss of aortic knob contor, deviation of trachea or espophagus to right, left hemothorax. However the most sensitive test remains aortography. CT scan with contrast may be more accurate screening examination. 7. The finding of two or more rib fractures in children less than two years of age is strongly associated with children abuse. 8. Penetrating chest injuries need to be explored. Anterior thoracic wounds below the nipple mandates investigation for abdominal injury (see Heading Abdominal Injury). Head injury and spinal injury, abdominal injury and pelvis with extremity injury are covered elsewhere in this book. SUMMARY The ultimate goal of resuscitation of a multiple injured child’s delivery of oxygen to intracellular organs and to maintain aerobic metabolism. This can be done with immediate attention to the “ABCDE’S” of the ATLS protocol with repeated revaluation of the adequacy of resuscitation maneuvers. After stabilization, seriously injured children should be transferred to tertiary care centers managing pediatric trauma with careful resuscitation and urgent timely intervention surgically injured children can be returned to their families in better mental and physical condition with reasonable expectation of a full and productive live.

TRAUMA IN CHILDREN

REFERENCES 1. ATLS - Advanced trauma and life support course 1997 Ed. 2. Potoka DA, Nadler EP, Shultz BL, Morrision KE, Ford HR, Gaines BA. The high morbidity associated with handlebar injuries in children. J Trauma, 2005;58(6):1171-4. 3. Taylor CA, Eichel Berger MR - Abdominal CT in children with neurological impairment following blunt trauma. Ann Surg 1984;210 229-33. 4. Perry W Stafford, Thane A Blinman, Michael L Nance. Practical points in evaluation and resuscitation of the injured child Surg Clin N Am 2002;82:273-301. 5. Chu UB, Clevenges FW, Mani ER, et al. The impact of selective laboratory evaluation on utilisation of laboratory resources and patient call in Level I trauma centre AMJ surgery 1996;172:558-62. 6. Mahayamma DK. Ramenofshy MR, Rowe MI. chest injuries in childhood Ann Surg 1989;210:790-95. 7. Miller JL, Little AG, Shermeta DW. Thoracic trauma in children pediatrics 1984;74:813.

ABDOMINAL PELVIC AND EXTREMITY INJURIES IN CHILDREN ABDOMINAL INJURIES Approximately one third of children with multiple injuries will have significant intraperitoneal injuries that must be recognized and treated urgently. Blunt abdominal injuries predominate in 90% of children with abdominal injuries with injuries mainly to spleen and liver.1,2 Overall mortality is relatively low (less than 5%) and will depend on injury mechanism with highest mortality noted in victims of assault or abuse 12.5%3. The diagnosis of intra-abdominal injury in a child with torso trauma can be difficult due to co-existing injury, anxiety and abdominal wall contusion.1-5 The evaluation of a child with blunt abdominal trauma begins during primary survey resuscitation and secondary survey with decompression of the stomach and bladder.2,3 Look for abrasions and contusions of the lower thoracic and abdominal wall. “Repeated, careful examination of the abdomen will allow early identification of significant solid organ and hollow viscus injuries requiring laparotomy.” As most injuries to solid organs in hemodynamically stable children is managed non-operatively the importance of repeated, careful examination cannot be over emphasized.3 All children with significant mechanism of injury and abdominal tenderness should undergo double contrast CT scan of abdomen and pelvis. The role of focused abdominal sonography for trauma (FAST) is controversial in children.4,5 Early evidence suggests accurate identification of presence of intraperitoneal fluid but a high false negative rate.5 The evolution of non-operative management to abdominal injuries in children has evolved over the past 40 years. The reports of overwhelming post-splenectomy sepsis (OPSS) has approached more than 85 times the rate of infection in the normal population with a mortality approaching 50%. The risk was greatest in the first two years after splenectomy and in children less than five years of age.6 This has led to a splenic salvage in children in pediatric trauma centers.7 Over the last decade this non-operative close observation algorithm has been extended to liver and renal injuries.8,9

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Salient Points in Abdominal Injury Management a. Have a very high suspicion for hollow viscus injury (HVI). Gastric blow out injuries, liver and splenic injuries may occur with minimal signs of external abdominal wall injury. b. Early gastric decompression in children is very important. Anxious and injured children swallow large amount of air, which when added to mask ventilation and paralytic ileus can cause massive gastric distension. Gastric decompression will facilitate clinical examination of abdomen and prevent hypoventilation. A bulging abdomen post properly placed gastric tube in a hypotensive child indicates hemoperitoneum. c. All trauma CT scan of abdomen and pelvis should be double contrast using gastrograffin (2%) orally and IV Hypaque 2.0 cc/kg IV bolus. Role of FAST in evaluating blunt abdominal injury in children is evolving.5,6 d. Management of penetrating abdominal injuries that penetrate peritoneum require emergent laparatomy. Pelvic Fractures and Extremity Injuries The goal of initial assessment and management of pelvic and extremity injuries is to identify major life threatening injuries (major pelvic disruption with hemorrhage, arterial injuries with hemorrhage and crush syndrome) and limb threatening injuries (open fractures and joint injuries, vascular injuries, compartment syndrome and peripheral nerve injury).1 Pelvic fractures are reliable indicators of significant traumatic energy transmission. Significant bleeding into the retroperitoneum due to pelvic shear injury can cause life threatening hemorrhage. Direct surgical intervention is fraught with considerable morbidity and potential mortality. The venous bleeding can be controlled by external fixators but arterial bleeding requires angiographic embolization11,12 (Figs 27.4 and 27.5). Genitourinary injuries occur in 5-10% and abdominal injuries in 10-20% of significant pelvic fractures. Mortality is usually due to concomitant head injury. All perineal injuries in children should be examined under anesthesia in the operating room by the surgeon. Evaluation in the casualty one is prone to miss injuries. Sexual abuse is involved in a significant number of rectal and perineal injuries.

Fig. 27.4: Superior and inferior ramii fractures

Fig. 27.5: External fixator applied

TRAUMA IN CHILDREN

Many extremity injuries are subtle and often parent notice changes in childs behavior which may indicate occult bony or soft tissue injury. Salient Points in Extremity Injuries a. Be alert for evidence of child abuse. – Fractures of differing ages on X-ray – Discrepancy between history and injury – Prolonged and/or unexplained delay in treatment – Poor health and hygiene. b. Open fractures must be suspected whenever a laceration is noted in the proximity of fracture. All open fractures should be treated with emergent debridement and fracture stabilization within first 8 hrs of injury.13 A cephalosporin plus (aminoglycoside) is usually adequate with penicillin for contaminated or farm injuries. Tetanus booster or prophylaxis is also appropriate. c. Joint penetrating injuries require urgent debridement and irrigation in the same lines as open fractures. d. Pediatric crushing injuries comprise a spectrum of muscle extremity injuries resulting in impaired muscle perfusion ischemia and release of myoglobin and other toxic byproducts of acute muscle injury. Myoglobin is rapidly cleared in urine and has a direct toxic effect or renal tubules if urine pH is lower than 5.4. Treatment is aggressive hydration with normal saline.10 e. Compartment syndromes (CS) can develop in a closed or open fracture, crushed extremity. Forearm and leg being commonly involved (Fig. 27.6). In the leg, compartment syndrome will be found more frequently in the anterior than the lateral or posterior compartment. CS can develop when interstitial tissue pressure increases above that of capillary bed, local ischemia of nerve and muscle occurs or decrease in the size of a compartment (a constricting plaster cast or dressing) (Fig. 27.6). The end stage of CS if untreated is Volkman’s ischemic contracture. Traditionally the “Five P’s define the syndrome. 1. Pain on passive extension 2. Pallor

Fig. 27.6: Compartment syndrome showing swollen fingers

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PEDIATRIC INTENSIVE CARE

3. 4. 5. 6.

Paresthesia (loss of two point discrimination). Paralysis Pulselessness although gross pulses are usually present Presssure measurement (6th P) in a given compartment. If pressures 10 mm of Hg or less are normal. Pressures in excess of 30 mm of Hg in a given compartment may need decompression.14

Treatment in Compartment Syndrome 1. Remove all restrictive dressing and cast immediately 2. Aggressive hydration with alkaline diuresis to keep urine pH 6.5 3. If in 30 mins swelling has most markedly decompressed proceed directly to fasciotomy (Figs 27.7 and 27.8). A two incision, four compartment fasciotomy may be needed in leg.14 4. A prophylactic fasciotomy should be performed whenever limb ischemia time from vascular injury or occlusion > 4 hours. 5. Most obvious fractures can be splinted in the post injury position as the child awaits orthopedic evaluation. However if a pulse is absent a single attempt to place the extremity in an anatomic position may allow the return of pulses. Prolonged attempts is counter productive. 6. Vascular injuries should be suspected in all extremity injuries “Soft Signs” of vascular injury are history of moderate hemorrhage, diminished but palpable pulses, peripheral nerve deficits, history of posterior knee or elbow dislocations. Angiography with surgical repair is then indicated. “Hard Signs” suggest the need for immediate operation and intraoperative angiography. These include pulsatile bleeding, expanding hemotoma, a palpable thrill. SUMMARY In the initial assessment of multiple injured child life threatening situations must be properly assessed and managed before attention is directed to the injured extremity. A high index of suspicion needed for hollow viscus injury with repeated abdominal examination. A very high proportion of abdominal

Fig. 27.7: Decompression for CS (For color version see Plate 1)

Fig. 27.8: Improvement after decompression (For color version see Plate 1)

TRAUMA IN CHILDREN

injuries can be managed non-operatively however one needs to recognize the ones requiring laparatomy. Early operative fixation of fractures, with debridement of open fractures may reduce mortality and morbidity. REFERENCES 1. Pohlgeers A, Ruddy R. An update on pediatric trauma. Emerg Med Clin North America 1995, 13(2) 26789. 2. ATLS –Advanced Trauma LIFE support Course 1997, 1999 Ed. 3. Perry W Stafford, Thane A Blinman, Michael L Nance. Practical points in evaluation and resuscitation of the injured child. Surg Clin N Am 2002;82:273-301. 4. Coley BD, Mutagaini KH, Martin LC, et al. Focused abdominal sonography for trauma (FAST) in children with blunt abdominal trauma. J Trauma 2000;48:902-6. 5. Patel JC, Tepas JJ III. The efficacy of focused abdominal sonography for trauma (FAST) as a screening in the assessment of injured child. J Pediatr Surg 1999;34:44-7; discussion 52-4. 6. Eraklis As, Filler RM, Splenectomy in childhood a review of 1413 cases J Pediatric Surg 1972;7:382-8. 7. ElinSH, Shandling B, Simpson JS, et al. Non-operative management of the traumatized spleen in children how and why? J Pediatric Surgery 1978;13:117-9. 8. Karp MP Cooney DR, Pros GA, et al. The non-operative management of pediatric hepatic trauma. J Ped Surg 1983;4:512-18. 9. Smith EM, Elder JS, Spirnale JP. Major blunt renal trauma in the pediatric population. J Urol 1993;149:5468. 10. Bywaters EGL, Beall D. Crush injuries with impairment of renal function. BMJ 1941;427-32. 11. Flint LM, Brown A, Richardson JD, et al. Definitive control of bleeding from severe pelvic fracture. Ann Surg 1979;189(6):709-16. 12. Trode I, Zieg D. Pelvic fractures in children. J Pediatr Ortho 1985;5:76-84. 13. Gustilo RB, Anderson JT. Prevention of infection in the treatment of 1025 open fractures of long bones. JBJS 1976;58A:453 . 14. Mubarak SJ, Owen CA. Double incision fasciotomies of the leg for decompressing in compartment syndromes. J Bone Joint Surg 1977;59:184-7.

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28

Indira Jayakumar

Adrenal Insufficiency in Critical Illness

INTRODUCTION “The survival of the fittest is the ageless law of nature, but the fittest are rarely the strong. The fittest are those endowed with the qualifications for adaptation, the ability to accept the inevitable and conform to the unavoidable, to harmonize with existing or changing conditions.” “When the lesion is acute and rapid, I believe the anemia, prostration, and peculiar condition of the skin will present a corresponding character and that whether acute or chronic, provided the lesion involve the entire structure of both organs (suprarenal glands), death will inevitably be the consequence” (Thomas Addison, MD 1855). Addison first noted the essential role of the adrenal for survival in 1855 in patients with hyperpigmentation, prostration and diseased suprarenal glands.1 In 1894 Voelcker reported three patients who died with acute bacterial infections and suprarenal disease without hyperpigmentation and described it as adrenal insufficiency related to acute infection hypothesizing hyperpigmentation to be related to chronic adrenal insufficiency.2 Soon afterwards Waterhouse and Friderischsen reported patients who died of bilateral adrenal hemorrhage and acute bacterial infection.3 In the 1950s Lillehei and others evaluated role of hydrocortisone treatment in experimental models of endotoxic septic shock.4 Based on three adult studies in 1980’s the usage of steroids in septic shock fell into disrepute. From the publication of the study by Annane in 2002, in favour of supplementing steroids to a cohort of critically ill adult patients, to the recently concluded largest randomized study evaluating the role of steroids in septic shock (CORTICUS study) the controversy surrounding this enigmatic therapeutic intervention still looms large. In the latest CORTICUS study though the rates of shock reversal appeared better in the responders (not statistically significant) but there was no difference in mortality and there was increased risk of superinfection, insulin requirement in those treated with steroids.5, 6 The overall incidence of AI in critical illness has been variable with little pediatric studies. Studies in adults suggest that the overall incidence in high-risk, critically ill patients, such as those with

ADRENAL INSUFFICIENCY IN CRITICAL ILLNESS

hypotension, shock, and/or sepsis, is high (approximately 25 to 40%) and increases with the severity of illness . The incidence from studies in pediatric patients is close to that observed in adults, ranging from 52% in septic shock patients and 31% in the other documented studies.7-12 Pizarro et al reported an 18% incidence of absolute adrenal insufficiency in 57 children with septic shock and 26% incidence of relative adrenal insufficiency.13 Hydrocortisone was first introduced into clinical practice by Hench in 1950 and steroids were first introduced for the management of sepsis in 1951. Since then therapy with this drug has undergone transformation from “steroid success” in 1970 and early 1980s to “steroid excess ” (30mg /kg/methylprednisolone) in severe sepsis in mid to late 1980 leading to total abandonment in early 1990. However steroids made a comeback when data from few RCTs comparing placebo and hydrocortisone showed improved hemodynamic status and vasopressor weaning with the use of steroids .In 2002 Annane et al published the results of prospective, randomized trial of steroids in septic shock which showed decreased mortality in the steroid group .However it has been criticized on a number of accounts. A contributory factor to the high prevalence of RAI ( relative adrenal insufficiency) in this study was the use of etomidate an adrenal suppressant . The Surviving Sepsis Campaign Guidelines of 2004 endorsed the use of steroids in management of shock with the following recommendation – • IV hydrocortisone 200-300 mg/day for 7 days (grade C ) • 250 mcg corticotropin stimulation test (grade E) • addition of 50 mcg of fludrocortisone to hydrocortisone (grade E) • avoidance of high dose steroids, >300 mg /day (grade A) The basis for corticosteroid supplementation in septic shock is thought to be the presence of a syndrome termed Relative Adrenal Insufficiency (RAI) since absolute AI is not common in critically ill patients . The concept of RAI emerged as early as 1991 to describe a syndrome where the adrenal glands partly respond to stress but the magnitude of the response is not commensurate with the degree of stress. However both the use of steroids and the diagnosis of RAI in septic shock have been sources of intense controversy. NORMAL PHYSIOLOGY The adrenal gland is primarily divided into a cortical and medullary portion with different embryological derivation. The cortical portion, derived from embryonic mesoderm is further divided into three functionally distinct zones producing and releasing the glucocorticoid cortisol and cortisone, mineralocorticoid aldosterone and the sex steroid androgen and its derivatives. The medullary portion, derived from neural crest cells of the embryonic ectoderm, secretes the catecholamines, adrenaline and noradrenaline. The various governing factors on adrenals is depicted in Figure 28.1. Cortisol (also called hydrocortisone or compound F) secreted by the zona fasciculata, is considered the primary active glucocorticoid hormone. It is needed for the adaptation and maintenance of stress homeostasis during any critical illness. Its secretion is stimulated normally by the pulsatile release of ACTH from the pituitary glands, which inturn is released by the pulsatile release of CRH from the hypothalamus.

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Fig. 28.1: The figure depicts the various factors that control the relese of hormones from the adrenals

Figs 28.2A to C: Activity of the hypothalamic- pituitary –Adrenal axis under normal condition (Panel A), during an appropriate response to stress (Panel B), and during an inappropriate response to critical illness (Panel C). A plus sign indicates a stimulatory response and a minus sign an inhibitory response

ADRENAL INSUFFICIENCY IN CRITICAL ILLNESS

The cellular actions of Cortisol include its effects on metabolism, immunological, antiinflammatory pathways and cardiovascular system. The metabolic effects increase the blood glucose by various mechanisms, induce lipolysis, proteolysis, inhibits intestinal uptake of calcium and induce calciuria with increase in the osteoclastic and suppression of osteoblastic activity, The immunological effects vary and will not be dealt with in great detail in the current text. Cortisol plays a role in the cardiovascular effects in maintenance of vascular tone, endothelial integrity, vascular permeability, and distribution of the TBW in the vascular compartment, potentiating the vasoconstrictor effects of catecholamines and antagonizing the vasodilatory effects of nitric oxide. Cortisol circulates in the plasma in an inactive form, mainly bound to proteins (90-95%) and the free active form. The two main binding proteins are the steroid binding globulin (CBG) and albumin. Cortisol enters the cells passively, binds to the glucocorticoid receptor in the cytoplasm and exerts its action. It later gets metabolized by the liver (reduced and conjugated) and the kidney, where it is converted into its inactive metabolite cortisone before excretion.14 Stressed HPA Axis and Cortisol Response during Critical Illness (Fig. 28.2) • Stress activates the HPA axis with increasing ACTH levels thereby increasing the cortisol blood levels. The rate of production is roughly proportional to the severity of illness. In protracted illness there is a decrease in the plasma ACTH concentration inspite of elevated Cortisol levels suggesting that Cortisol secretion is being regulated by alternate pathways (ANF, substance-P and cytokines) other than classic hypothalamic CRH. • There is reduced negative feed back from the cortisol to ACTH and CRH. • There maybe decreased metabolism of this cortisol due to associated hepatic, renal and thyroid dysfunction. • There is initially increase in the receptor affinity for glucocorticoids. • The circadian rhythm of the cortisol secretion is lost. • Serum total cortisol levels maybe reduced while the free forms of the cortisol are elevated due to decreased levels of proteins (transcortin, albumin). • There is a shift in the pregnenolone metabolism from the mineralocorticoid and steroid synthetic pathway to cortisol pathway. • Many drugs used in critical illness and physiological states impair cortisol metabolism (Table 28.1). Implications of the above Disturbances in the HPA Axis • Hypercortisolism in critical illness provides the energy and protects the body reflected by an increase in gluconeogenesis, maintenance of intravascular volume ( fluid status and vascular tone ), and inhibition of the acute inflammatory response. • The shift in the pregnenolone metabolism to Cortisol synthesis indicates a resetting between the immunostimulatory (DHEA) to immunosuppressive (Cortisol) phase–an attempt of the organism to mute its own inflammatory cascade. • Persistence of hypercortisolism could lead to undesirable effects like hyperglycemia, myopathy, poor wound healing etc.15-18

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PEDIATRIC INTENSIVE CARE Table 28.1: Drugs that impair cortisol metabolism

Mechanism of Adrenal Insufficiency in Critical Illness Adrenal insufficiency in critically ill patients may be PRIMARY AI—adrenal failure (exhausted adrenal cortex with no cortisol reserve, impaired capacity to produce Cortisol). SECONDARY AI—(hypothalamo-pituitary failure), ABSOLUTE AI—diagnosed by very low plasma Cortisol levels (primary or secondary) RELATIVE AI—The Cortisol level, despite being normal or high, is still considered inadequate for the current physiologic stress, and the patient may be unable to respond to any additional stress. It is currently defined as an inadequate incremental response to exogenous ACTH (delta Cortisol1 mo), encephalopathy, malignancies, disseminated mycobacterial infection, Pneumocystis jiroveci pneumonia (PCP), cerebral toxoplasmosis (onset after 1 mo of age) and severe weight loss. THE SPECTRUM OF DISEASES IN THE PICU Respiratory Diseases Complicating HIV Infection While acute respiratory failure secondary to PCP remains one of the most frequent causes of ICU admission among HIV-infected patients,22 other opportunistic pathogens also cause considerable

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morbidity and mortality in these patients. Adult data from United States shows decreasing proportion of hospitalization due to respiratory disease, on the other hand proportion of hospitalizations due hepatic renal and CVS disease has increased in recent years.23

Pneumocystis Jiroveci Pneumonia (PCP) PCP pneumonia is a common cause of respiratory disease in HIV patients. PCP is predominantly an infection of early infancy, and infants between 4 and 6 months are commonly affected.24 Patients who are not on HAART or anti PCP prophylaxis are more likely to be affected. During recent years both diagnostic techniques (sputum induction and fluorescent staining or PCR for pneumocystis mitochondrial large-subunit ribosomal RNA)25 and outcome for this infection has improved significantly. Majority of adults patients with PCP pneumonia have CD4 counts of less than 200/ µl (10-15% have higher counts),23 in contrast to adults, pediatric patients can develop PCP pneumonia even at higher counts. Children with PCP pneumonia present with tachypnea, non-productive cough, low grade fever and dyspnea. Physical examination shows tachypnea, tachycardia and respiratory distress. Typically, chest auscultation does not reveal any abnormality in these patients.25 PCP is characterized by rapidly progressive hypoxemia and elevated LDH levels.24 LDH elevation is a sensitive marker for diagnosis of PCP pneumonia but lacks specificity.26 Chest radiographic findings typically vary from hyperinflation early in the course of illness to bilateral symmetrical alveolar or interstitial infiltrates spreading peripherally from perihilar region. Less typical findings include focal or patchy infiltrates (50% of pediatric patients) and effusions. Pulmonary air cysts or thoracic air leaks are noted during the course of the illness in approximately one-third of all cases.27 When chest radiographic findings are normal or equivocal, high-resolution CT may be helpful, because it is more sensitive than chest radiographs for detecting PCP. The classic CT finding is extensive ground glass attenuation.28 Treatment of choice is trimethoprim-sulfamethoxazole (TMP-SMZ). Recommended dosage is 20 mg/kg/day in 4 divided doses intravenously for 21 days. Corticosteroids should be added in patients with room air PaO2 less than 70 mm Hg or alveolar–arterial oxygen gradient above 35 mm Hg (prednisone 2-4 mg/kg/day in 4 divided doses for 4-5 days and then tapered). Intravenous pentamidine (4 mg/kg/day for 21 days) is recommended for patients who fail to improve on TMPSMZ (within 5-7 days) or have severe reactions to it.24, 25 Other agents that have been used in adults are dapsone-trimethoprim,29 clindamycin-primaquine30 and atovaquone.31 The recommended agent for P. carinii pneumonia prophylaxis is trimethoprim sulfamethoxazole. Dapsone and atovaquone are possible alternatives. Because of the side effects of these medications, the complete blood count should be evaluated at the initiation of therapy and monthly thereafter. P. carinii pneumonia prophylaxis should be started after completion of six weeks of zidovudine therapy. Prophylaxis is not recommended before four weeks of age because of the low incidence of this pneumonia in neonates. Also, trimethoprim-sulfamethoxazole can exacerbate the anemia caused by zidovudine and increase adverse effects on the newborn’s immature bilirubin metabolism. Prophylactic medication can be discontinued when two HIV DNA PCR tests are negative (one after the infant is one month old and the other after the infant is four months old). Prophylaxis in an HIV-infected infant should be continued until the age of 12 months, regardless of the CD4+

CRITICALLY SICK CHILD WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION

lymphocyte count. After the age of 12 months, the need for prophylaxis is determined by theCD4+ lymphocyte count.32

Bacterial Pneumonia The rate of invasive bacterial infection is higher in HIV-infected children than in their peers, especially after 1 year of age.33 In pediatric patients, impaired B-cell activity is an early and prominent manifestation of HIV infection. Infants infected with HIV do not develop the antigen-specific B- and T-cell clones required for immunologic memory, amplification, and production of specific antibodies. B-cell defects and lack of memory B cells result in a high rate of serious bacterial infections in HIVinfected children.34 Streptococcus pneumoniae and Haemophilus influenzae are the commonest cause of bacterial pneumonia in HIV infected patients. Incidence seems to increase with a fall in CD4 counts.35, 23 There is also an increased risk of extrapulmonary dissemination of pneumococcus. HIVinfected children with invasive pneumococcal infection were less likely than controls to have leukocytosis and more likely to have isolates with penicillin resistance.36 Other important pathogens in these patients are Staphylococcus aureus and Pseudomonas. These infections are frequently accompanied by sepsis and acute respiratory distress syndrome. It is recommended that empirical therapy in these patents should cover these organisms.37 Propylaxis against bacterial infections should include H influenzae type b vaccine and pneumococcal vaccine. Children with recurrent bacterial infections also benefit from daily TMPSMZ prophylaxis. In children with advanced HIV disease who are receiving zidovudine, intravenous immune globulin decreases the risk of serious bacterial infections. However, this benefit is apparent only in children who are not receiving trimethoprim-sulfamethoxazole as prophylaxis.38 IVIG is only indicated for children with hypo-gammaglobulinemia, and should be considered for children with 2 or more serious invasive bacterial infections in last 1 year, especially those who have failed or are poorly tolerant to antibiotic prophylaxis.24

Mycobacterial Infection Mycobacterium tuberculosis is an important cause of pulmonary and extrapulmonary disease in HIV infected patients in most of the developing world. Shahab et al estimated seroprevalence of HIV in tuberculosis patients who were less than 12 yrs old to be 2%. All the patients had disseminated tuberculosis. They suggested regular screening of children with disseminated/miliary tuberculosis for HIV co-infection.39 TB manifestations are more severe in HIV-positive children and progression to death is more rapid than in HIV-negative children. The response to standard short-course therapy in HIV-positive children is not as good as in HIV-negative children due to lower cure rates and higher mortality. TB hastens the progression of HIV disease by increasing viral replication and reducing CD4 counts further.40 Likelihood of clinical disease is 10% per year as opposed to 10% in a lifetime in HIV uninfected individuals. Treatment of tuberculosis in an HIV infected individual is likely to be complicated by drug reactions and immune reconstitution syndrome. Diagnosis of TB in infected children poses greater challenges than in other children.41 Even with the use of a lower cut-off of 5 mm, the tuberculin test is often negative, particularly in children with severe immunosupression. In extensive disease, the bacteriological confirmation rates are likely to be greater. All attempts should be made to isolate Mycobacterium tuberculosis. Other than providing

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definitive diagnosis, it offers the opportunity to do sensitivity analysis. The incidence of multi-drug resistant tuberculosis is higher in HIV infected patients. All HIV-infected children with active TB should receive longer duration of antitubercular therapy. A 9 to 12 month therapy is preferred. The AAP recommends a total duration of 12 months of anti-TB therapy for children infected with HIV, while the ATS/CDC recommendation is a total of 6-month of therapy, regardless of HIV status.42, 43 A close follow up is essential to diagnose nonresponse/drug resistance early. In contrast to mycobacterium tuberculosis, MAI causes disease only when CD4 counts are less than 50 to 75/ul. The infection is frequently disseminated with lymphadenopathy and enteritis. Solitary pulmonary dysfunction is rare. Current therapy for disseminated MAI infection involves use of a combination of clarithromycin or azithromycin with ethambutol.

Lymphoid Interstitial Pneumonitis Lymphoid interstitial pneumonitis (LIP) occurs in 30 to 50% pediatric AIDS patients. In contrast to PCP, this condition usually manifests later in life (after 1yr) and these children also have a better prognosis. Pathological hallmark of LIP is peribronchial lymphoid nodules with plasma cell and lymphocytic infiltrates.37 The etiology of LIP is not clear and autoimmune mechanisms and viruses (HIV, EBV) have been strongly implicated.44 There is great variability in the clinical course of LIP, from resolution without treatment to progressive respiratory failure and death.44 Usually, LIP initially presents with mild pulmonary symptoms (cough, tachypnea) which gradually progress to hypoxia and chronic oxygen dependency.37 Chest radiographs may show hilar adenopathy, bilateral lower zone reticulonodular opacities and sometimes patchy alveolar infiltrates.45 While this pattern may be observed in other entities, such as Pneumocystis carinii pneumonia, miliary tuberculosis, or cytomegalovirus pneumonitis, a distinguishing feature of the infiltrates of LIP is their indolence, chronicity, and lack of response to treatment that would be expected to resolve other pulmonary processes.44 Definitive diagnosis is made by transbronchial or open lung biopsy.46 Corticosteroids, zidovudine and HAART have been found to be effective.37, 44 Prognosis is variable and often unpredictable from clinical, morphologic, and radiographic parameters. Stabilization or resolution of disease is reported in some patients, but in others there is progressive decline in pulmonary function and development of honeycomb lung.44

Fungal Infections Various fungal species are known to cause pulmonary infections in HIV infected patients. Patients with high CD4 counts typically have localized disease while those with low CD4 counts have diffuse disease.37 Candida is a common cause of bronchitis but infrequently causes pneumonia in HIV patients. Aspergillus is known to cause tracheobronchial or pulmonary invasive disease in debilitated HIV patients, usually following broad spectrum antibiotic therapy, corticosteroid use or neutropenia. Chest radiographs show a variable picture and patterns include upper-lobe cavitary disease (sometimes mistaken for tuberculosis), nodules, pleural-based lesions, and diffuse infiltrates, usually of the lower lobe. Transbronchial biopsies are usually negative, but positive cultures can be obtained from bronchoalveolar-lavage fluid or percutaneous aspirates. Denning et al described

CRITICALLY SICK CHILD WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION

a poor response to therapy with Ampotericin B or Itraconazole with median survival of only 3 months following initiation of therapy.47 Cryptococcal pneumonia usually occurs as part of a disseminated infection, with meningoencephalitis and fungaemia.48 Other fungal species like Histoplasma capsulatum, Penicillium marneffei and Coccidioides immitis are important causes of fungal pneumonia in certain endemic regions.49

Immune Reconstitution Syndrome (IRS) Immune reconstitution syndrome in response to pneumocystis, mycobacterial and cryptococcal antigens is a well known and important cause of respiratory worsening in HIV patients after starting HAART. Onset is variable, and IRS is known to occur days to weeks after starting the therapy.50,37 Puthanakit et al demonstrated IRS in 19% of patients with advanced HIV infection. IRS occurred after a mean duration of 4 wks after start of HAART.51 Shelburne et al found IRS to be common among HIV-infected persons coinfected with M. tuberculosis, M. avium complex, or C. neoformans. Antiretroviral drug-naive patients who started HAART in close proximity to the diagnosis of an opportunistic infection and had a rapid decline in HIV-1 RNA level were more likely to develop this disorder.52 There is no consensus on therapy but corticosteroids have been found to be useful.50 Cardiac Dysfunction Cardiac dysfunction is known to occur in 18 to 39% HIV positive children and is associated with increased risk of death.53 Subclinical cardiac abnormalities in HIV-infected children are common, persistent, and often progressive. Dilated cardiomyopathy (depressed contractility and dilatation) and inappropriate LV hypertrophy (elevated LV mass in the setting of decreased height and weight) are commonly noted. Depressed LV function correlated with immune dysfunction at baseline but not longitudinally, suggesting that the CD4 cell count may not be a useful surrogate marker of HIVassociated LV dysfunction.54 Starc et al calculated 2-year cumulative incidence of cardiac impairment (left ventricular fractional shortening (LV FS) 1 year

ET size 2.5 mm/ID 3.0 mm/ID 3.0-3.5 mm/ID 4.0 mm/ID 4 + age in years divided by 4

GLASGOW COMA SCALE Standard Eye opening Spontaneous To voice To pain None Verbal Oriented Confused Inappropriate words Incomprehensible None Motor Obeys commands Purposeful (pain) Withdraws (pain) Flexion (pain) Extension (pain) None Total (3-15) ANALGESIA AND SEDATION Morphine Meperidine (Pethidine) Midazolam Fentanyl

Pediatric 4 3 2 1

Spontaneous To speech To pain None

5 4 3 2 1

Coos and Babbles Irritable cries Cries (pain) Moans (pain) None

6 5 4 3 2 1

Spontaneous movement Withdraws (touch) Withdraws (pain) Abnormal flexion Abnormal extension None

0.1 mg/kg IV, IM 1 mg/kg IV, IM 0.1 mg/kg IV, IM 1 to 10 microgram/kg IV

REVERSAL AGENTS Naloxone Flumazenil

0.1 mg/kg IV, IM, ET (> 20 kg = 2 mg) 0.01 mg/kg IV (> 20 kg = 0.2 mg)

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ANTIBIOTICS Acyclovir Ampicillin Amikacin Cefotaxime Ceftazidime Ceftriaxone Cefuroxime Gentamicin Oxacillin Vancomycin

10 mg/kg/dose 25-100 mg/kg/dose 7.5 mg/kg/dose 50 mg/kg/dose 30-50 mg/kg/dose 25-75 mg/kg/dose 25-50 mg/kg/dose 1.7-2.5 mg/kg/dose 25-40 mg/kg/dose 10 mg/kg/dose

ASTHMA, ANAPHYLAXIS, STRIDOR Albuterol (Salbutamol) Adrenaline (Epinephrine) Nebulize Methyl prednisolone Terbutaline load Drip Dexamethasone Hydrocortisone Diphenhydramine

0.5 ml (2.5 mg) in NS 3 ml nebulized 0.01 ml/kg (1:1000) SQ max 0.5 ml 0.25 ml in 3 ml NS 1-2 mg/kg IV, IM 10 mics/kg/dose, IV, SQ 0.1-1.0 mic/kg/min 1 mg/kg/IV, IM 2 mg/kg IV, IM 1 mg/kg IV, IM

CARDIAC MEDICATION AND DRIPS Adenosine Amrinone Alprostadil (PGE1) Amiodarone Calcium chloride Dobutamine Dopamine Epinephrine (adrenaline) Milrinone Nitroprusside Norepinephrine Propranolol Furosemide Lidocaine Drip Magnesium sulfate

0.1 mg/kg rapid IV push (max 0.4 mg/kg or 12 mg) 3-10 mic/kg/min 0.05-0.4 mic/kg/min IV 5 mg/kg IV over at least 20 minutes 10% 20 mg/kg (0.2 ml/kg slow IV) 2-20 mic/kg/min 2-20 mic/kg/min 0.1-1 mic/kg/min 0.375-0.75 mic/kg/min 03-10 mic/kg/min 0.05-2 mic/kg/min 0.01-0.1 mg/kg IV over 15 min 0.5-1 mg/kg IV 1 mg/kg (can repeat maximum of 3 mg/kg) 20-50 mg/kg/min (within 15 min of bolus) 25-50 mg/kg IV over 20-30 min (max 2 g)

DOSES OF DRUGS USED IN EMERGENCY SITUATIONS

Phenylephrine

Procainamide Vasopressin (GI bleeding) bolus

0.01 mg/kg slow IV (max 5 mg) 0.1 mg/kg IM or SQ (max 5 mg) drip 0.1-0.5 mic/kg/min (titrate) 3-6 mg/kg over 5 min IV (max 100mg/dose) 0.3 U/kg (maximum 20) then 0.002-0.01U kg/min (Calculation of drip = 6 × body weight in mg/kg to place in 100 ml) (1 ml/hr = 1 mic/kg/min)

ENDOCRINE Glucose Glucagon Insulin

D10W 4 ml/kg IV, IO (neonates) D25 W 2 ml/kg IV, IO (children) 0.1 mg/kg IV, IM, SQ (maximum 1 mg) 0.1 unit/kg/hr

HYPERKALEMIA Sodium polystyrene sulfonate (kayexalate) Calcium chloride10% Insulin Glucose D25 Sodium bicarbonate

1gm/kg PR, PO 20 mg/kg/dose = 0.2 ml/kg IV 0.1 U/kg with glucose 0.5 gm/kg = 2 ml/kg IV 1-2 mEq/kg IV (maximum 50 mEq)

MALIGNANT HYPERTENSION Labetalol Diazoxide Nifedipine Captopril

0.3-0.5 mg/kg/dose every 10 min (do not use if asthma or bradycardia) 1-3 mg/kg rapid IV (max 150 mg) 5-10 mg PO 6.25-25 mg PO Resistant hypertension—Use Na nitroglycerin/Na nitroprusside

SEIZURES Lorazepam Diazepam Midazolam Phenobarbital Phenytoin

0.05-0.1 mg/kg IV, IO 0.1 mg/kg IV 0.5 mg/kg PR 0.2-0.3 mg/kg IV 20 mg/kg at 1 mg/min 20 mg/kg IV in NS at 1 mg/kg/min

INCREASED INTRACRANIAL PRESSURE • 100% oxygen • Hyperventilate to 25-30 mm Hg • Keep head elevated in midline position

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• Maintain adequate perfusion (avoid hypotension) • Mannitol 0.25-0.5 gm/kg IV • Lidocaine 1 mg/kg IV before intubation RAPID SEQUENCE INTUBATION • Oxygenate • Atropine 0.02 mg/kg • Lidocaine 1 mg/kg (if increased ICP or bronchospasm) • Sedation (Normotensive) • Thiopentone 2-5 mg/kg IV • Midazolam 0.2-0.3 mg/kg IV (Shock without head injury and status asthmaticus) • Ketamine 0.5-2 mg/kg IV HEAD INJURY Thiopentone Midazolam Cricoid pressure Muscle relaxants Succinyl choline Vecuronium Pancuronium Atracurium (if liver failure/renal failure)

2-5 mg/kg (if hypotensive reduce thiopentone) 0.2-0.3 mg/kg IV

1-2 mg/kg (do not use if potassium level increased or risk of malignant hyperthermia) 0.1 mg/kg 0.1 mg/kg 0.2-0.5 mg/kg IV

MISCELLANEOUS DRUGS Charcoal Digoxin (digitalization) Diphenhydramine Hydrocortisone Adrenal insufficiency Stress dose Metoclopramide Ipecac syrup Nifedipine Methylprednisolone Status asthmaticus Spinal cord injury Vasopressin (GI bleeding) Vasopressin pressor dose

1 gm/kg PO/NG < 40 weeks gestation: total 20 to 30 microgram/kg IV, IM Term-12 year: total: 30-40 microgram/kg IV, IM 1 mg/kg (IV, IM, PO) 1-2 mg/kg bolus IV 0.25-0.5 mg/kg IV, IM 1-2 mg (antiemetic) IM, IV 15 (child) to 30 ml (adolescent) PO 0.25 mg/kg (sublingual) 2 mg/kg then 1 mg/kg Q 6 hr 30 mg/kg over 15 min, then 5.4 mg/kg/hr for 23-48 hours. 0.3 U/kg bolus (aqueous 20 U/ml) IV (Oil 5 U/ml) IM 0.0001-0.0005 u/k/min

Index A Abdominal injuries in children 311 salient points 312 Abdominal surgical catastrophy 346 evaluation of child 346 acute pancreatitis 349 appendicitis 348 constipation and Hirschsprung’s disease 350 initial management 348 intussusception 349 mesenteric lymphadenitis 349 torsion of ovarian cyst or ovary 350 urinary tract infection 352 volvulus 350 Acid-base analysis 103 Acute heart failure 133 AHF in postoperative congenital heart disease 136 RV failure 137 systemic ventricular failure 136 classification and etiology 136 clinical presentation 137 factors affecting cardiac output 133 factors affecting myocardial performance 134 investigations 137 blood gas and electrolytes 140 cardiac catheterization 140 echocardiography 140 electrocardiography 139 management 142 pulse oximetry 140 radiography 137 pathophysiology based etiology of AHF 134 pathophysiology of symptoms in AHF 134 left ventricle (LV) failure 134 right ventricle (RV) failure 134 Acute renal failure in PICU 121 etiology and classification 122 investigations 123 treatment 124 continuous renal replacement therapies (CRRT) 127

1

indications of renal replacement therapy in ICU 125 modalities of RRT 126 preventive measures for ARF in ICU 124 Acute severe asthma 107 first line therapy in the emergency department 109 continuous or intermittent nebulization 109 inhalation therapy with â agonists 109 intravenous terbutaline in acute severe asthma 110 MDI V/s nebulizers 109 oxygen 109 treatment for incomplete response 109 prognosis 112 ventilation in asthma 112 supportive treatment 112 Adrenal insufficiency in critical illness 316 diagnosis 322 mechanism 320 normal physiology 317 clinical diagnosis 322 laboratory diagnosis 322 treatment 324 Advanced airway considerations 61 Alternative approaches to airway management 51 laryngeal mask airway 51 tracheostomy 51 contraindications 52 indications and usage 52 Antiarrhythmic drugs for acute care 163 Antihypertensive drugs 172 general approach 172 pharmacology 173 adrenergic inhibitors 178 angiotensin receptor blockers (ARBs) 178 angiotensin-converting enzyme inhibitors 177 calcium channel blockers 180 central á-agonists 180 combined á- and â-blockers 179 direct vasodilators 181 diuretics 177 peripheral adrenergic inhibitors 179

448

PEDIATRIC INTENSIVE CARE vasodilators in pediatric practice 181 vasopeptidase inhibitors (VPIs) 181 á-blockers 179 â adrenergic receptor blockers 178 Automated external defibrillators 61 Avoiding hyperventilation during CPR 60

B Basic for use of inotropic support 198 Blood components in intensive care practice 254 cryoprecipitate 263 fresh frozen plasma (FFP) 262 granulocytes 260 leukodepleted blood components 260 packed red blood cells 256 indications 256 platelet transfusions 258 storage and shelf life 255 ABO and Rh compatibility 255 whole blood 256 indications 256

C Carbon monoxide poisoning 403 Choice of empiric antibiotics in severe sepsis and septic shock 250 Choice of inotropes and vasopressors 199 digoxin 215 dobutamine 202 dopamine 199 epinephrine 204 milrinone 207 norepinephrine 210 vasopressin 212 Clinical hemodynamic parameters 230 Collapse rhythm (pulseless arrest) 161 management 161 nonshockable rhythm 162 shockable rhythm 162 torsades de pointes 162 Cost of oxygen 20 CPR for infants 59 Critically III child 1 appearance of the child 2 airway 2 breathing 2 circulatory status 3 Critically sick child with human immunodeficiency virus infection 429

clinical features 431 epidemiology 429 natural history of pediatric HIV 430 spectrum of diseases in the PICU 431 cardiac dysfunction 435 neurological complications 437 renal failure 436 respiratory diseases complicating HIV infection 431 septic shock 436 transmission 430 blood transfusion 430 perinatal transmission 430 sexual transmission 430

D Defibrillators 165 automated external defibrillators (AEDs) 165 defibrillation sequence 166 energy dose 165 interface 165 paddle position 165 paddle size 165 Dertermine tissue oxygenation 15 Determinants of cardiac output 231 contractility assessment 232 preload assessment 231 pulmonary artery chatheter 231 Diabetic ketoacidosis (DKA) 328 cerebral edema 335 management 335 complications 336 frequency of DKA 329 children with established TIDM 329 morbidity and mortality of DKA in children 329 management of DKA 329 care in PICU 329 confirm the diagnosis 331 general issues 329 monitoring 331 supportive therapy 335 Dose of oxygen 19 Doses of drugs used in emergency situations 442

E Electrical injury 362 fluid resuscitation in burns 363 Endocrine emergencies in PICU 338

INDEX diagnosis 338 clinical indicators 339 laboratory indicators 338 select endocrine emergencies 339 Addisonian crisis 342 cerebral salt wasting 344 hypocalcemia 341 hypoglycemia 339 syndrome of inappropriate ADH 344 Evaluation of a comatose child 265 history 266 investigations 268 management 269 pathophysiology 265

H Hazards of oxygen 20 Head injury in children 277 assessment 278 assessment and management of moderate and severe head trauma 281 blood pressure in head injury 282 cervical spine immobilization 283 medical management 285 minor head injury 281 objective 277 Hemodynamic monitors 230 blood pressure monitoring 231 electrocardiography monitoring (ECG) 230 invasive BP monitoring (IBP) 231 non-invasive BP monitoring (NIBP) 231 Hirchsprung’s disease 350 Humidification of oxygen 15 Hyperbaric oxygen 19 Hypertensive crises 184 etiology 185 evaluation 185 hypertensive emergency 187 hypertensive urgency 187 pathophysiology 184 treatment 186

I Indications for oxygen supplementation 13 Inhalation injury 360 types 361 carbon monoxide (CO) poisoning 361 parenchymal dysfunction 362 upper airway obstruction 361

Intensive care and emergency room management of arrhythmia in children 151 bradyarrhythmias 158 impulse conduction disturbances 159 sinus bradycardia 158 management of bradyarrhythmias 160 management of tachyarrhythmias 156 atrial fibrillation or flutter 158 electrical (synchronized) cardioversion 158 narrow-complex 157 tachycardia with hemodynamic instability 156 tachycardia with hemodynamic stability 158 wide-complex 157 normal rhythm disturbances 151 extrasystoles 152 sinus arrhythmia 151 sinus bradycardia 152 pathological rhythm disturbances 52 tachyarrhythmias 153 atrial fibrillation and atrial flutter 154 hyperdynamic cardiac activity (sinus tachycardia) 153 true arrhythmias 153 ventricular tachycardia 155 Iron poisoning 399 clinical and laboratory manifestations 401 decontamination 400 dose of ingested iron 399 early clinical assessment and simple laboratory screening 400 iron chelation therapy 400 life support measures 401

M Management of poisoning 387 admission in PICU 388 clinical presentation 387 hydrocarbons 391 cardiac effects 394 CNS effects 391 gastrointestinal effects 391 pulmonary effects 391 organophosphates and carbamates 395 clinical effects 395 clinical presentation 397 treatment of organophosphate intoxication 396

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PEDIATRIC INTENSIVE CARE principles of management 388 treatment 389 Mechanical afterload reduction 145 adjunctive therapy 147 extracorporeal membrane oxygenation 145 intra-aortic balloon pump (IABP) 145 predictors of mortality 148 treatment of underlying condition 147 ventricular assist device 145 Multiorgan dysfunction syndrome 221 apoptosis 225 endothelial activation/injury 224 epidemiology 221 pathophysiology 223 prognosis 227

N Neonatal ventilation 82 alternative modes of neonatal ventilation 83 assist/control ventilation 84 mandatory minute ventilation (MMV) 84 patient triggered ventilation (PTV) 83 pressure support ventilation (PSV) 84 proportional assist ventilation (PAV) 84 synchronous intermittent mandatory ventilation 84 conventional neonatal ventilation 82 pressure limited time cycled ventilation 82 Neuromuscular diseases in critically III children 291 clinical features 292 features 293 acute intermittent porphyria (AIP) 296 acute poliomyelitis 295 axonal neuropathy 296 botulism 296 diphtheria 296 diseases of muscle 297 Guillain-Barre syndrome (GBS) 293 myasthenia gravis 295 organophosphates 296 spinal muscular dystrophy (SMA) 295 tick paralysis 297 management of respiratory failure in children 298 other considerations 299 respiratory management 298 pathophysiology 291

Nutritional support in the critically III child 408 general principles, philosophies and calorie delivery 409 macronutrients 410 vitamins and minerals 410 concept of immunonutrition 412 optimal route of nutritional delivery 411 special nutritional requirements in specific situations 413

O Oxygenation determination 13 clinical markers of hypoxia 13 arterial blood gases (ABG) 14 measuring oxygenation 14 pulse oxymeter 14 advantages of SpO2 15 drawbacks of SpO2 14 precautions 15

P Pain management in the PICU 365 Pathophysiology of intracranial pressure 272 Pediatric airway management 36 anatomic and physiologic considerations 36 approach to airway management 37 bag mask ventilation 40 check equipment 44 difficult airway 44 endotracheal intubation 44 oxygen administration 37 Pediatric mechanical ventilation 63 basic physiology 64 commonly used nomenclature 65 gas exchange 65 indications of mechanical ventilation 65 modes of ventilation 66 oxygenation 64 time constant 65 ventilation 64 basic fundamentals of ventilation 67 advanced modes 68 control every breath 69 gas exchange related problems 69 initial ventilator settings 68 pressure limited ventilation 67 pressure vs volume control 67 trigger/sensitivity 68

INDEX usually based on blood gases and oxygen saturations 69 volume limited ventilation 67 respiratory care during ventilation 71 aerosol therapy 73 chest physiotherapy (CPT) 71 disease specific ventilation 77 endotracheal suctioning 75 extubation 77 humidification 73 mucolytics 75 weaning from mechanical ventilation 76 weaning methodology 77 Pelvic fractures and extremity injuries in children 312 salient points 313 Physiology of fluids and electrolytes 190 electrolytes metabolism 192 functions of electrolytes 192 calcium 194 chloride 194 magnesium 94 phosphates 194 potassium 193 sodium 193 regulation of electrolytes 195 maintenance requirement of fluids and electrolytes 195 parenteral fluids 196 regulation of water 192 water metabolism 191 Prism score 8 organ specific scoring system 9 Pulmonary edema 114 diagnosis 116 pathophysiology 114 increased pressure edema 115 treatment 119 Pulmonary function tests 98

R Rapid sequence intubation 50 contraindications 50 indication 50 Relief of choking in children and infants 61 Respiratory monitoring in PICU 89 invasive monitoring 100 arterial blood gas analysis 100 basic concepts 100

basic introduction of arterial blood gases 100 systematic analysis of arterial blood gases 100 non-invasive respiratory monitoring 90 capnography 94 clinical applications of CO2 monitoring 97 history 90 limitations 97 limitations of pulse oximetry 92 PaCO2-EtCO2 gradient 97 types of CO2 monitors 95 physical examination 89 Resuscitation 55 basic life support (BLS) 55 cardiopulmonary resuscitation (CPR) 55 chest compressions 58 positioning the child 56 rapid assessment (beginning CPR) 56 bag-and-mask technique and rescue breathing 57 breathing 56 opening the airway 56 pulse check 58 rescue breaths 57

S Scorpion sting 382 clinical features 383 epidemiology 382 investigations 384 management 385 pathophysiology 383 Scoring systems in PICU 7 Septic shock 234 choice of fluid for volume replacement 241 dosing, preparation and administration 245 emergency management 238 hypocalcemia and hypoglycemia 241 initial resuscitation 241 priorities of treatment 239 rapid cardiopulmonary assessment and clinical examination of a patient in shock 236 therapeutic end points 246 Severe acute pancreatitis 353 clinical picture 354 complications 357 local complications 357 systemic complications 358

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PEDIATRIC INTENSIVE CARE prognosis 358 diagnostic tests 355 lab investigations 355 radiological findings 355 etiology 354 management 356 fluid resuscitation and rehydration 356 pathophysiology 354 Snake bite envenomation 374 laboratory diagnosis 378 management 378 pathophysiology 375 clinical features 375 special situations 377 bite by killed snake 377 envenomation without bite 377 snake bite to a lactating mother 377 Systematic analysis of arterial blood gases 101

T Transcutaneous oxygen monitor 15 Transcutaneous pacing 167 Transport of critically III child 416 air transport 424 communication 422 history of transport medicine 417 modes of transport 418 personnel and training 419 preparation for transport 419 reasons for transport 418

risk management 423 stabilization during transport 420 systems errors 423 Trauma in children 302 airway management 305 anatomic peculiarities in child 305 management 305 chest trauma 309 management of a severely injured child 302 resuscitation phase 309 venous access 306

U Upper airway diseases 22 differential diagnosis 24 history 23 investigations 24 CT/MRI 27 endoscopy 27 monitoring 28 radiology 24 management 28 airway management 29 initial management 28 pathophysiology 23 physical examination 24

V Ventilation for acute respiratory distress syndrome (ARDS) 79