Failure to anesthetize human subjects by intravenous administration of magnesium sulfate

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THE JoumiAn OFPHARMACOLOGY ANDEXPERIMENTAL THERAPEUTICS

Vol. 154,No. 3 Printedin

Copyright ©1966 by The Williams & Wilkins Co.

FAILURE

TO ANESTHETIZE

INTRAVENOUS ,

HUMAN

ADMINISTRATION

MAGNESIUM

G. SOMJEN, Department

of Physiology

SUBJECTS

U.S.A.

BY

OF

SULFATE1

M. HILMY

AND C. R. STEPHEN2

and Pharmacokgy

and Division

of Anesthesiology,

Duke University Medical Center, Durham, North Carolina Accepted for publication July 26, 1966 ABSTRACT

SOMJEN,G., M. HILMY ANDC. R. STEPHEN: Failure to anesthetize human subjects by intravenous administration of magnesium sulfate. J. Pharmac. exp. Ther. 154: 652—659, 1966. Two human subjects were given MgSO4 by slow intravenous infusion. The concentration of Mg rose to 15.3 and 14.6 mEq/liter of plasma, from a control value of 1.4 mEq/liter. Profound paralysis of skeletal muscles was produced, with the exception of the diaphragm, the adductors of the vocal cords and some of the facial muscles. The electrocardiogram showed slowing of atrioventricular conduction and alterations of the ventricular action potential. Both subjects remained aware of the surrounding, and in rational contact with the observers. Pain was keenly felt ; vision and hearing were normal. Eye centering and conjugate eye movements did not fail. Nystagmus could be provoked in one subject. The electroencephalogram showed diminished a rhythm and decreased voltage, but none of the common signs of sleep, coma or anesthesia. One of the subjects had amnesia over a short period of time coincident with the occurrence of cyanosis. The other subjects, whose ventilation remained adequate, could remember every detail of the experiment. It is con eluded that general anesthesia, or analgesia, cannot be produced by parenteral administra tion of magnesium. It is doubtful whether in these two experiments any depression of the central nervous system was produced at all by the drug.

1960, p. 910; Goodman and Gilman, 1965, p.

causing depression of the central tem (Wiki, 1934 ; Cloetta et al., dissenting opinions were largely example, Bohdanecky and Weiss could not find any change in the

803) . A narcotic

action

gram,

was first

by Meltzer

That sants,

magnesium capable

salts

of causing

are

central

general

depres

anesthesia,

is

stated as a matter of fact in most pharmacology texts (e.g., Gaddum, 1959, p. 12 ; Groliman,

proposed

of magnesium and Auer

sulfate in 1906.

The ensuing controversy (Straub, 1915; Mans feld, 1915) seemed settled in 1916 when Peck and Meltzer performed three operations on hu man patients with no other anesthetic drug used except magnesium sulfate. The clinical use of magnesium as an adjuvant in anesthetic combinations

has

been

recently

advocated

by

Kretzschmar and Schikorski (1952) , Scherer (1953) and Prisco and Prisco (1956). Yet throughout the years some investigators continued to doubt whether parenterally admin istered salts of magnesium were capable of Received for publication June 17, 1966. 1 Aided

by

Grant

NB

05330

of

the

National

Institute of Neurological Disease and Blindness of the U.S. Public Health Service. 2 Present

@

address

Dallas, Texas.

: Parkland

Memorial

Hospital,

nor

an

alteration

of

nervous sys 1942) . These ignored. For (1964) , who electrocortico

the

threshold

of

electrical “¿arousal― evoked by stimulation of the reticular formation, in rats immobilized by magnesium

sulfate,

believed

were asleep. They concluded was

a

“¿dissociation― of

that

these

animals

that the Mg effect

behavioral

sleep

from

the typical electrical signs of central depression. Since we did not find in the literature any confirmation

of the

observations

of Peck

and

Meltzer (1916), nor any published EEG re cordings of human subjects in magnesium “¿an esthesia,― we proceeded to test the effects of this drug on ourselves. METHODS.

Six

percent

magnesium

sulfate

was

administered to two human subjects by slow in travenous infusion. The solution was prepared by diluting 25% MgSO4 7 1120 with 5% glucose in water. The assayed strength of the final dilution was 0.49 Eq/liter

652

of

measured

by

atomic

1966

EFFECT

OF MG ON HUMAN

absorption spectrophotometry. An electrocardio gram (lead II) was taken continuously ; arterial blood pressure was read at intervals. In experiment I (subject G. S.), a single channel electroenceph alogram (frontooccipital) was used ; in experiment II (subject M. H.), eight monopolar EEG leads were run (for details, see RESULTS). The experiments were performed in an operat ing room, with equipment for positive pressure artificial respiration available, but not used. A solution of CaCI, was kept in readiness. Five-milliliter blood samples were taken from a vein into heparin-wetted syringes, the blood was centrifuged and the Mg content of the plasma was measured by atomic absorption spectrophotometry (Willis, 1959). The control plasma samples were diluted 50 times, and the samples

taken

after

Mg

loading

were

diluted

250 times in 0.1 N HC1 containing 0.1% La,03. Voluntary muscle strength of the flexors of the right index finger was tested at frequent intervals during the infusion of magnesium and, thereaf ter, with a simple spring-loaded grip-ergometer in the shape of a trigger. This instrument was later calibrated with weights. Skin sensibility was tested with a pin and also with a towel forcep. The subject was asked from time to time to perform certain movements. Questions were asked as long as voice communication was pos sible. In the second experiment, a signal was l)rearranged

to permit

communication

after

loss

of speech : one movement of the eyebrow meant “¿yes,― and two movements meant “¿no.― A detailed

protocol

was kept

during

the

first

experiment ; a tape recorder was installed during the second. Each subject made a detailed written summary of his recollections on the morning following the experiment (both experiments were conducted be tween 3 and 4 p.m.). He was confronted with the protocol or tape recording after completing hissummary.

still move his fingers and toes, albeit very weakly, but not the large muscles of his arms and legs. Jaws, tongue, mouth and pharynx were paralyzed in both cases, so that speaking and swallowing became impossible, but the ad ductors of the vocal cords remained intact so that both subjects were able to groan. Partial ptosis was an early symptom in the second experiment, but the first subject could open his eyes widely even at the termination of the in jection. Similarly, tile external eye muscles were weakened in the second subject, but not notice ably in the first. There was no diplopia in either case. The eyebrows

The

rate

of

infusion

and

the

total

dose injected are shown for both experiments on table 1. Both subjects lost control of most of their skeletal muscles without impairment of skin sensation, hearing or sight. Figure 1 shows the loss of force of voluntary muscle contraction, measured on the fiexors of the fin ger. The measured levels of plasma Mg are also entered on the chart of figure 1. Details of the most important observations follow. Skeletal muscles. Paralysis of the limbs was complete in the first experiment, and nearly complete in the second. The second subject, whose plasma Mg level was slightly lower, could

remained

mobile.

Breathing. As paralysis progressed, breathing became more and more predominantly abdom inal. The first subject felt an urge to breathe somewhat faster and more deeply than in the control period. He did not feel air hunger, but apparently overcompensated for the diminished efficiency

of his neuromuscular

apparatus.

Ven

tilation of the second subject became shallow and slow, and in the last 6 mm of the infusion and the first 2 or 3 mm of the recovery period his nailbeds were distinctly cyanotic. Upon inquiry

whether

he

felt

short

of

breath

or

wanted artificial respiration, he responded with unmistakable denial, using the prearranged sig nal of two movements of the eyebrow. Circulation. Changes of blood pressure and of pulse rate are shown in table 1. The first subject had a marked sinus arrhythmia during the control period, even with quiet breathing. After about 10 mm of infusion, sinus arrhyth mia could no longer be detected on the electro cardiogram tracing (see fig. 2) . The second subject showed sinus arrhythmia only during forced deep breathing ; during the experiment, sinus

RESULTS.

653

SUBJECTS

arrhythmia

could

not be evoked

anymore.

There were distinct electrocardiographic changes in both subjects : the T wave all but disappeared, the S-T segment became depressed, the voltage of the R wave diminished and the P-R interval increased by about 0.04 sec. Skin sensation. Pain was keenly felt through the entire period of observation. Both subjects could easily distinguish the head from the point of a pin. Sight. Both subjects could see well. The second subject experienced some difficulty of fixing, following and focusing on objects, proba

bly because of a weakening of the muscles of the eyes. There was no diplopia.

654

SOMJEN

TABLE

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Vol.154

AL.

1

Amounts of magnesium injected, rate of infusion, plasma magnesium levels, blood pressure and heart rate in two human subjects Expt. l.a (Subj@t G. S.. 36 yr. male, 66 kg. Rate of injection: kg.)TimeDosePlasma 8 mi/min)E@t. MgBlood

ratemis

11b (Subj@t M. H., 34 yr., male, 60

pressure of @d heart rateRate injectionDosePlasma

b. ml.

pressure @d heart

b. tel.

1.43120/70

0

0

MgBlood

67/mm 10mEq/kg 130/75 94/mmmZ/mi@a

4mEq/kg 0.24mEq/t

110/mm150.

1.42130/84

0

0.33mEq/l

84/mm 130/90

.22140/90

89130/75 118/miii20

102/mm81

96/mm61.55 221.19 1.31118/60 102/miii442.6415.3116/60

1.6910.5105/66

107/mm 100/60

3.0714.6115/70

120/80

94/mm42.73110/70

90/mm52

99/miii

57Recovery2 90/mm11

Recovery2.99

86/mm11.4130/80 1313.15120/60

80/mm60

2.2

20c10.6 a Duration

of infusion;

443/@ mm.

b Duration

of

57 mm.

C

infusion;

Hours.

Hearing. Everything said in a soft conver sational voice was heard and perceived nor mally. Appropriate responses were given to requests to breathe deeply, to move the eyes or eyebrows or to make a sound. Other signs and si.thjective symptom@s. Almost immediately after the start of the experiment, the subjects experienced the well known hot sensation in the skin, abdominal viscera and mouth. This sensation increased for awhile, and was moderately unpleasant. The first subject perspired profusely, the second subject moder ately ; the second subject was unaware of the perspiration. A distinct slow nystagmus was

observed in the second subject when he at tempted to look sideways. The nystagmus was first seen after 27 mm (1.94 mEq of Mg/kg b. wt.) , and became more intensive as the experi ment progressed. There was a “¿dizzy― or “¿light― feeling in the head, in both cases, but no vertigo (no feeling of turning or changed position in space) . The “¿dizziness― began early, after 5 to 7 mm, and may have been a vascular phenome non or caused by a change of intracranial pres sure ; there was, however, no headache. The mouth and tongue of both subjects felt rather dry. Nevertheless, the first subject was troubled by the small amount of saliva collecting in his

1966

EFFECT

OF

MG ON

HUMAN

655

SUBJECTS

C

0

U 0 C

0 0 0 V U

20

2.@ mEq/kg

FIG. 1. Force of voluntary

Minutes,

Mg Injected

contraction

Recovery

of the flexors of the right index finger, and plasma

Mg levels

during the infusion of 6% MgSO4.7 H20. 0 and @, force of contractmon; z@and A, plasma Mg. 0 an@i & expt. I; •¿ and A, expt. II. The left hand ordinate shows force in kilograms; full scale deflection of the ergometer corresponds to 14.5 kg on ordinate reading; the minimum necessary to overcome the holding force of the spring of the ergometer was 3 kg, and this amount should be added to values mdi cated to obtain true force exerted. The scale for plasma Mg is on right hand ordinate. pharynx,

of

which

he

could

not

get

rid

by

swallowing. Electroencephalogram. The tracing taken during magnesium infusion did not at any time show /3 activity, sleep spindles, slow waves or other common signs of anesthesia or diminished consciousness (fig. 3) . Dr. W. P. Wilson sup plied the following reading of the EEG tracing of the second subject. “¿A normal electroencephalogram was obtained on M. H. on 4/29/66, using a monopolar re cording, with ear reference leads. Parasag gital electrodes, including the F-3, F-4, C-3, C-4, T-3, T-4 and 0-1, 0-2 electrodes were ap plied and referred to the ipsilateral ear. These were recorded on a Grass model 6 electro encephalograph. In the control period, the elec troencephalographic traces were characterized by a normal distribution of a rhythm in both parietal and occipital areas, with minimal f3 activity in the record. The a frequency was that of approximately 10 cps, with the usual variation

around

this

mean.

No

change

was

observed in the a rhythm immediately after the beginning of the record. Its persistence, as well as its voltage, remained essentially the same. As the infusion progressed, however, there was a gradual decrease in the a index from 0.5 to a 0.1, and, at times, even lower, to a 0.05 index. Thus the a persistence decreased profoundly. There was concomitantly a change in the volt

CONTROL

0.7

80@

0.8

60 C

E U) 0

a,

5C

.2 > 0.6 c

100

0.7 80

0.8 0.9

6C Fia. 2. Disappearance first subject.

The

points

MAGNESIUM

of sinus arrhythmia show intervals

in

of succes

sive heart beats during approximately two respira tory cycles, as shown on right hand ordinate scales ; intervals converted to corresponding heart rate, on left hand ordinates. Upper graph, before commencing the injection ; lower graph, after about 35 mm of Mg infusion. age, with a decrease in voltage to approximately 50% of the resting initial values. stimulation, the patient's a rhythm

With verbal would reap

pear. There was no activation of the record such as one might expect to see from the alerting affects of being paralyzed, and any anxiety

that

was

produced

certainly

was

not

manifest in any EEG change. In this instance, there was a gradual decrudescence of the elec

656

SOMJEN

ET

Vol.154

AL.

A F3-A1

C3-A1 P3-A1

01-A1 F4-A2 C4-A2

P4-A2 0@-A2

B F3-A1 C3-A1

01 -A1

f:4-A2 C4-A2 P@-A2

@

O@-A2 _rg;;._J5OILV

FIG.

3. A, electroencephalogram

channels.

takeii

B, EEG at end of magnesium

before

magnesium

prolonged

post

infusion

record

Monopolar

recording

in all eight

infusion.

trical activity, both in voltage and persistence, and there was no appearance of /3 activity in the recording. A

infusion.

was

not

obtained.― Recovery period. Speech was regained in a few minutes; movements of hands and feet followed soon. Sitting was possible after ½hr. Within 2 hr the subjects could get out of bed, but the gait was unsteady. Muscle strength was nearly normal 6 hr after the experiment. The expected diuresis occurred about 45 mm ifter the infusion was stopped, and continued for more than 1 hr. The second subject had difficulty emptying his bladder, and had to use manual compression through the abdominal wall. The first subject experienced some nausea in the first 20 mm after the infusion, but there was

no vomiting. Both subjects felt perfectly well the day after the experiment. Recall. The first subject could remember well every detail of the experiment, the stimulations applied to him and the conversations occurring around him. He wrote, among others, on the day following the experiment: “¿Towardthe very end, when paralysis was nearly complete, things seemed slightly distant, and somewhat irrelevant. I do recollect that a blood sample was taken, and after that a little more magnesium given and that M. H. said to Dr. St. that the injection should have been stopped right when the sample was taken. But these saliva

things seemed less important than the collecting in my pharynx, which I could

keep out of my trachea only by blowing. I cannot now recall the emotional coloring of the experience. In an intellectual way, I know that

1966

EFFECT

it was unpleasant, and for a little while dis quieting, but I cannot retrieve the experience of the emotion itself. Characteristically, I un derestimated the flow of time during the infu sion, while during the recovery—while impa tiently waiting for a return of motor control—I overestimated it.― The second subject had a gap in his memory of the experiment. The following is an excerpt from his notes made on the day after the experiment:

“¿I was able to think all the time, and re member what was going on around me until a few

minutes

after

the

rate

of

infusion

was

changed to 2 ml/min. I do not recall now whether I was asked if I wanted to stop, or if I requested to stop. I remember Dr. St. saying: ‘¿he is breathing all right now.' That was after stopping the infusion. There must be a period of lost contact with the outside world in be tween.― In fact, contact with the subject was never lost. From the notes made by the observers, and the tape recording, it is clear that in the amnestic period the subject continued to re spond to requests, like taking a deep breath or moving his fingers, within the limits of his residual motor power. He also responded ade quately with “¿yes― and “¿no― signals to questions like : “¿Would you like to have oxygen ?““¿Do you feel short of breath ?“ “¿We will stop now: is that

all

right

with

you ?“He

also

groaned

painfully when the needle for the blood sample was inserted, and gave the “¿yes― signal upon the inquiry : “¿Did this hurt ?“English is not the native tongue of this subject, and it may be assumed that considerable clarity of mind was necessary for him to respond appropriately to requests and questions spoken in this lan guage. DISCUsSIoN.

Contrary

to our

expectation,

we

could not induce general anesthesia in our two subjects, in spite of the profound peripheral effects. In retrospect this is hardly surprising. The uptake of magnesium from the bloodstream into the brain is very limited (Cloetta, 1942; Somjen and Hilmy, 1966) . It would have been remarkable indeed if a substance which was entering

the

central

nervous

system

657

OF MG ON HUMAN SUBJECTS

in

only

very small quantities, and had no effect on the electrical activity of brain and spinal cord (Bohdanecky and Weiss, 1964 ; Somjen, 1966), would have had a powerful narcotic action.

There is no doubt that a high concentration of magnesium ions applied directly to central nerv ous tissue, by-passing the blood-brain barrier, may cause general anesthesia and does block central synaptic transmission. The most recent experiments

showing

these

effects

were

per

formed by Feldberg (1958) and by Katz and Miledi (1963). The plasma Mg levels reached in our 2 ex periments were comparable to those which are supposed to cause general anesthesia in ani mals. According to Moore and Wingo (1942), plasma concentrations in the range of 9.9 to 14.8 rnEciJliter (mean 12.4) are sufficient to abolish any response to skin incision ; 14.8 to 22.2 mEqJliter (mean 19.8) result in a state resembling profound surgical anesthesia. Simi lar figures were published by Neuwirth and Wallace (1929), by Smith et at. (1942) and by Engbaek (1948) . In our experience, rabbits immobilized by injected magnesium, but breath ing spontaneously, have plasma concentrations ranging from 13 to 20 mEciJliter (Somjen and Hilmy, 1966) . Had there been no intelligent communication

and

recollection,

the state

of our

two subjects could easily have been mistaken for general anesthesia. Two questions remain essentially unanswered by the experiments just described. First, whether there was any depression of the cen tral nervous system at all ? Second, could we have achieved general anesthesia, had we con tinued injecting more of tile drug? Some of the changes seen in the two subjects could indeed have been signs of mild central

depression. The most notable one is the gap in the memory of the second subject. Mazzia and Randt@ (1966) have called attention to the isolated amnesia for on-going events, correlated with lack of eye centering, that occurs in first stage anesthesia. Mazzia and Randt (1966) emphasize

the fact

that

in this stage

of anesthe

sia the subjects are oriented, rational, aware of the surroundings and able to perform arithme tic. In our experiment, in clear distinction to Mazzia and Randt's (1966) subjects, eye move ments remained conjugate and eye centering did not fail, although movements of the eyes became sluggish and nystagmus was observed when the gaze was directed to one side. The amnesia of our subject could, nevertheless, have been due to a central effect of the injected magnesium. It could also have been due to hypoxia or hyper

658

SOMIEN

capnia, for it was during this time that cyanosis of the nailbeds was noted. This latter conclu sion is reinforced by the fact that our first sub ject, who did not become cyanotic, did not experience amnesia either. At the time when the nailbeds were cyanotic, the second subject did not feel short of breath, although his ventilation was obviously inade quate. This lack of respiratory discomfort could have been the consequence of sedation by the injected magnesium. An alternative explanation is offered by the observation of Eyzaguirre and Koyano (1965) that the transmission of excitation from chemoreceptor cells of the ca rotid body to sensory nerve endings is drasti cally reduced after 3 to 4 mm exposure of the receptor organ to a high (10 mEcijliter) con centration of magnesium ions. This effect could account for the tranquility of the subject in the presence of partial asphyxia. Sinus arrhythmia disappeared early during the infusion. Experiments on spinal cats indicate that vagal inhibition of the cardiac pacemaker is blocked by pharmacologic quantities of mag nesium (Baskerville and Somjen, in prepara tion) . Lack of vagal modulation is the most likely cause of the disappearance of sinus ar rhythmia and the concomitant increase of the heart rate. Some minor changes did occur in the EEG tracing taken during the infusion. But the usual electrographic signs of general anesthesia, or of coma by other causes or of natural sleep were all absent. The diminished a rhythm of the subject could have been due either to drowsiness or to mild hypercapnia (Swanson et al., 1958). Judged by the EEG, however, the subject was not very deeply asphyctic either. In our experience, in animals under magne sium,

the

electrical

activity

of the

cerebral

cor

tex is depressed only when respiration becomes insufficient, or, under artificial respiration, when the circulation fails (see also Rubin et al., 1943; Bohdanecky and Weiss, 1964; Somjen, 1966). Our second problem, whether larger quanti ties of magnesium given under artificial respira tion could have caused sleep, could not be ex plored for reasons of safety. Although in animals cardiac arrest occurs only with higher mag nesium levels (over 25 m.EaJliter in plasma), and resuscitation is frequently possible by a prompt injection of calcium chloride, obviously

ET

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AL.

the risks involved in the human experiment were too high. Our remaining task is now to attempt to ex plain how Peek and Meltzer (1916) could per form surgical operations on three human sub jects using intravenous magnesium sulfate as anesthetic drug. Tentatively, we would like to suggest that these patients seemed to be anes thetized because of a combination of peripheral paralysis, asphyctic narcosis caused by made quate ventilation, perhaps also failure of the circulation due to the magnesium, or neurogenic or surgical shock and a merciful amnesia. Care ful reading of the original paper lends some support to this speculative reconstruction of events. It will be recalled that, prior to the controlled experiment of Smith et at. (1947), some observers thought that large doses of curare can cause unconsciousness (e.g., Whit acre and Fisher, 1945). CoNcLusIoNs.

Magnesium

sulfate,

injected

intravenously by itself, does not cause general anesthesia nor analgesia in a dosage compatible with the safety of the subjects. Mild central de pression

may

possibly

occur

after

a large

dose

of magnesium, but the signs observed in our two subjects could be explained by causes other than a central effect of the drug itself. ACKNOWLEDGMENTS.

Our

thanks

are

due

Dr.

W. P. Wilson of the EEG Laboratory of the Department of Psychiatry, Duke University, for his cooperation, and to Dr. W. D. Obrist, also of the Department of Psychiatry, for dis cussions. REFERENCES BOHDANECKY,

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