659

Hypothesis

SALT LOADING AS A POSSIBLE FACTOR

IN THE PRODUCTION OF

POTASSIUM DEPLETION, RHABDOMYOLYSIS,AND HEAT INJURY

Summary The benefits of supplementary salt inunacclimatised people performing physical

labour in humid heat are well known: without suitable

quantities of salt and water there is a risk of hypertonicdehydration and cardiovascular collapse. Features of

potassium depletion, including hypokalæmia, pitressin-resistant polyuria, and possibly rhabdomyolysis, occur ina number of young men with heat injury. Those whoseem to constitute a high-risk group are military recruitsor football players undergoing training or conditioning inthe summer months. Acclimatisation to heat is accom-

panied by increased aldosterone excretion and an expandedextracellular fluid space. Since salt loading may notsuppress aldosterone production in the heat-acclimatisingindividual, salt loading may well lead to serious potassiumdepletion. The widespread practice of vigorous salt

supplementation in military and athletic training pro-grammes may thus induce significant potassium losses inthese individuals. Evidence is presented which suggeststhat potassium depletion may constitute an importantfactor in the production of certain forms of injury observedin those undergoing strenuous exertion in hot climates.

INTRODUCTION

ACCLIMATISATION to heat may be accompanied bypotassium depletion 1; but whether such depletion has abearing on the subsequent development of heat stroke orother forms of serious heat injury cannot be answeredcategorically at present. But there is evidence that a dis-turbance of potassium metabolism is indeed an associated,and perhaps related, finding in many, if not all, victims ofheat stroke. We have examined the evidence that

potassium depletion is not merely associated with, but mayactually play a role in the development of heat injury andperhaps certain of its complications.

A TYPICAL CASE

We are not concerned with the type of heat illness seenin the elderly, retired gentleman living in an air-condi-tioned apartment who might develop a fever greater than106°F (41°C), anhydrosis, and coma after a single day’sexposure to extreme heat and humidity. Since such a manwould hardly have had time to develop significant deple-tion of body potassium, this factor cannot be the funda-mental cause of heat stroke per se, although experimentalevidence 2 suggests that disturbances of intracellular

potassium concentration may occur even with acute

thermal injury. We are mainly concerned with the young,strong person in good health, who has been subjected tosevere physical stress under hot, often humid conditions,and who is well fed, well hydrated, and has sufficient salt.Typically, after several days of activity, his appetitebecomes poor, he complains of weakness and fatigability,and may appear briefly to have a psychiatric illness withbizarre, inappropriate behaviour. At this stage, there maybe slight fever but also sweating may cease and frank1. Knochel, J. P., Beisel, W. R., Herndon, E. G., Jr, Gerard, E. S.

Barry, K. G. Am. J. Med. 1961, 30, 299.2. Benjamin, F. B., Anastasi, J. N., Helvey, W. M. Proc. Soc. exp. Biol.

Med. 1961, 107, 972.3. Burger, F. J., Fuhrman, F. A. Am. J. Physiol. 1961, 206, 1057.

hyperpyrexia may develop. Thus, a stage of heatacclimatisation can merge into one of heat exhaustion orprogress to frank heat stroke. In this setting, heat strokeis complicated by disturbances of body water and electro-lytes. For this reason, the term heat injury has beensubstituted for heat exhaustion and heat stroke since thistype of patient has features of both disorders.

POTASSIUM DEPLETION

Hypokalasmia occurs very commonly in heat stroke 1 4-6 andmay reflect actual potassium depletion or result from an intra-cellular shift of potassium in response to respiratory alkalosis. 7

lampietro has shown that some healthy individuals developparaesthesias and frank tetany upon exposure to heat and thatthese events can be correlated with a rapid rise of blood pH asa result of hyperventilation. Hyperventilation, paraesthesias,and tetany may also develop as a prodrome of severe clinicalheat injury.On the other hand, there is strong evidence that hypokalaemia

in acute heat stroke is explainable by frank potassium depletion.Ladell examined a group of British soldiers during prolongedexposure to extreme heat and found that as a severe form ofheat exhaustion developed-a significant number of those menbecame weak, easily fatigued, anorectic, anhydrotic, and poly-uric. Daily urine volumes of up to 8 litres were recorded and,significantly, injections of pituitrin did not influence the

polyuria. Although Ladell 9 suggested that polyuria of thisdegree was a physiological necessity in the face of a continuedhigh fluid intake and anhydrosis, Edholm 10 described similarpatients who excreted as much as 10 litres of urine daily in theabsence of anhydrosis. These features, especially the pitressin-resistant polyuria, although not diagnostic, suggested the

presence of potassium depletion and kaliopenic nephropathy. 1

Stronger support for this hypothesis was provided by Sobelet al.ll who described antecedent polyuria and hypokala:mia atthe onset of heat stroke in several of fourteen patients withheat stroke. Renal biopsy showed that vacuolation of tubularepithelium was a frequent change. This alteration correlatedwell with low serum-potassium levels and was considered to becharacteristic of kaliopenic nephropathy.Coburn and Reba 12 have measured exchangeable body

potassium in a patient with heat stroke and renal failure andfound it to be significantly depressed, but in another study 13

they showed that of four unacclimatised subjects only oneresponded abnormally to acute heat stress while modestlydepleted of potassium. Gordon and Andrews 14 have demon-strated that potassium depletion does occur during artificialacclimatisation in a heat chamber.

MECHANISM OF POTASSIUM LOSS

If potassium depletion is implicated in this disorder,then a mechanism by which potassium is lost in excess ofintake must be demonstrable. Several workers 15-18 haveshown that the adrenal cortex participates in heatacclimatisation by increasing secretion of aldosterone.Increased sweating and cutaneous losses of sodium duringearly acclimatisation result in contraction of extracellular4. Ferris, E. B., Jr, Blankenhorn, M. A., Robinson, H. W., Cullen, G. E.

J. clin. Invest. 1938, 17, 249.5. Austin, M. G., Berry, J. W. J. Am. med. Ass. 1956, 161, 1525.6. Baxter, C. R., Teschan, P. E. Archs intern. Med. 1958, 101, 1040.7. Burnell, J. M., Villamil, M. F., Uyeno, B. T., Scribner, B. H. J. clin.

Invest. 1956, 35, 935.8. Iampietro, P. F. Fedn Proc. Fedn Am. Socs exp. Biol. 1963, 22, 884.9. Ladell, W. S. S., Waterlow, J. C. Lancet, 1944, ii, 491.

10. Edholm, E. G. Fedn Proc. Fedn Am. Socs exp. Biol. 22, 107.11. Sobel, S., Johnson, W. C., McPhaul, J., McIntosh, D. A., Miller, W. E.,

Jr, Rhoades, E. R. Clin. Res. 1963, 11, 252.12. Coburn, J. W., Reba, R. C. Milit. Med. 1966, 131, 678.13. Coburn, J. W., Reba, R. C., Craig, F. N. Am. J. Physiol. 1966, 211, 117.14. Gordon, R. S., Jr, Andrews, H. L. Fedn Proc. Fedn Am. Socs exp. Biol.

1965, 24, 280.15. Conn, J. W. J. Am. med. Ass. 1963, 183, 775.16. Conn, J. W. ibid. p. 871.17. Itoh, S., Nishimura, Y. Jap. J. Physiol. 1963, 13, 182.18. Fletcher, K. A., Leithead, C. S., Deegan, T., Pallister, M. A., Lind, A. R.,

Maegraith, B. G. Ann. Trop. Med. Parasit. 1961, 55, 498.

660

fluid and plasma-volume. In response, aldosterone pro-duction increases and promptly induces renal sodiumconservation and ultimate re-expansion of extracellularfluid. Although this mechanism comes into play rapidly,the action of aldosterone on sweat glands is sluggish,requiring 5-10 days to become maximal.14 19-21 Thus,during normal acclimatisation to heat, conservation ofsodium by the sweat gland lags behind that effected by thekidney. In contrast to the characteristically high potassiumconcentration of urine under the influence of aldosterone,potassium concentration does not change appreciably.17-21However, as the individual becomes acclimatised to heat,the volume of sweat produced for a given amount of workrises so that the relative rate of potassium loss in sweatmust increase with acclimatisation. Indeed, Schwartzand Thaysen 19 have indicated that sweat potassiumexcretion in an acclimatising individual may be comparableto the quantity lost in diarrhoea. Under normal circum-stances, these potassium losses are probably replenishedby diet in a quantity sufficient to maintain satisfactorybalance.

If it is assumed that acclimatisation to heat establishes asituation in which potassium depletion is potential, thenwhat might be the consequences of dietary salt supple-mentation as currently practised ? Although salt loadingsuppresses aldosterone production under normal circum-stances,22 Conn 15 reported that the adrenal cortex wasnot only unsuppressed but remained physiologicallyhyperactive in volunteers examined during heat acclima-tisation, despite administration of up to 500 mmole ofsodium chloride daily. It has also been shown 15 23 24that total body-sodium content remains high and extra-cellular-fluid volume remains expanded during theacclimatised state. Thus Conn 15 described a situationwhich is closely similar to certain disease states charac-terised by overproduction of aldosterone-good examplesof these are primary aldosteronism or certain patients withcongestive heart-failure, in both of which potassiumwasting characteristically occurs in direct relation to theintake of sodium.

Thus, there are two physiological mechanisms wherebypotassium depletion could occur during heat acclimatisa-tion. The first concerns potassium losses in sweat. Sincethe volume of sweat rises but the concentration of potassiumremains the same, the quantity of potassium lost in sweattends to increase. Secondly, renal wasting of potassiumcould conceivably occur in the wake of an accentuatedsodium-potassium exchange system. This system isdriven by aldosterone which is produced in abundance bysuch people.I5 The exchange of luminal sodium for

potassium from the tubular cell and therefore, potassiumexcretion, may be sharply increased by sodium loading.Under most circumstances, cutaneous losses of

potassium would probably not reach alarming proportionsunless the acclimatising individual were secreting largequantities of sweat. It seems likely that potassium lossescould be much more pronounced by the second mechanism.There may be a relation between potassium depletion

and the high incidence of heat stroke among otherwisehealthy soldiers in basic training or football players inpreseason conditioning. The liberal use of sodium-

19. Schwartz, I. L., Thaysen, J. H. J. clin. Invest. 1956, 35, 114.20. Robinson, S., Robinson, A. H. Physiol. Rev. 1954, 34, 202.21. Leithead, C. S. Fedn Proc. Fedn Am. Socs exp. Biol. 1963, 22, 901.22. Bartter, F. C., Gann, D. S. Circulation, 1960, 21, 1016.23. Bazett, H. C. J. Am. med. Ass. 1938, 111, 1841.24. Bazett, H. C., Sunderman, F. W., Doupe, J., Scott, J. C. Am. J. Physiol.

1940, 129, 69.

chloride tablets is generally urged and these are abundantin every mess hall, barracks, or locker room. Under theseconditions, such individuals sweat voluminously, probablyconsume sodium far out of proportion to potassium, andmay thus be considered likely candidates for potassiumdepletion.

Ladell, while discussing the implications of his work onheat acclimatisation,25 stressed his observation that thepeasants of Indonesia and Nigeria consume a daily dietwhich is high in potassium but contains less than 3 g. ofsodium. These people are extremely resistant to that formof heat injury characterised by electrolyte disturbances,polyuria, and variable degrees of pyrexia. He suggestedthat man, phylogenetically an avid salt saver, does notnaturally require a high salt intake. Conn 15 demonstratedthat men could acclimatise to heat and perform work loadssatisfactorily on a daily sodium-chloride intake of 5 g.

EFFECT ON INTRACELLULAR METABOLISM

The effect of potassium depletion on intracellular metabolismis not open to unambiguous investigation in the intact man.Thus, only guarded implications can be drawn from experi-mental studies which demonstrate gross abnormalities in themetabolism of carbohydrate 26 and protein,27 electrochemicaleffects,28 renal function,29 and specific enzymatic function 30in the presence of hypokalxmia or significant potassiumdepletion. While there is no evidence to suggest that potassiumdepletion per se is the factor responsible for failure to becomeacclimatised to heat, it seems logical to suspect that depletionof this important cation may at least enhance the risk to developheat injury.

Experimentally, perhaps the most important evidence is therelation between maintenance of intracellular potassium byoutward active transport of sodium which in turn derives itsenergy from oxidation of carbohydrate. 31 In potassiumdepletion, utilisation of carbohydrate is depressed and as aresult of a shift from the efficient aerobic glycolysis to themuch less efficient anaerobic glycolysis,32 production ofadenosine triphosphate and oxidative phosphorylation are

disturbed. If these experimental events are analogous to themetabolic disturbances of potassium-depleted man, provisionof energy sources for vital cellular functions might then bedisordered sufficiently to increase his susceptibility to heatinjury.

Certain data suggest that cellular injury in tissues other thanthe renal tubule may occur with potassium depletion. Gross etal. 33 provided additional evidence that in some instances

potassium depletion may be accompanied by rhabdomyolysisand we have described 34 the clinical course and features ofacute renal failure associated with heat injury and found severemyoglobinuria in four out of ten patients. Although hyper-kalaemia is usual in patients with acute heat injury and acuterenal failure, for reasons cited previously, good evidenceexists which suggests that potassium depletion is often present.Indeed, a patient treated in the Brooke Army Medical Centerfor acute renal failure due to classical myoglobinuria unassoci-ated with heat injury had a serum-potassium of 3-2 mEq. perlitre 36 hours after onset of anuria. This happened despiterapidly increasing azotaemia and acidosis. This patient, attend-ing Officers Candidate School in the Southern United States,had ingested 12-18 g. of supplemental sodium chloride daily.

25. Ladell, W. S. S. Trans. R. Soc. trop. Med. Hyg. 1957, 51, 189.26. Conn, J. W. New Engl. J. Med. 1965, 273, 1135.27. Lubin, M. in The Cellular Functions of Membrane Transport (edited

by J. F. Hoffman); p. 193. New Jersey, 1963.28. Grundfest, H. in Electrochemistry in Biology and Medicine (edited by

T. Shedlovsky); p. 141. New York, 1955.29. Relman, A. S., Schwartz, W. B. Am. J. Med. 1958, 24, 764.30. Kernan, R. P. Cell K; p. 121. London and Washington, 1965.31. Whittam, R. in Cellular Functions of Membrane Transport (edited by

J. F. Hoffman); p. 139. New Jersey, 1964.32. Elliott, K. A. C., Bilodeau, F. Biochem. J. 1962, 84, 421.33. Gross, E. G., Dexter, J. D., Roth, R. G. New Engl. J. Med. 1966, 274, 602.34. Vertel, R. M., Knochel, J. P. Am. J. Med. (in the press).

661

Whether or not the customary strenuous exertion, such as squatjumps or similar violent muscular activity, may provokerhabdomyolysis more readily in a potassium-depleted indivi-dual is unknown. It is perhaps noteworthy that Smith et al. 35described acute degenerative changes in skeletal muscle of dogswhen depleted of potassium.

Obviously, specific studies of potassium balance underthe influence of various sodium loads during naturalacclimatisation to heat are needed. While it is clearly notintended to decry the use of supplemental sodium chloridewhile an individual is undergoing acclimatisation, perhapsdata drawn from such studies would indicate that salt

supplementation should be less vigorous or perhaps beadministered in conjunction with supplemental potassium.

U.S. Army Surgical Research Unit,Brooke Army Medical Center,

Fort Sam Houston,Texas 78234, U.S.A.

JAMES P. KNOCHELM.D. Loyola

ROBERT M. VERTELM.D. Illinois

35. Smith, S. G., Black Schaffer, B., Lasater, T. E. Archs Path. 1950, 49, 185.

Methods and Devices

FLEXIBLE RENAL GRID-SLING FOR LOCALISING

STONES DURING LITHOTOMY

ORDINARILY, during a pyelolithotomy or nephrolithotomyevery fragment of stone can be removed with relative ease.Sometimes, however, this is impossible without careful X-raycontrol by means of sterile contact X-ray films placed behindthe kidney in the wound during the operation.A flexible wire grid-sling (fig. 1) is helpful in localising

fragments of stone on these films. The grid-sling suspends thekidney in front of the sterile X-ray film during exposure. Theresulting negative (fig. 2) enables the urologist to localise smallstone fragments to an area of about 2 cm. square with great

Fig. 1-Grid-sling, made of asymmetrically arranged flexible wirtmeasuring about 5 x 4 in.

Fig. 2-Contact X-ray showing accurate localisation of stone.

accuracy. The sling should be asymmetrical so that the wetX-ray film can be rapidly oriented. The original sling was madeof picture wire and, if you " do it yourself ", costs ninepence.A more elegant model is obtainable from the EndoscopicInstrument Company, 62 Shirland Road, London W.9.

Institute of Urology,Henrietta Street,London W.C.2

HOWARD G. HANLEYM.D. Lpool, F.R.C.S.

Reviews of Books

Man-Apes or Ape-Men ? ?The Story of Discoveries in Africa. Sir WILFRID E. LE GROSCLARK, professor emeritus of anatomy, University of Oxford.New York: Holt, Rinehart and Winston. 1967. Pp. 150.$3.95.

THE australopithecine fossils found in South Africa duringthe past forty-odd years have brought the mythical " missinglink " into the realms of reality; but when, in 1925, Prof.Raymond Dart described the first skull as " intermediatebetween living anthropoids and man ", he was ridiculed by hisfellow anthropologists. Despite accumulating discoveries, theanthropoid-hominoid controversy was still raging in the 1950s.But the dust seems to have settled, leaving the australopithecinesfirmly established as early forerunners of man; and Sir Wilfridsees the time ripe both to review the australopithecine findsand to explore the origins and nature of the dispute. Thedetails of the anatomical argument have been difficult for the

non-specialist to follow, but Sir Wilfrid whittles them down tothe essential facts, describing, clearly and concisely, thestructure and functional implications of the australopithecineskull, teeth, pelvic girdle, and limbs, and contrasting themwith those of the chimpanzee and modern man. The smallbraincase and pronounced prognathism of the australopithecinesled some anthropologists to overlook the undoubtedly hominidfeatures of the dentition and pelvis, and this example providesan excuse for an instructive digression into the assessment oftaxonomically relevant characters. The story of humanevolution is confusing, but in Sir Wilfrid’s skilful hands theaustralopithecine chapter (which has been further obscured byan apparently unnecessary profusion of generic names) becomesdelightfully simple. The style throughout is lively, and

speculations on the way of life of these small hominids ofshuffling gait add a lighthearted touch to a fascinating story.

Textbook of RadiotherapyGILBERT H. FLETCHER, M.D., radiotherapist, professor of

radiology, head of department of radiotherapy, University ofTexas, M. D. Anderson Hospital and Tumor Institute, Houston,Texas. London: Henry Kimpton. 1966. Pp. 580. E7 10s.

THIS textbook will provide the trainee in radiotherapy witha sound foundation for his technique and practice. Thevolume opens with a full description of radiation physics asapplied to the day-to-day management of a large department.There are interesting chapters on radiobiology and on advancesin clinical experimental radiotherapy. In the section on treat-ment of tumours the space devoted to the clinical backgroundhas deliberately been kept in check; and here and there thisrestraint may have been carried too far. As would be expectedin a publication from Houston, the description of the manage-ment of carcinoma of the uterine cervix is full of interest.There are also very full accounts, with copious illustrations, oftechniques used in most of the common tumours, togethersometimes with useful information on nursing care and generalmanagement. The bibliography is excellent. Besides its valueto those in training, this work forms an up-to-date book ofreference for all interested in radiotherapy.

Shock

Chemistry, Physiology and Therapy. WILLIAM C. SHOEMAKER,M.D., professor of surgery, Chicago Medical School. Springfield,Illinois: Charles C. Thomas. 1967. Pp. 306.$11.50.

WRITING a small book on shock is a difficult exercise, andProfessor Shoemaker is to be congratulated on a gallant