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Jouirnal of Neurology, Neurosurgery, and Psychiatry, 1973, 36, 228-243

Malignant hyperpyrexiaFurther muscle studies in asymptomatic carriers identified

by creatinine phosphokinase screening

HYAM ISAACS AND M. B. BARLOW

From the Department ofPhysiology Medical School and the Department of Aniaesthesiology,Coronation Hospital, Witwatersrand University, Johannesburg, South Africa

SUMMARY The history, clinical presentation, and management of malignant hyperpyrexia are

presented. The aetiology seems to be associated with some inherited abnormality which affects themovement and binding of calcium ions in the sarcoplasmic reticulum, sarcoplasm, and mitochondria.Whether this is a primary muscular defect or secondary to some trophic neural influence is yet to beestablished. The subjects carrying the abnormal trait show evidence of a myopathy which is sub-clinical in most instances and revealed only by estimation of serum CPK or biopsy. In some familieswhere the myopathy is clinically obvious there may be, in addition, a variety of musculoskeletalabnormalities. A plea is made for routine monitoring of temperature during anaesthesia and forprocainamide or procaine to be readily available in all operating theatres. A history of anaestheticdeaths in a family calls for special care, and, if the serum CPK is elevated, suxamethonium and halo-thane are to be avoided. Families with orthopaedic and muscular abnormalities are at increased riskand should have estimation of serum CPK before surgery. As a bonus of this study it is suggestedthat serum CPK estimations be used to screen pigs for selective breeding and so eliminate thedisease, which causes soft exudative pork.

Malignant hyperpyrexia may be defined as a

specific potentially fatal condition which occursin susceptible individuals in response to varioustriggering mechanisms, of which anaestheticagents have been found to be the most commonoffenders. Once initiated, the heat generationwhich is characteristic of this condition soexceeds the capacity of the heat-losing mechan-isms that a continuous rise in body temperatureoccurs and, unless the offending agent is with-drawn at an early stage and treatment started,death will occur in most cases.The syndrome of malignant hyperpyrexia has

been recognized only in the past decade andonly since the publication by Denborough andLovell (1960) who reported on the death of 10members of a particular family who died duringanaesthesia has this condition become widelyreported. Britt. Locher, and Kalow (1970)gathered cases from the literature and added

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these to their own series, thereby accumulatingno less than 170 cases. Since this time, as thesyndrome has become more widely appreciated,many additional cases have appeared in theliterature.One of the earliest reported cases which can be

identified as malignant hyperpyrexia was re-ported by Guedel (1951) in his monograph oninhalation anaesthesia. It is certain that this syn-drome is not new and must have accounted fordeaths occurring during anaesthesia for as longas inhalation anaesthetics have been in use. It isalso difficult to speculate retrospectively aboutmany of the deaths recorded as being due eitherto ether convulsions or to high fever attributed tooverheating in the operating theatres of thattime, but it is likely that some of these wereexamples of malignant hyperpyrexia. To supportthis contention, a typical case history, datingback to 1948 before this syndrome was recog-

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Malignant hyperpyrexia

nized, has been made available to us by Dr. J. F.Riccards of the South Staffordshire MedicalCentre.

'The anaesthetic was given to a 10 year old male andthe operation was for the suture of a left olecranonprocess. Premedication was with atropine 0 01 gr andNembutal 0 7 gr. Anaesthesia was maintained withgas, oxygen, and ether after induction with trileneadministered through a semi-closed Boyle circuit.Death occurred one hour and 45 minutes after com-mencing the anaesthetic and the nature of the symp-toms preceding death are recorded as follows:

" Induction complicated by slight amount ofmucusin respiratory tract. Tensed jaws and pursed lips.Maintenance on 5000 gas and oxygen with 50o ether,total flow 6 litres. Esmarch on limb, and face coveredwith towels. Maintenance difficult owing to mucus

in trachea. Anaesthesia had proceeded for about 10minutes when face was uncovered to display a

moderate degree of cyanosis despite hyperpnoea andrich oxygen intake. Cyanosis cleared on full oxygenbut returned when gas was added to the mixture.General rigidity was commencing at this stage, withlegs and arms in slight flexion and eyeballs deviatedupwards and to the right. The operation was

hurriedly concluded and 100%0 oxygen continued.The colour was now flushed and pink but rigiditywas increasing. The patient felt hot, the rectaltemperature of 108° mounted to over 1100 within a

few minutes. Over the course of the next hourrespiratory function was well maintained but cardiacaction became embarrassed with slowing and soften-ing of the pulse. Colour remained pink until about10 minutes before death. Respiratory function failedquickly and suddenly about five minutes beforedeath."'

The progressive rigidity of the limbs pre-

ceded by the early rigidity of the jaw muscles andsubsequent hyperpyrexia make this a classicalexample of malignant hyperpyrexia. This patientdied in the Casualty Theatre on 8 July 1948. Sostriking was this mode of death that Dr. J. F.Riccards was able to recall this case dating back24 years.There are many reasons why people die during

anaesthesia and malignant hyperpyrexia is butone of these. This complication of anaesthesia isof particular interest and has stimulated a greatdeal of work into the pathogenesis of muscledisease and muscle physiology. Research workersin this field have been most fortunate in thatcertain strains of pigs have been found to

develop malignant hyperpyrexia after exposureto suxamethonium and halothane (Hall, Woolf,Bradley, and Jolley, 1966). The work of Harrison,Biebuyck, Terblance, Dent, Hickman, andSaunders (1968); Harrison, Saunders, Biebuyck,Hickman, Dent, Weaver, and Terblance (1969)on susceptible pigs has made a notable contribu-tion to our understanding of this disease. Theonset of malignant hyperpyrexia in pigs may betriggered off by exertion or by fear, as beforeslaughter, and is known as the porcine stresssyndrome (PSS). This condition is proving aproblem in some countries as malignant hyper-pyrexia produces a high lactic acid contentwhich causes the meat of involved animals tobecome pale, soft, and exudative (PSEP) andgenerally unsatisfactory for consumption. TheScandinavian countries are particularly involved,as the Landrace breed of pig is prevalent there.It is expedient at this stage to make the assump-tion that the disease in pigs and man is the same,though further study may prove that there aresignificant differences in these two species. It isunlikely, however, that such differences would beof prohibitive consequence in the overall under-standing of this reaction.

CLINICAL ASPECTS

In many patients the first indication of impend-ing trouble is a failure of relaxation of the jawmuscles after the administration of suxamethon-ium. Such rigidity is often mistaken as being dueto inadequate suxamethonium dosage and conse-quently the relaxant is unfortunately repeated.The rigidity of the jaw muscles may be so pro-found as to make intubation impossible. Morefrequently the rigidity is mild or absent. The onsetof malignant hyperpyrexia may be insidious onthe one hand and apparently fulminating on theother. The early rise in temperature, however,has been frequently overlooked in the latter. Itmust also be realized that not all patients developmuscular rigidity, so that malignant hyper-pyrexia occurs in two forms, the rigid and thenon-rigid, the latter accounting for about 20%of cases. In the former, the rigidity of the musclesis indistinguishable from the rigidity of rigormortis and in 70%0 of such cases the rigiditymerges with and becomes rigor mortis.The body temperature is perhaps the most

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important clinical aspect of this condition andmay rise within minutes after induction or bedelayed for as long as four hours after commence-ment of anaesthesia and may even occur in therecovery phase after the anaesthetic has ended.The rise in temperature varies from case to casebut may reach 440 C (1120 F) and perhaps evenhigher. The mortality rate correlates very closelywith the level of the pyrexia and where thepyrexia has not been allowed to develop beyond390 C (102° F) the survival has been 100%,whereas at 44° C (1120 F) there have been nosurvivors. As the temperature begins to rise, sotachypnoea occurs and this is noted long beforethe onset of rigidity. Once rigidity occurs theinvolvement of respiratory muscles furtherembarrasses respiration. Tachycardia is an earlymanifestation and pulse rates have been recordedup to 200 per minute. The blood pressure falls,bradycardia and arrythmias may superveneusually associated with hyperkalaemia, reflectingthe characteristic electrocardiographic changes.

Heart failure occurs at this stage and on cessationof cardiac activity the heart is found in a state ofcontraction.As far as the skin is concerned, there is no

constant pattern and cases have been describedas sweating, flushed, pale, vasoconstricted, andmottled.

In the advanced stage of malignant hyper-pyrexia, the nervous system becomes involvedand the pupils may be found to be widely dilatedor unequal and in most cases the patients remainin coma until death.The laboratory findings during the phase of

malignant hyperpyrexia reveal a reduced arterialoxygen tension despite enriched oxygen admini-stration. The arterial CO2 tension is elevated,the arterial blood pH is low, varying between6-6 and 7-4 and the base deficit has varied from-6 to -30 m-equiv/l. The serum potassiumrises and very high levels are recorded beforedeath. The serum phosphorus is usually elevated,while the serum calcium generally falls, par-

KEY

MALE FEMALE

Do1 Serum CreatinePhosphokinese(C.P.K.) normal

C.P.K. females 60 end over

meles S0 end over

Survived malignanthyperpyrexia

Died from malignanthyperpyrexia

* Died of natural causes

FIG. 1. Moses genieration 114.

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ticularly in the rigid variety of malignant hyper-pyrexia in humans. Because of the massivebreakdown during this phase, the serumenzymes such as serum glutamic oxaloacetictransaminase (SGOT), lactic dehydrogenase(LDH), aldolase and creatine phosphokinase(CPK) are found to be elevated. Myoglobinuriais present in varying amounts and adds to thelikelihood of surviving patients developing renalfailure. Haemoglobinuria occurs and defects inblood coagulability have also been noted present-ing a picture of consumptive coagulopathy.

GENETIC ASPECT

The first clear-cut family history relating to thisdisease was reported by Denborough, Forster,Lovell, Maplestone, and Villiers (1962). Britt,et al. (1969) in an extensive study described themode of inheritance of malignant hyperpyrexia,the pattern of inheritance being clearly that of anautosomal dominant abnormality. Direct trans-mission was demonstrated over several genera-tions and affected the sexes to an equal degree.Most of the reported cases have occurred inyoung adults.As we believed that all cases developing

malignant hyperpyrexia did so because of a

IV

|v

genetically-determined predisposition, manifest-ing when the muscles and possibly the liverwere challenged by noxious agents, it wasdecided to reinvestigate a family in whom threehyperpyrexial deaths had occurred within thespace of two years at the Coronation Hospital,Johannesburg.

CASE STUDIES

The clinical examination of these patients wasentirely normal, there being no evidence of muscularweakness or of complaints referable to muscle. Anelectrophysiological study of these patients was un-rewarding, though the motor-unit voltages anddurations were at the lower limits of normal. Therewas no evidence of myotonia or of increased muscu-lar irritability. There was no denervation activity andno increase in polyphasic activity. The motor unitsshowed normal recruitment activity on volition.Nerve conduction studies, both motor and sensory,were carried out on median, ulnar, and medialpopliteal nerves and the results again were withinnormal limits. The myoneural junctions examined byassessing the response to repetitive stimulation werenormal. The number of cases subjected to electro-diagnostic testing was 14, of whom six were malesand eight females. Ages varied from 7 to 50 yearsand all were close relatives of the three cases thatdied of malignant hyperpyrexia.

FIG. 2. Trichaardt generation 112.

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FIG. 3. Degenerating fibre. x 300. FIG. 4. Degenerating fibre. x 750.

It was next decided to examine various serumenzymes of the members of this family in the hope offinding some evidence of muscle abnormality. Thisinvestigation produced startling evidence of diseasein many of the asymptomatic members of this family.At the onset the enzymes estimated included SGOT,lactic dehydrogenase, aldolase, and creatine phospho-kinase. The most reliable index proved to be creatinephosphokinase (CPK), so that after a pilot surveythe serum estimations were confined to this oneenzyme. Over 10 cases (Isaacs and Barlow, 1 970a, b;Barlow and Isaacs, 1971; Isaacs and Barlow, 1971)were examined and the study extended over fourgenerations. The CPK abnormality was found to beinherited as a Mendelian dominant and was con-siderably elevated in many members and it waspostulated that the elevated CPK reflected a sub-clinical myopathy. Figures 1 and 2 illustrate examplesof such inheritance. Occasional examples of failureof expression were noted, which is not an unusualfinding for an autosomal dominant abnormality.

Metabolic studies were carried out on 10 of thepatients with the highest levels of CPK. The serumelectrolytes and urea were normal, full blood count,and erythrocyte sedimentation rates were normal.Serum calcium, phosphorus, blood sugar, cholesterol,uric acid, alkaline phosphatase, and protein-boundiodine estimations were normal. Protein electro-phoretic patterns were normal. Urine analysisrevealed no evidence of sugar or albumin, nor wasthere any indication of aminoaciduria. Porphyrinswere not present in excess.

After this study, the value of CPK estimationsin members of susceptible families was confirmedby Denborough, Ebeling, King, and Zapf (1970),who also found clinical evidence of myopathy.Kyei-Mensah, Lockwood, Tyrrell, and Willett(1970) published details of a family in whomdeaths from malignant hyperpyrexia had occur-red and further confirmed the value of CPK

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FIG. 5. Degenerating fibre with marked lymphocyticinfiltration. x 750.

FIG. 8 NAD diaphoras stain. Dark staining oftype I fibres x 75

G.6. Group of atrophic fibres. x 250FIG.*7.Groupof-atrof...i.re..x.. 2

FIG. 6. Group of atrophic fibr-es. x 250.

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FIG. 7. Group of atrophic fibres. x 250.



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|- pigs could be selected for breeding purposeswith the object of ultimately breeding out thesusceptible strain, with enormous saving to the

4 meat industry.

MUSCLE HISTOLOGY AND HISTOCHEMISTRY Asympto-matic members of the Coronation (Isaacs andBarlow, 1971) family with and without high enzymeactivity have been subjected to muscle biopsy for

_l | l ||histological and histochemical study. The musclewas removed under local anaesthesia and in all casesthe posterior fibres of the deltoid on the non-dominant side were studied. After removal, themuscle was maintained at its resting length by meansof ties at each end being stretched over woodenspatulas. The tissue was then covered with gauzesoaked in saline for 20 minutes. The muscle wassubsequently orientated on pieces of cork andsecured with gum tragacanth for both transverse andlongitudinal sectioning. The specimen was thenfrozen in isobutane which was in turn cooled by

FIG. 9. EDTA ATPase reversal stain, showing darkstaining type I fibres. x 75.

estimations. Steers, Tallack, and Thompson(1970) described a susceptible family who, in.addition', were suffering from a myopathy similarto that described by Barnes. They also showed ..d;.............

elevated blood CPK levels. We have investigatedtwo other families in which malignant hyper-

... 2 t | : ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.... ..

pyrexial deaths have occurred and have founda..

.....................'" ,. .

similar pattern of high CPK activity occurring ..-over several generations. Exact data on the genefrequency of this CPK abnormality is not as yetavailable. The frequency of the malignant hyperpyrexial reaction under anaesthesia has beenplaced at 1/14,000 by Britt and Kalow (1970)XA correlation between high CPK andsusn

ceptibility to malignant hyperpyrexia has beenconfirmed by Berman, du Toit, and Kench (1971)in Landrace pigs and by Jones (1971) for Poland-China swine. This could be a most valuable FIG. 10. Phosphorylase stain, showing dark stainingcorrelation as it indicates a method by which type IIfibres. x 300.

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KEY

MALE FEMALE

Serum CreaiinePhosphokinass

(C.P.K.) normal

C.P.K. females 60 and over

males 80 and over

Survived malignanthyperpyroxia

Died from malignanthyperpyrexia

Died of natural causes

III

Muscular skeletal

abnormalities

FIG. 11. Ludik family.

liquid nitrogen. Sections were cut to a thickness of10 ,u on a cryostat at - 250 C. These sections were

subjected to routine haematoxylin and eosin (H andE), and a modified trichrome stain (Engel andCunningham, 1963). The histochemical study inclu-ded phosphorylase (Takeuchi and Kuriaki, 1955),ATPase (Padykula and Herman, 1955), EDTAATPase (Drews and Engel, 1966), succinic dehydro-genase (Pearse, 1957), and NAD diaphorase(Scarpelli, Hess, and Pearse, 1958). Modifications tothe ATPase and EDTA ATPase were carried outaccording to Dubowitz (1971).

Muscle from asymptomatic carriers with high CPKactivity showed evidence of destruction of singlemuscle fibres (Figs 3 and 4). In most sections theabnormal muscle fibres were scattered apparently atrandom and in some areas there was evidence ofconsiderable cellular infiltrate (Fig. 5). In one casethe pattern of degeneration of the muscle fibres wasgrouped in a manner highly suggestive of primaryneuronal pathology (Figs 6 and 7).The histochemical study revealed areas of excess-

ive grouping of individual fibre types but for themost part the staining reactions were normal (Figs 8,9, 10). The glycogen content was normal and therewas no evidence of nemaline rod formation. Themuscle of the uninvolved members of the family washistologically normal.

ASSOCIATION WITH MUSCULOSKELETALABNORMALITIES

The overall incidence of malignant hyperpyrexiawould at first appear to be higher in cases whohave undergone minor orthopaedic proceduresbut, on closer scrutiny of the cases involved, it isobvious that there are large families afflictedwith the predisposition to develop malignanthyperpyrexia who have no increase in musculo-skeletal abnormalities, as in the family of Brittet al. (1969) and the family of Isaacs and Barlow(1971). In some other families there is a highincidence of musculoskeletal abnormality and in

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2Hyam Isaacs and M. B. Barlowv

these families there appears to be some linkbetween the inheritance of the musculoskeletaldisorder and the trait for malignant hyper-pyrexia. The musculoskeletal abnormality can-not be used as a marker for malignant hyper-pyrexia, as some members of these families with-out the musculoskeletal abnormalities showelevated levels ofCPK (Isaacs and Barlow, 1971).Such a dissociation has been found in a familyunder investigation at present (Fig. 11), wherethe common musculoskeletal abnormalities areptosis, high arched palates, and dislocatedpatellae. The commoner musculoskeletal dis-orders which have been associated with malig-nant hyperpyrexia are ptosis, strabismus, dis-located patellae, dislocated shoulder, kyphosco-liosis, high arched palate, and various types ofhernias (Britt and Kalow, 1970).

TREATMENT

The most important aspect of treatment dependson the awareness of the disorder and thus acontinuous recording of the temperature duringanaesthesia. Any rise in temperature above37-8° C (100° F) calls for an urgent end to theanaesthetic. The patient must be cooled byapplying ice externally and, if available, icewater can be applied internally, either rectally orintraperitoneally. The Wangensteen gastric cool-ing apparatus was effectively used by Ryan andPapper (1970). Care must be taken, however, tosee that the patients are not cooled excessively,as hypothermia creates additional problems.The hypoxia is treated by hyperventilation with100% oxygen. Sodium bicarbonate is givenintravenously to combat the acidosis butexcessive administration must be avoided. Aclose watch must be kept on the serum potas-sium, which may rise to dangerous levels beforetreatment and may rapidly fall to low levels withtreatment. Intravenous calcium chloride hasbeen of benefit in a few cases in correcting thebradycardia (Hogg and Renwick, 1966), butthis is best avoided until the more specific therapyoutlined below has been given. The bloodvolume must be maintained by means of fluidreplacement. Pressor agents are best avoided, ifpossible, as there is theoretical evidence that theymay aggravate the heat-producing state (Keaney

and Ellis, 1971). This objection does not applyonce procainamide or procaine has beenadministered. Frusemide and/or mannitol maybe used to maintain adequate production ofurine. There does not seem to be any place forthe use of anticoagulants or cardiac glycosides-in fact, this latter group of drugs may be harmful.The most important aspect of therapy, how-

ever, apart from immediate cessation of theanaesthetic and cooling, is the administration ofintravenous procainamide (Kalow, Britt, Ter-reau, and Haist, 1970; Beldavs, Small, Cooper,and Britt, 1971). Katz (1970) used lignocainesuccessfully in one case but there is experimentalevidence suggesting that this substance shouldnot be used (Strobel and Bianchi, 1971). Afterthese publications, Harrison (1971) found thatintravenous procaine could abort the hyper-pyrexial reactions in pigs. Procaine offers, there-fore, an alternative to procainamide andHarrison suggests the following dosage: a load-ing dose of 30-40 mg/kg intravenously followedby an intravenous infusion of 0X2 mg/kg/minuntil the muscle rigor relaxes. With this regime,isoprenaline has been necessary to maintain theblood pressure and, of course, electrocardio-graphic monitoring is a standard procedure. It ispossible that a much smaller dose will prove tobe equally effective and so avoid the severehypotensive effect.

LATE PHASE The phase of late treatment corre-sponds with the time when the temperature hasbeen brought down to normal with a return ofrespiratory and cardiovascular functions tonormal. At this stage, electrolyte disturbancesmust be watched and corrected, with particularattention to the serum potassium which may fallprecipitously.A close watch must be kept on the renal out-

put, as oliguria and renal failure may develop. Itmay be necessary to control the renal failure bymeans of haemodialysis until renal functionrecovers.

Because of the intense muscular wasting andweakness which follows recovery from malignanthyperpyrexia, prolonged rehabilitation by wayof physiotherapy, employing splintage, passivemovements, and later active exercise is mostimportant.

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Maligniant hyperpyrexia

DISCUSSION

There are several interesting aspects of muscledisease that emerge from the study of malignanthyperpyrexia.

It is our opinion that malignant hyperpyrexiais always associated with a myopathic process,usually subclinical, as revealed by CPK studies(Isaacs and Barlow, 1970a). Furthermore, wehave now shown that the muscle of susceptiblemembers of the family reported by us (Isaacsand Barlow, 1971) may be histologically ab-normal. The histological examination of musclefrom a known carrier whose CPK was normalvas found to be abnormal (Fig. 7). Beforeobtaining this histological evidence, we had con-sidered this case to be an example of suppressedexpressivity of the disorder but it is now obviousthat either the myopathic lesions are too few atany one time to produce a rise in serum CPK orthere must be modifying factors in this patientwhich have prevented a rise in serum CPK,though the myopathy exists. It remains to beseen whether the normal serum CPK indicates alessened susceptibility to develop malignanthyperpyrexia. Such modification may also beplaying some part in determining the relativerarity of malignant hyperpyrexia in the elderly.

Further evidence of myopathy in familiesprone to develop malignant hyperpyrexia hasbeen published by Denborough et al. (1970). Inaddition to their confirmation of the value ofCPK in carrier detection, they found clinicalevidence of myopathy. Steers et al. (1970) foundevidence of a myopathy in their susceptiblefamily similar to that described by Barnes(1932). King, Denborough, and Zapf (1972)have suggested that susceptible individuals mayshow one of a number of specific myopathiesconsisting of a group with a dominantly inheritedmyopathy, a group who have myotonia con-

genita, and a third group with physical abnor-malities and a progressive congenital myopathy.The second group implicating myotonia con-genita with malignant hyperpyrexia will requiresubstantiation as 45 patients with myotoniadystrophica and 11 patients with myotoniacongenita, studied retrospectively by one of us(H.I.), were found to have survived a total of 68general anaesthetics and there was no history ofhyperpyrexial deaths in their families.

LaCour, Juul-Jensen, and Reske-Nielsen (1971)suggested that the myopathic changes found intheir cases were secondary to both central andperipheral neurological disease. Their biopsiesrevealed evidence of degeneration and regenera-tion in motor nerves which also showed evi-dence of excessive sprouting and an increasednumber of endplates. The pattern of atrophyseen in Figs 7 and 8 from a known carrier of thisdisease lends support to this concept.

After the application of CPK screening inman, elevated CPK levels were found in sus-ceptible pigs by Berman et al. (1971) and Jones(1971). Harrison et al. (1969) have shown thatthe muscle of susceptible Landrace pigs showsan abnormal fall in the level of ATP on exposureto halothane vapour. Venable (1971) has shownelectron microscopic evidence of myopathy insusceptible strains of Poland-China pigs in theapyrexial state. The abnormalities varied fromdistorted myofibrillar patterns to areas of frankdegeneration. The combined evidence of enzyme,biochemical, and microscopic abnormalitiesindicates that an underlying myopathy is activein susceptible pigs as well.

In considering the aetiology of malignanthyperpyrexia, the basis of the abnormal heatproduction is all important. A central neuro-logically mediated cause for the rise in tempera-ture does not have much support, as the heat-regulating mechanisms appear to be intact untilan advanced and sometimes preterminal stagehas been reached. Sweating, vasodilatation, andtachypnoea occur as the temperature rises but, asthe overall heat production in this disease farexceeds that of normal physiological heat pro-duction, the processes of heat dissipation areinadequate. Hyperthermia of central neurologicalorigin would not give rise to the extreme hyper-kalaemia and metabolic acidosis that occurfairly early in this disease.That the muscle tissue is ultimately inde-

pendent of the nervous system in this process ofabnormal production of heat is exemplified byone of the cases dying of malignant hyper-pyrexia at the Coronation Hospital. The patientwas undergoing surgery to the lower limb andbefore the injection of suxamethonium a tourni-quet had been applied to this limb. This occlusionof perfusion caused the limb to remain flaccid asthough it were protected from the noxious

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effects of the suxamethonium and subsequenthalothane inhalation. The rest of the bodybecame rigid and contributed to the enormousheat production. Though the site of heat produc-tion in malignant hyperpyrexia is largely frommuscle and independent ofneurological influence,one cannot exclude some prior predisposing ormodifying effect that the nervous system mayhave produced in the muscle.

Agents which block neuromuscular trans-mission do not protect the muscle from malig-nant hyperpyrexia nor do they alleviate thecondition once established. Harrison (1971) hasfound that the prior administration of curareprevents the triggering action of succinylcholinebut does not block the effects of halothane insusceptible Landrace pigs.Theye (1970) has shown that dogs anaes-

thetized with halothane show an increasedoxygen consumption after the administration ofsuccinylcholine to the extent of 5060% in thefirst 20 minutes. After this period an increasedoxygen consumption of 20% above normal ismaintained. The initial massive increase wasshown to be due to end-plate generation ofaction potentials causing contraction of themuscle fibres; the sustained increase results froman altered energy requirement of the muscleitself. The sustained increased heat productionis subsequent to the entry of succinylcholine intothe muscle cell and this altered oxygen consump-tion is not influenced by blocking agents. Theinitial massive fasciculation which suxamethon-ium administration induces may be damaging tothe muscle and Kalow (1971) considers that themass release of potassium after this depolariza-tion is indicative of damage to the sarcolemma.Tammisto and Airaksinen (1966) have shownincreases in serum levels of CPK after adminis-tration of suxamethonium. The increased heatproduction as seen in dogs and outlined abovedoes not account for the heat of malignanthyperpyrexia.

There are similarities between the rigidity ofthe muscle in malignant hyperpyrexia and experi-mentally produced muscle contractures. Malig-nant hyperpyrexia occurs in humans as alreadystated in two forms; the common form accountsfor about 80% of the cases and is associatedwith muscular rigidity, the remaining casesshowing no evidence of alteration in muscle tone.

When halothane and dinitrophenol are ad-ministered to dogs they develop a state of muscu-lar rigidity associated with excessive heat pro-duction. It has been stated that the heat produc-tion in these circumstances is due to uncouplingof oxidative phosphorylation (Wilson, Nicols,Dent, and Allen, 1966; Gatz, Hull, Bennett, andJones, 1970). Uncoupling of oxidative phos-phorylation alone, however, does not seem tooffer the entire explanation for the heat produc-tion in malignant hyperpyrexia (Wang, Moffitt,and Rosevear, 1969), and increased or acceleratedglycolysis (anaerobic metabolism) would benecessary to ensure an effective source for therephosphorylation of ATP (Britt and Kalow,1970). Britt and Kalow (1967) showed that halo-thane did not increase the dinitrophenol con-tracture in rats and rabbits, nor in the case ofchickens (Viguera and Conn, 1967). 2,4-dinitro-phenol blocks the second and third ATP forma-tion of the respiratory chain of the mitochondria,while halothane tends to inhibit the first ATPformation according to Miller and Hunter (1971)and, as such, is not considered a true uncouplingagent. Halothane is an anaesthetic with a mildpositive charge and so tends to reduce themembrane permeability to calcium and sodiumbut it has the effect of displacing the calciumwhich is bound to the cell membrane and sarco-plasmic reticulum. It is, nevertheless, reasonableto accept that the greatest source of heat inmalignant hyperpyrexia is produced by un-coupling of oxidative phosphorylation. Suchenergy release, as shown by Williams (1971), canbe achieved by cations such as calcium which areable to penetrate the mitochondrial membraneas calcium or as lipid soluble complexes whichmove into the mitochondria and disrupt thechemo-osmotic potential. This situation in turndisturbs the proton gradients disrupting theequilibrium of the primary energy conservationsystems of the mitochondria. Halothane has, inaddition, a direct though non-specific effect uponthe mitochondrial membrane, affecting the lipidphase, and in this way may pave the way forother substances, again, possibly calcium, toinitiate the uncoupling process.Apart from the contracture and heat produc-

tion which is associated with poisoning bydinitrophenol, additional and vital informationhas been obtained by comparing the rigid form

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of malignant hyperpyrexia with caffeine-inducedrigor. Caffeine contracture of muscle in vitro hasbeen well documented by Sandow (1970) whowas able to show that this contracture occurs inconsequence of the release of calcium into thesarcoplasm, thereby initiating ATPase activity.Weber and Hirtz (1968) claimed that the in-creased sarcoplasmic concentration was achievedby the release of calcium from the sarcoplasmicreticulum, while Weber (1968) correlated theevents with an uncoupling of sarcoplasmicreticulum ATPase activity effecting the re-

accumulation of calcium.From all the evidence available there can be no

doubt that the sarcoplasmic reticulum is in-volved in malignant hyperpyrexia. The calciumis released from this site after depolarization ofthe cell membrane and T-tubules and it formspart of the excitation-contraction couplingmechanism. The sarcoplasmic reticulum, byvirtue of its ability to regulate the release ofcalcium into the sarcoplasm, exerts metaboliccontrol over muscular contraction directly andthereby indirectly over glycogenolysis, ATPformation, and heat production. The sarco-

plasmic reticulum has been analysed by Mac-Lennan (1971) who has found two proteinswhich appear to be involved in calcium transpor-tation. One is ATPase, its activity dependingupon magnesium and ATP concentration as wellas calcium concentration. The second is a solubleprotein called calciquestrin which he extractedfrom the sarcoplasmic reticulum and showed tobe capable of binding up to 43 moles of calciumper mole. Once in the sarcoplasm, calciuminteracts with troponin complex, which in therelaxed state is bound to the actin filaments, andfrees binding sites which then cross-bridge withmyosin and set in action the sliding contractionprocess. Reaccumulation of calcium by thesarcoplasmic reticulum results in relaxation anda return to the resting state.

Britt and Kalow (1970) were the first to suggestthat, as a result of various anaesthetic substances,the sarcoplasmic reticulum was unable to re-

accumulate the calcium from the sarcoplasm. Inorder to test this hypothesis, Kalow et al. (1970)decided to test the susceptibility of humanmuscle to caffeine contracture and examinedmuscle taken from three volunteers who hadsurvived a malignant hyperpyrexial reaction.

The isolated muscle was mounted so that iso-metric tension could be measured while themuscle was bathed in a solution resemblinghuman plasma. The muscle was electricallystimulated and the responses to caffeine andhalothane administration were noted. Musclestrips of two of the three patients who had pre-viously developed the rigid form of malignanthyperpyrexia showed increased susceptibility todevelop caffeine contracture when comparedwith normal controls. This increased suscepti-bility was enhanced by halothane. They were alsoable to show that the accumulation of calcium bythe sarcoplasmic reticulum was lowered by theadministration of 500 halothane in two of thesusceptible cases, while it remained normal inthe controls. These results are in keeping withearlier work of Sabawala and Dillon (1968) whodemonstrated that halothane was able to enhancethe twitch response in human muscle after directstimulation, suggesting that halothane may havesimilar action to caffeine and act by blocking thereturn of calcium to the sarcoplasmic reticulum.The failure to demonstrate halothane-inducedcontracture in the one specimen of susceptiblemuscle by Kalow et al. (1970) may be due to thefact that their experiment was carried out atphysiological temperatures, as suggested byKeaney and Ellis (1971). Ellis, Harriman,Keaney, Kyei-Mensah, and Tyrrell (1971) havebeen able to demonstrate that halothane iscapable of inducing a reversible contracture insusceptible muscle. Strobel and Bianchi (1971)produced contracture in isolated frog sartoriusmuscle by administering halothane to the musclewhich had been previously exposed to caffeine.This action of halothane, as pointed out byKalow, is similar to the effect seen after theadministration of ether which was demonstratedby Fiehn and Hasselbach (1969).Kalow et al. (1970) conclude that malignant

hyperpyrexia with rigidity is caused by an inbornmetabolic error in skeletal muscle which rendersthe muscle susceptible to disturbances of intra-cellular calcium distribution. They further sug-gest that malignant hyperpyrexia without rigidityis a different disease and that both are inheritedas autosomal dominant abnormalities and bothare equally lethal. This opinion, however, is notacceptable to us as we find it difficult to reconcilethe fact that both forms of malignant hyper-

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pyrexia have occurred in the same family and weprefer to regard both forms as a manifestationof the same basic underlying abnormality whichis modified by sarcoplasmic, mitochondrial, orother factors as yet unknown which presumablywould alter the intracellular environment in aparticular direction at that particular time.Animal experimentation to the present time hasnot given any indication as to what the differencemay be as only the rigid form occurs.

Little is known of the way caffeine exerts itseffect on sarcoplasmic reticulum but in recentyears a few points of importance have emerged.Caffeine is capable of blocking phosphodiester-ase, the degradation pathway for cyclic adeno-sine mono-phosphate (AMP) resulting in in-creased concentrations of intracellular cyclicAMP (Rasmussen, 1970; Sutherland, 1970). Forthis reason, an objection was raised to the use ofisoprenaline and related pressor substances as aform of therapy for hypotension during malig-nant hyperpyrexia, as these substances increasecyclic AMP by their stimulatory action onadenylcyclase. Increased concentration of thecyclic AMP has been proposed as a basis for thegeneration of the heat process in malignanthyperpyrexia by Pollock and Watson (1971).Harrison et al. (1969), however, infused 1: 100,000adrenalin into a susceptible pig without trigger-ing a hyperpyrexial reaction. Other drugs such asamine-oxidase inhibitors and imipramine act bystimulating adenylcyclase and blocking phospho-diesterase respectively (Abdulla and Hamadah,1970). The net result is an increase in intracellularcyclic AMP and both drugs have been known toproduce hyperpyrexial syndromes. It would betempting to group all these hyperpyrexial syn-dromes together but there is insufficient evidencefor this and it must yet be shown that patientswith non-anaesthetic reactions belong to familieswith either a clinical history or biological evi-dence of malignant hyperpyrexia. Patients withdifferent hypermetabolic states such as hyper-thyroidism, the hypermetabolic syndrome ofLuft, Ikkos, Palmieri, Ernster, and Afzelius(1962), osteogenesis imperfecta (Aldrete, Pad-field, Solomon, and Rubright, 1971) and the syn-drome of continuous muscle-fibre activity(Isaacs, 1961) have shown no predisposition todevelop malignant hyperpyrexia. Neither havepatients with megaconial or pleoconial muscle

mitochondrial abnormality (Shy, Gonatas, andPerez, 1966) or with abnormal lipid storage andabnormal mitochondria (Bradley, Hudgson,Gardner-Medwin, and Walton, 1969; Isaacs,1972) shown any such tendency. Cases withDuchenne type muscular dystrophy have beenshown to have abnormalities in the sarcoplasmicreticulum by Samaha and Gergely (1969) butthese patients are not prone to develop malignanthyperpyrexia. All this evidence tends to indicatethe rather specific nature of the sarcoplasmicreticulum abnormality in malignant hyper-pyrexia. A febrile state that warrants close studywith the possibility of correlation with malignanthyperpyrexia is the liver necrosis and unexplainedfever after halothane administration (Sharp-stone, Medley, and Williams, 1971).The correlation of malignant hyperpyrexia

with caffeine contracture has had far-reachingbenefits in that it opened the way for a mostimportant therapeutic approach. As far back as1963 Feinstein was able to show that the rigorinduced by caffeine could be blocked by theadministration of procaine. Weber and Hirtz(1968) recorded that procaine in vitro could blockthe onset of caffeine rigor and was also capableof reversing the early effects of caffeine rigor ifadministered at this stage. Katz (1970) adminis-tered lignocaine to a case of malignant hyper-pyrexia in an attempt to correct a cardiacarrythmia and noted a dramatic drop in tempera-ture. An equally dramatic response was obtainedby Kalow et al. (1970) in a case where procain-amide was given in a total dose of 1,100 mg.This case has been written up in great detail byBeldavs et al. (1971). These dramatic responsesled Strobel and Bianchi (1971) to examine themerits of both lignocaine and procainamide inthe prevention of caffeine contracture in the frogsartorius muscle. They found that procainamidehad a blocking action, while lignocaine stimula-ted the caffeine responses. These findings were inkeeping with the work of Bianchi and Bolton(1967) and Bianchi (1968).

Harrison (1971), following on the successof Katz (1970) and Kalow et al. (1970) withlignocaine and procainamide respectively, usedprocaine in susceptible Landrace pigs. Notonly was procaine found useful in protecting themuscle from malignant hyperpyrexia induced byhalothane and succinylcholine but it also helped

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Malignianit hyperpyrexia

to reverse the fully established syndrome,enabling two out of five pigs to survive. Ellis etal. (1971) were able to show that procainehydrochloride was able to prevent and reverse

the halothane-induced muscle contracture insusceptible muscle strips.Though it seems likely that an effective therapy

has become available in the form of procain-amide or procaine this should not be taken as an

indication to relax vigilance with regard toprophylaxis. Careful interrogation of the patientwith regard to anaesthetic deaths in the family isof paramount importance. The fact that a

patient with such a history has had a previousuneventful anaesthetic is no safeguard and infact may sensitize the patient in some way tosubsequent anaesthetic challenge. Several testswhich may point to susceptibility are availableand the most widely used is the serum creatinephosphokinase (Isaacs and Barlow, 1970a).Aldrete et al. (1971) have shown that estimationsof serum pyrophosphate are equally reliable.Subjects who carry the abnormal trait, with fewexceptions, show an elevation of the serum CPKand it seems logical to correlate the degree ofsusceptibility with the height of the CPK, thougha normal or only slightly elevated serum CPKshould not lull the anaesthetist into a false sense

of security.If serum creatine phosphokinase is used as a

general screening test there will be some falsepositives, as several otherwise normal membersof the population who give no family history ofmuscular dystrophy or malignant hyperpyrexiawill be found to have elevated levels which may

reflect some other unrelated non-specific defect(Emery and Spikesman, 1970). However, we

would suggest that these cases remain suspectand should not be challenged with drugs or

anaesthetics without caution. If need be, musclehistology per se, as shown in this paper, or

exposure of muscle strips to halothane (Harrisonet al., 1969) or halothane and caffeine (Kalow etal., 1970) as described could presumably solvethe problem.

Our thanks are due to both Mr. A. Sherwitz andMiss J. Walker and the photographic department ofthe Department of Medicine for the photographs.This work was made possible by research grantsfrom the Medical Research Council, I.C.I. South

Africa and the Muscular Dystrophy section ofCripple Care South Africa. Particular thanks go toDr. E. H. Murcott of I.C.I. Miss J. Frere, seniortechnician, is thanked for her untiring work indeveloping the histochemistry unit. We thank theeditor of the British Journal of Anaesthesia forpermission to reproduce Figs 1 and 2.

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