INTRAVENOUS MAGNESIUM SULFATE IN THE TREATMENT...

INTRAVENOUSMAGNESIUMSULFATE IN THE TREATMENTOFNEPHRITIC CONVULSIONSIN ADULTS1'2

By ALEXANDERW. WINKLER, PAUL K. SMITH, AND HEBBELE. HOFF(From the Department of Internal Medicine and the Laboratories of Pharmacology and

Physiology, Yale University School of Medicine, New Haven)

(Received for publication November 1, 1941)

Since 1926 the intravenous injection of mag-nesium sulfate has been employed in this clinicfor the treatment of the twitchings and convul-sions of advanced chronic nephritis in adults.This report is based on over forty cases sotreated. Cases of eclampsia, acute nephritis ofchildhood, and various other vascular disordersalso treated with intravenous magnesium sulfatehave been included. For comparative purposesthe physiological effects of intravenous magnesiumwere observed in subjects without cardiovasculardisease.

REVIEW OF LITERATURE

On the basis of animal experiments Meltzer (1) rec-ommended the use of magnesium intravenously in thetreatment of tetanus, and there have been several reportsof cases treated in this way (2, 3). In 1916 Peck andMeltzer described three cases in which magnesium sulfatewas employed intravenously as a general surgical anes-thetic (4). However, amounts sufficient to induce an-esthesia were found to produce marked respiratory de-pression, so intravenous magnesium proved impractical asa general anesthetic. Attempts have been made to useit in combination with other anesthetics, but such sugges-tions have met with little favor (5).

In 1923 Blackfan (6), on the basis of Meltzer's work,introduced intravenous magnesium sulfate therapy in thetreatment of the convulsions of acute nephritis in children.He was convinced of the efficacy of the treatment onpurely clinical grounds, but was uncertain as to the exactmode of action. Originally, Blackfan was impressed withthe importance of cerebral edema in the etiology of con-vulsions in his patients and combined intravenous mag-nesium sulfate therapy with dehydration produced bymagnesium sulfate catharsis. Since magnesium sulfateintravenously injected acts through the specific pharma-cological action of the magnesium ion, while its effects

1 Aided by grants from the Ella Sachs Plotz Fund, theCommittee on Therapeutics of the American MedicalAssociation, and the Fluid Research Fund of the YaleUniversity School of Medicine.

2A preliminary report was presented to the AmericanSociety for Clinical Investigation in May 1940; J. Clin.Invest. (Proc.), 1940, 19, 783.

are simply those of any saline cathartic when it is givenorally, it is clear that two quite different modes of treat-ment were used in conjunction by Blackfan. In hisearlier reports he is not clear as to the relative importanceof the specific magnesium ion effects and of the non-specific dehydration effects. If cerebral edema were asimportant a factor in these cases as he originally be-lieved, then dehydration should be most effective, andspecific nervous system depression by magnesiumn shouldbe harmful rather than otherwise; this, however, did notseem to be the case. In his last report in 1931 (7) he isinclined to stress the importance of dehydration but recog-nizes that intravenous magnesium sulfate may be quiteeffective without any dehydrating measures. Whateverthe mode of action, Blackfan's work demonstrates that inacute nephritis of children the intravenous injection ofmagnesium sulfate in isotonic or hypotonic solution lowersblood pressure, stops convulsions, and in many instancesis followed by immediate clinical improvement. It isremarkable that these effects are produced by amountsof magnesium sulfate far smaller than those required inMeltzer's experiments to produce anesthesia or to checktetanic spasms. Rubin and Rapoport (8) have also re-ported favorably on the use of intravenous magnesiumsulfate in children but have emphasized the occasionaldangers.

In 1925 and 1926 Lazard (9), Alton and Lincoln (10),and Lazard, Irwin and Vruwink (11) reported favorablyupon the use of intravenous magnesium sulfate in con-trolling the convulsions of eclampsia, and it has since beenused quite extensively for this purpose (12, 13). Its use,however, has been empirical, and its mode of action butlittle studied.

MATERIAL AND METHODS

Adult patients ordinarily received intravenously 500 cc.of a 2 per cent solution of the hydrated salt, MgSO, X7 H20, during a thirty- to sixty-minute period. Some-times smaller or larger amounts were given. The rateof injection was occasionally altered during the course ofthe infusion. The injection of 500 cc. was repeated aftera few hours if convulsions recurred or if twitchings sug-gested that another convulsion might be impending. Ina few instances a third injection was given. Over twentyof these cases have been observed by one of us (A. W.W.) during the course of the infusions. In the remainderit has been necessary to rely upon observations recorded

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ALEXANDERW. WINKLER, PAUL K. SMITH, AND HEBBEL E. HOFF

in the chart; only those cases are included in which noteswere made by observers of known competence.'

In most patients blood pressure was followed duringand after the infusion. In certain cases serial electro-cardiograms from lead two were taken. Concentrationsof magnesium in serum, urine and feces were determinedin a number of instances, using chemical methodspreviously described (14). Cerebrospinal fluid pressurewas followed during the infusion in one case.

RESULTS

(A) Cardiovascular effectsFlushing, perspiration and a subjective sensa-

tion of extreme warmth were reported by all theconscious patients. This was usually first notedwithin less than half a minute after the commence-ment of the injection, and continued to a greateror less degree throughout the infusion. The face,neck and hands were particularly affected, and arise in skin temperature was easily demonstrated.These evidences of cutaneous vasodilatation wereas marked in subjects with acute and chronic vas-cular disease as in normal subjects. The intensityof the effect depended in part on the rate ofinjection.

Blood pressure was essentially unchanged dur-ing the infusion in four control subjects withoutcardiovascular disease, while in three others itdropped sharply (Figure 1). The drop, when itoccurred, was usually quite sudden. Blood pres-sure varied but little during the earlier stages ofthe infusion; then quite suddenly both systolic anddiastolic pressures broke sharply, and within oneor two minutes might drop so low that they weredifficult to measure (Figure 2). The fall inblood pressure sometimes continued for one or twominutes after the infusion had stopped. Withinthe next five or ten minutes the pressure then re-turned promptly to the normal range. This sharpcollapse in blood pressure was regularly accom-

8 For help in this connection we are indebted to theentire past and present staff of the Metabolism Divisionof the Department of Medicine. Particular use has beenmade of the meticulous observations of certain cases by thelate Dr. Maurice Wakeman, who originally introducedthe use of intravenous magnesium sulfate in this clinic in1926. Dr. John P. Peters has had the responsibility fordirecting the treatment since its introduction and hasmade available the records of cases not studied by uspersonally. Acknowledgment is made to Dr. Arthur H.Morse and to Dr. Grover F. Powers for permission toinclude the obstetrical and the pediatric cases.

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FIG. 1. EFFEcT OF INTRAVENOUSMAGNESIUMSULFATEON THE BLOOD PRESSUREOF SEVEN SUBJECTS WITHOUTHYPERTENSIONOR VAScULAR DISEASE

The upper circle in each case represents the initial bloodpressure; the lower, the minimum pressure reached duringor after the injection. In the first four subjects therewas no significant fall in blood pressure, while in the lastthree. there was sudden collapse. One unresponsive pa-

tient received 250 cc., the other three 500 cc. each. Thepatients exhibiting decline of blood pressure received 220,370 and 375 cc., respectively, of 2 per cent magnesiumsulfate.

panied by nausea, thirst, extreme restlessness,mental confusion and a subjective sense of immi-nent doom. These alarming symptoms disap-peared at once when the pressure rose again afterstopping the infusion. So disturbing were thesemanifestations that at the height of the reactionadrenalin was administered to one subject and in-travenous calcium chloride to another. Since re-

covery was as rapid in the third untreated case as

in these two, these procedures cannot be held solelyresponsible for the rapid return of the blood pres-

sure to normal. The pulse rate was always slowduring the period of hypotension. The four sub-jects exhibiting no significant fall in blood pres-

sure complained of no such violent subjective dis-turbances but only of a feeling of warmth.

The response of the blood pressure in patientswith cardiovascular and renal disease to the intra-venous injection of magnesium sulfate in certainrespects resembled, and in others differed from,

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FIG. 2. SUDDEN COLLAPSE OF BLOOD PRESSUREIN ANORMALSUBJECT WHILE RECEIVNG MAGNESIUMSUL-FATE INTRAVENOUSLY

Just after the termination of the injection the patientwas unconscious and the diastolic pressure was unobtain-able. CaCI, was given intravenously at this time. Re-covery was complete within a few minutes.

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that of subjects without vascular disease. As withnormal subjects, the blood pressure was but littleaffected in one group of cases (Figure 4), whileit fell markedly in another group (Figure 3). Thedifferent types of chronic renal and cardiovasculardisease were evenly distributed between the twogroups which were indistinguishable on the basis ofage and sex distribution or on the basis of amountor rate of injection of magnesium. In occasionalcases the blood pressure reacted at one time andfailed to react at another during the course of thesame illness. In contrast to this irresponsive be-havior of many of these chronic patients, the bloodpressure fell promptly in all but one of the sub-jects with eclampsia and acute nephritis (Figure5).

In one important respect the reaction of hyper-tensive subjects differed from that of those with-out cardiovascular disease. The sharp collapse ofthe blood pressure in normal subjects receivingintravenous magnesium was rarely observed inthose with hypertension. On the contrary, theblood pressure usually fell rather slowly and gradu-

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RESPONDINGFIG. 3. CHANGEIN BLOOD PRESSUREFOLLOwING INTRAVENOUSMAGNESIUMSUL-

FATE IN THE FIFTEEN SUBJECTS WITH CHRoNIC RENAL AND VASCULAR DISEASEWHOSEPRESSUREDI DECINE

The symbols are the same as those used in Figure 1. Multiple injections in the samepatients are indicated by the bracketing lines at the top and bottom. The usual dosewas 500 cc. in each injection.

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WITH CHRONIC RENAL AND VASCULARDISEASE WHOSEPRESSURE DID NOT DECLINE SIGNIFICANTLYThe symbols are identical with those used in Figures 1 and 3. The usual dose was 500 cc.

ally (Figure 6) without any distressing subjectivesymptoms. It was hardly ever necessary to dis-continue the infusion because of symptoms asso-

ciated with fall in blood pressure, and the shock-like levels reached in normal subjects were seldomseen. The degree to which blood pressure fell was

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ACUTENEPHRITIS ECLAMPSIAFIG. 5. CHANGEOF BLOOD PRESSUREFOLLOWINGIN-

TRAVENOUS MAGNESIUM SULFATE IN SIX SUBJECTSWITH ACUTE NEPHRITIS AND IN FIvE SUBJECTS WITHECLAMPSIA

The symbols are identical with those used in previousfigures. The subjects with acute nephritis were children,the dose varying between 100 cc. and 300 cc. The ec-

lampsia patients usually received 500 cc.

not closely correlated with the amount of mag-

nesium which had been given but rather with therate of administration. It is not unlikely thatsome of the "unresponsive" subjects, with or with-out cardiovascular disease, might have developedhypotension if the rate of infusion had been greatlyaccelerated. The fall in blood pressure, when itoccurred, was apt to be somewhat more persistentin the hypertensive than in the normal subjects,frequently lasting half an hour to an hour andoccasionally lasting several hours. The returnto the previous level took place in spite of the con-

tinued presence of an increased concentration ofmagnesium in the serum (Table II).

No correlation could be found between cessationof convulsions and the presence or absence ofblood pressure changes. Electrocardiograms were

taken during the entire course of magnesium in-jection in six instances. Minor changes onlywere observed, consisting chiefly of slowing andslight prolongation of the PR interval. No in-traventricular block and no arrhythmia were de-tected. The only case in which the prolongationof the PR interval was at all evident was also theone in which the serum magnesium reached thehighest concentration found in this series.

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0 min. 20 40 60 80-FIG. 6. GRADUALDECLINE OF BLOOD PRESsUREDURING THE INTRAVENOUS INJECTION OF 500 CC. OF MAG-

NESIUM SULFATE IN A PATIENT WITH CHRONIC GLOMERULONEPHRITISAND SEVERE HYPERTENSIVE CARDIO-VASCULARDISEASE

(B) Effects on convulsions and twitchings

It is difficult to evaluate the effect of any thera-peutic measure on the convulsions in "uremic"patients for several reasons. First, only a portionof the patients with pre-terminal nitrogen reten-tion and manifestations of "uremia" develop con-

vulsions. Although twitching of the muscles-sometimes fibrillary, sometimes involving wholemuscles and groups of muscles-is often a preludeto the development of actual convulsions, theappearance of convulsions is by no means in-variable. Secondly, therapy instituted after thedevelopment of convulsions cannot readily beevaluated since convulsions tend to disappearspontaneously. Finally, the great majority of thepatients studied here were near death when ther-apy was instituted, since convulsions and twitchingin chronic nephritis with nitrogen retention seldomoccur until shortly before death. Failure of con-

vulsions to recur after a single injection in many

cases was therefore inevitable. Nevertheless itwas possible to make an analysis of the relationof the convulsions to therapy. This is presentedin Table I.

Some two-thirds of the cases of chronic nephri-tis with convulsions had no more convulsions aftera single injection of magnesium sulfate, while theremaining third required two injections. No pa-

tient who received full amounts in each injectionrequired more than two injections. The precise

interpretation of this apparently effective controlof convulsions is uncertain, since it is impossibleto say how many patients in an untreated group

TABLE I

Effectiveness of intravenous magnesium sulfate in relievingconvulsions and muscular twitching

Cases receiving magnesium for other causes are notincluded.Group A: Chronic nephritis with convulsions (25 cases)

Complete cessation of convulsions after oneinjection * 17

Complete cessation of convulsions after twoinjections 7

Complete cessation of convulsions after threeinjections t I

In only one of these 25 cases had the patient beengiven magnesium therapy for twitching prior to thedevelopment of convulsions.

Group B: Chronic nephritis without convulsions butwith twitching (9 cases)

"Believed helpful" 5"Believed useless" 3Uncertain 1

In none of these nine cases did actual convulsionsdevelop.

Group C: Acute nephritis with convulsions and subse-quent recovery in children (2 cases)

Convulsions ceased after one injection 1

Single recurrence after one injection 1

Group D: Eclampsia and convulsions (8 cases)Convulsions ceased completely after one in-

jection $ 7Convulsions ceased completely after two in-

jections 1

* In three instances convulsions recurred after a freeinterval of a week or more.

t Convulsions continued during the third injection.The first two injections were half the usual size.

t Of these one died during the infusion and one diedtwelve hours after the infusion.

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of cases would have had more than two sets ofconvulsions. It is our general clinical impressionthat, while convulsions are often single in uremia,cases are not infrequently met with in whichrepeated sets of convulsions occur. If this be so,there are grounds for believing that magnesiumtherapy is effective, since in every instance in ourtreated series convulsions were readily controlled.

More definite is the fact that, consideringgroups A and B together, in only one instanceout of the ten in which preliminary twitchings hadbeen treated with magnesium did convulsionsdevelop. Since twitchings are ordinarily so fre-quently followed by convulsions, it seems almostcertain that this represents a genuine prophylacticaction of magnesium. The effects of magnesiumin stopping the twitching itself are very slight.In no instance was magnesium followed imme-diately by disappearance of the twitching.

Magnesium is apparently effective in controllingthe convulsions in acute nephritis and in eclampsia(Table I, groups C and D). It is difficult to in-terpret these figures, however, since convulsionsare somewhat less apt to be persistently recurrentin cases of this type, and the total number ofcases studied is small.

(C) General clinical improvement

Notes stating that there was a "general clinicalimprovement" are frequently found in connectionwith the eclampsia and acute nephritis cases andare notably absent in the cases with chronicnephritis. This is such a vague expression thatextended discussion is out of place in an attemptat objective evaluation of the results of therapy.Diuresis was but little stimulated; vomiting andmental status were not often affected. A deepnatural sleep sometimes occurred not long afterthe infusion.

(D) Effects on cerebrospinal fluid pressure

It is well known that, whatever may be the casewith the acute nephritis of children, the brains ofadult uremic patients do not regularly show edemaat autopsy (15). Lumbar puncture frequentlyreveals a slightly increased pressure during life,but rarely a markedly increased pressure (16).Of the seven instances in this series in whichlumbar punctures were done, a significantly in-

creased pressure was found in only one, a patientwho proved at autopsy to have a meningioma.In view, however, of Blackfan's suggestion thatintravenous magnesium sulfate might in somemanner achieve its effects by lowering cerebro-spinal fluid pressure, a lumbar puncture needleattached to a manometer was inserted in the spinalcanal just before an infusion of magnesium sul-fate. The patient was a stuporous young womanin the last stages of glomerulonephritis who hadbeen having convulsions shortly before the infu-sion. Before the infusion the cerebrospinal fluidpressure was 260 mm. of water, during the halfhour infusion it was 230 mm., and for some timethereafter it remained at this same level. Evi-dently magnesium sulfate had no significant effecton the cerebrospinal fluid pressure in this case.

(E) Untoward reactions

Some 100 or so injections were given to fifty-three patients, most of whomwere in a pre-mortalstate with advanced renal and cardiac disease.Nevertheless death only occurred once during aninfusion, and this was just after the infusion hadbegun. This patient was desperately ill with anacute eclamptic syndrome, and it is probable thatshe would have died within an hour or so even ifno magnesium sulfate had been given. With thissingle exception no serious ill effects which mighthave been ascribed to the magnesium were noted.4The sudden fall of blood pressure occasionallyappeared alarming but was never followed by anypersistent shock-like state. Even after hypoten-

4Through the courtesy of Dr. Charles Aring we havebeen informed of a fatality immediately following therapid intravenous injection of 30 cc. of 25 per cent mag-nesium sulfate. This patient received in less than aminute as much magnesium as that contained in 375cc. of our 2 per cent solution. Such a rapid injectionproduces a sudden great elevation of magnesium in theserum followed by a rapid fall. The maximal concen-tration attained in serum under these circumstances de-pends as much upon rate of injection as upon the amountinjected, so that it is difficult to control it with anyprecision. In view of the narrow margin between ef-fective and dangerous concentrations, this is a seriousobjection. The occurrence of this fatality emphasizesthe dangers inherent in the rapid intravenous injectionof concentrated solutions of magnesium sulfate. In ourtherapeutic practice we use no greater concentration than2 per cent, and allow at least half an hour for the in-jections of 500 cc.

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sion had been established by the infusion of mag-

nesium sulfate, a convulsion invariably raisedblood pressure, indicating that vasoconstrictormechanisms were still effective and that bloodpressure was not fixed at the low level. Amountssufficient to cause failure of spontaneous respira-tion were never used. Vomiting during the in-fusion occurred twice.

(F) Concentrations in the blood, and excretionIn Table II are presented analyses of serum

for magnesium before and after infusion in nine

subjects. In four of them urinary excretion, andin one excretion in the stools, was studied as

well. The serum concentration immediately fol-lowing the infusion usually ranged from 4 to 10m.eq. per liter, although in two instances a con-

centration of 13.3 m.eq. per liter was found.These high values were associated with slightshallowness and slowing of respiration but no

respiratory failure. Knee jerks, however, were

absent. Patient Number five was comatose beforeand during the infusion; but patient Numbereight was awake and cooperative. Toward the

TABLE II

Magnesium in serum, urine and stools

Magnesium

SerumNum- Diagnosis Date Body Blood _ - - - Urine Volumeber ~~~~~~~~~~weight NPN 24 hours of

Injected After Next after distri-Initial infu- morn- infusion bution

Sion ing

mgm.ccpekgm. per m.eq. m.eq. per liter m.cq. kgm.cexit

(1) Chronic nephritis December 12 60 250 81.3 4.9 8.4* 7.5 36with edema

(2) Eclampsia February 2 50 40 122.1 2.7 5.8*

(3) Chronic nephritis November 15 50 185 37.7 2.4 4.3 2.6 37with edema November 17 2.0 1.0

November 18 to November 21 4.4tNovember 27 200 73.2 2.0 5.4 4.5 1.4 40

November 27 to December 5 3.Ot

(4) Chronic pyelo- February 10 60 113 81.3 1.6 6.6 4.3 25nephritis February 19 129 81.3 2.6 7.1 5.9 28

February 23 173 81.3 4.8 8.9 8.0 31

(5) Chronic nephritis . May 16 52 84 122.0 1.7 7.7 4.4 9.2 36with edema June 21 150 97.6 6.7t 13.3 12.2 26

(6) Chronic nephritis October 21 55 145 81.3 1.8 6.4 30without edema

(7) Chronic nephritis December 16 60 200 81.3 4.3 10.8 19with slight edema December 16 to December 18 7.0§ 7.5

(8) Acute necrotizing December 29 50 50 81.3 2.3 9.8 4.9hypertensive dis- December 30 81.3 ? 11.0 2.8ease December 31 24 81.3 2.8 13.3 3.0 83.0

January 5 81.3 2.5 8.5 2.4January 6 61.0 2.4 8.4 1.9§January 8 81.3 1.9 10.5 2.4§January 10 81.3 2.4 7.7

(9) Chronic nephritis March 4 55 50 81.3 1.5 4.4 2.5without edema

(10) Chronic nephritis May 29 50 45 81.3 2.3 6.7without edema May 30 81.3 8.2

May 31 81.3 8.5

* Six hours after infusion.t Stool magnesium 2.6 and 4.5 m.eq. per 24 hours during these two periods, respectively.$ 64.9 m.eq. of magnesium given during the previous night. § Forty-eight hours later.

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end of the infusion associated with this 13.3value, this second patient became very drowsy andresponded only with difficulty; sensitivity to pain-ful stimuli was also much reduced. These symp-toms disappeared not long after the end of theinfusion. Levels of 4 to 10 m.eq. per liter werenot accompanied by anesthesia, coma, motor paral-yses, absence of deep reflexes, or any subjectivesensation other than the feeling of warmth dur-ing the injection. This confirms the observationsof Peck and Meltzer (4), who found that amountssufficient to raise the concentration to about 15m.eq. per liter (estimated) were necessary toproduce surgical anesthesia in man. It is alsoconsistent with the observations of Neuwirth andWallace (17) and of Hoff, Smith and Winkler(18) that levels in excess of 10 m.eq. per literare necessary to produce neuromuscular blockand evidence of narcosis in dogs.

The rate of decline of the concentration of mag-nesium in the serum of subjects with high bloodNPNvalues is very slow. Thus in the first fivecases of Table II the magnesium concentrationhad usually dropped only a milliequivalent or soby the next morning. This rate of disappearancemeans that an elevated concentration must per-sist for several days. On the other hand, the rateof disappearance from the serum was very rapidin those patients whose renal function was morenearly normal (patients Number eight and Num-ber nine), so that the concentration had virtuallyreturned to normal by the next day. The urinaryexcretion is correspondingly low in the patientswith markedly impaired renal function. Thusonly 8 per cent of the injected magnesium was re-covered from the urine in the twenty-four hoursfollowing the infusion in patient Number five. InCase eight, on the other hand, with a normal NPN,the entire amount injected on December 31 wasrecovered from the urine the next day. Stoolexcretion was not increased following magnesiuminjection (patient Number three), so it must beassumed that the main channel of excretion of in-jected magnesium is the urine, and that in ad-vance nephritis with depressed clearances this ex-cretion is ordinarily much impaired. The impor-tance of renal excretion in the elimination of in-jected magnesium is consistent with the results ofMcCance and Widdowson with normal men (19)

and of Smith, Winkler and Schwartz with dogs(14).

In the last column of Table II are tabulated theapparent volumes of distribution of the injectedmagnesium in cases with renal insufficiency.These values were calculated by the formula (14):

Volume of distribution (per cent of body weight)Amount of Mg injected

xIncrease in concentration of Mg in serum

100 X 0.93

Body weight

This calculation ignores the urinary excretionduring the period of injection, an omission whichis only justified by the low rate of excretion ofmagnesium in patients with renal insufficiency.It cannot be applied to the cases with normal orslightly reduced renal function. The factor 0.93is assumed to be the fraction of water in serum.The results indicate that the immediate apparentvolume of distribution varies between 19 and 40per cent of the body weight and tends to be higherin edematous than in non-edematous subjects.These figures are consistent with those obtained innormal animals and indicate that the greater partof the injected magnesium is, at least at first, con-fined to the extracellular fluid (14).

DISCUSSION

Intravenous magnesium in the amounts given isapparently of some value in preventing and con-trolling the development of convulsions in chronicnephritis. These benefits, such as they are, occurwith amounts of magnesium so small that in ani-mals comparable amounts produce no demonstrabledepression of the nervous system (17, 18). Theydo, however, produce pronounced vasodilatation(20), and in man the same vasodilatation is regu-larly observed. It seems at first sight reasonable,therefore, to ascribe the therapeutic effectivenessof the ion more to this vasodilatation than tonervous system depression. This interpretationis, however, not consistent with the observationthat in many of the cases of chronic nephritis nofall in blood pressure occurred. It is precisely inthe chronic group that beneficial effects were alsoso irregular, in contrast to the much more con-sistent fall in blood pressure with clinical improve-

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ment in the subjects with acute nephritis and ec-lampsia. That some moderate peripheral or cen-tral depression of the nervous system occurred aswell cannot, of course, be excluded. With re-peated injections of magnesium (Table II (5, 8)),the concentrations of magnesium rose above 10m.eq. per liter, and with such concentrations de-pressions of the nervous system are demonstrablein dogs (17, 18). Slow single injections of 500cc. of 2 per cent MgSO4did not raise the serummagnesium to this extent.

The slow excretion of magnesium in the urineof nephritic patients caused a persistent elevationof magnesium in the serum, lasting some hours ordays. This makes repeated doses more effectiveand at the same time more dangerous. Since1000 cc. of 2 per cent MgSO4will raise the mag-nesium concentration to the 10 to 15 m.eq. per literlevel, and since in animals respiratory failure oc-curs at 15 m.eq. per liter, not more than two in-jections of 500 cc. each should be given within aperiod of two or three days. The situation withpatients with eclampsia is not comparable, sincerenal function is usually more nearly normal andrapid elimination of the magnesium from the bloodstream is to be expected.

The concentrations of magnesium attained wereinsufficient to cause respiratory arrest in any in-stance, but in several patients mild depression ofrespiration was observed. In all such cases tendonreflexes had already disappeared. The results ob-tained with animal experiments (18) were thusconfirmed, in that knee jerks disappear at a con-centration of magnesium below that at which re-spiration fails. Practical advantage may be takenof this fact in regulating the amount and rate ofinjection of magnesium in man. So long as theknee jerks are active, there is no need to be con-cerned about respiratory failure, while their disap-pearance is a warming sign.

The return of the blood pressure to its previouslevel in the continued presence of an elevated con-centration of magnesium in serum may only meanthat the concentration, though still greater thannormal, has fallen below the critical level necessaryto overcome vasoconstrictor impulses. During in-travenous injection the rate of diffusion of mag-nesium out of the blood stream into the tissuesmay well be somewhat less than the rate of injec-tion, so that the concentration rises sharply in the

serum. So long as this is in progress a concentra-tion greater than that in tissues and sufficient tolower the blood pressure may be temporarily main-tained in the circulating serum. After the infu-sion is concluded, magnesium in serum will gradu-ally decline until equilibrium with tissue fluids isreached, even if excretion is negligible. Thegreater persistence of hypotension in subjects withrenal impairment than in those without may in partbe due to the more rapid fall of magnesium ofserum in the latter, due to urinary excretion aswell as diffusion. It is also possible that powerfulvasoconstrictor forces may be called into play inorder to antagonize the action of magnesium. Thenature of these hypothetical stimuli is as obscureas the locus of action of magnesium itself. Evenafter a marked hypotension has been induced bymagnesium, any muscular activity of the patientraises the blood pressure sharply. From the easeand rapidity with which the fall of blood pressuremay be reversed, it may reasonably be concludedthat there is no capillary paralysis such as is seenin "shock." It seems reasonable to believe thatthe main site of its action is the arteriole. In thisevent it must be assumed that in the unresponsivesubjects the cutaneous vessels dilate but that thesplanchnic or somatic vessels contract, thus main-taining the blood pressure.

The effects on the cardiovascular system are notentirely comparable to those obtained experiment-ally in normal dogs (20, 21). Both cutaneousvasodilatation and fall in blood pressure are pres-ent in the dog. These follow the injection ofamounts too small to exert any demonstrable effecton the nervous system. The fall in pressure,however, is apt to be gradual in the dog and thesudden collapse seen in normal man was not ob-served. Indeed, the normal dogs behaved morelike the hypertensive patients. The action in dogsis usually transient, but repeated doses are effectiveeach time and there is a tendency for the bloodpressure to remain at a somewhat reduced levelas long as an elevation of magnesium in the serumpersists. This vasodilator effect occurs with aslittle as 3 to 5 m.eq. of magnesium per liter ofserum, whereas motor paralysis and respiratoryarrest do not occur until a level of 10 to 15m.eq. is attained. Significant electrocardiographicchanges also occur during magnesium injection inthe dog, consisting chiefly of progressive pro-

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longation of the PR interval and, finally, brady-cardia and cardiac arrest (21). These changesare, however, barely manifest at lexels below 15m.eq. per liter and can often be demonstrated onlywith the aid of artificial respiration. The slightchanges observed in man are entirely comparablewith those produced in the dog by similar concen-trations of magnesium in the serum.

CONCLUSIONS

1. The slow intravenous injection of 500 cc. of2 per cent magnesium sulfate (MgSO4 X 7 H20)is a safe procedure which is of some value in pre-venting and controlling the convulsive seizures ofchronic nephritis in adults. The benefits are,however, neither certain nor dramatic.

2. If convulsions are not controlled by a singleinjection, they will almost always be checked by asecond injection. After two injections magnesiummay attain such a high concentration in serum thatits depressant effects on the nervous system maybecome manifest.

3. After injection the concentration of mag-nesium may remain elevated for several days inpatients with chronic nephritis because of the re-tarded excretion of magnesium in the urine. Morethan 1000 cc. of 2 per cent magnesium sulfateshould therefore not be given within a forty-eight-hour period in the presence of severe renal insuf-ficiency, lest a concentration sufficient to producerespiratory paralysis be attained.

4. Magnesium in these amounts causes cutane-ous vasodilatation in all subjects. Blood pressureregularly falls in subjects with acute nephritis oreclampsia but is frequently unaffected in thosewith chronic cardiovascular disease.

BIBLIOGRAPHY

1. Meltzer, S. J., Inhibitory properties of magnesiumsulfate and their therapeutic application in tetanus.J. A. M. A., 1916, 66, 931.

2. Blake, J. A., The use of magnesium sulfate in theproduction of anesthesia and in the treatment oftetanus. Surg. Gynec., and Obst., 1906, 2, 541.

3. Meakins, J. C., The Practice of Medicine. Secondedition, C. V. Mosby Co., St. Louis, 1938, p. 1239.

4. Peck, C. H., and Meltzer, S. J., Anesthesia in humanbeings by intravenous injection of magnesium sul-fate. J. A. M. A., 1916, 67, 1131.

5. Beckman, H., The alleged synergism of magnesiumsulphate and morphine. J. A. M. A., 1925, 85, 332.

6. Blackfan, K. D., and Hamilton, B., Uremia in acuteglomerular nephritis. Boston M. and S. J., 1925,193, 617.

7. Blackfan, K. D., and McKhann, C. F., Acuteglomerular nephritis in children. Treatment ofcerebral manifestations. J. A. M. A., 1931, 97,1052.

8. Rubin, M. I., and Rapoport, M., The mode of actionof magnesium sulfate in reducing the hypertensionof acute glomerulonephritis. Am. J. M. Sc., 1941,201, 734.

9. Lazard, E. M., A preliminary report on the intra-venous use of magnesium sulphate in puerperaleclampsia. Am. J. Obst. and Gynec., 1925, 9, 178.

10. Alton, B. H., and Lincoln, G. C., The control ofeclampsia convulsions by intraspinal injections ofmagnesium sulphate. Am. J. Obst. and Gynec.,1925, 9, 167.

11. Lazard, E. M., Irwin, J. C., and Vruwink, J., Theintravenous magnesium sulphate treatment ofeclampsia. A collective report of 142 cases. Am.J. Obst. and Gynec., 1926, 12, 104.

12. Stroganoff, W., and Davidovitch, O., Two hundredcases of eclampsia treated with magnesium sul-phate (MgSO): a preliminary report. J. Obst.and Gynaec. Brit. Emp., 1937, 44, 289.

13. Lazard, E. M, An analysis of 575 cases of eclampsiaand preeclamptic toxemia treated by intravenousinjection of magnesium sulphate. Am. J. Obst.and Gynec., 1933, 26, 647.

14. Smith, P. K, Winkler, A. W., and Schwartz, B. M.,The distribution of magnesium following parenteraladministration of magnesium sulfate. J. Biol.Chem., 1939, 129, 51.

15. Foster, N. B., Uraemia. Harvey Lectures, 1920-1921,p. 52.

16. Merritt, H. H., and Fremont-Smith, F., The Cere-brospinal Fluid. W. B. Saunders, Phila., 1937.

17. Neuwirth, I., and Wallace, G. B., On the use ofmagnesium as an aid in anesthesia. J. Pharmacol.and Exper. Therap., 1929, 35, 171.

18. Hoff, H. E., Smith, P. K, and Winkler, A. W.,Effects of magnesium on the nervous system in re-lation to its concentration in serum. Am. J.Physiol., 1940, 130, 292.

19. McCance, R. A., and Widdowson, E. M., The fate ofcalcium and magnesium after intravenous admin-istration to normal persons. Biochem. J., 1939, 33,523.

20. Hoff, H. E., Smith, P. K., and Winkler, A. W., Therelation of blood pressure and concentration inserum of potassium, calcium and magnesium. Am.J. Physiol., 1939, 127, 722.

21. Smith, P. K, Winlder, A. W., and Hoff, H. E.,Electrocardiographic changes and concentration ofmagnesium in serum following intravenous injec-tion of magnesium salts. Am. J. Physiol., 1939,126, 720.

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