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Further studies in “heatstroke”
25;5 'FRANSACTIONS ()Iv 'FilE P~OYAL ~OCIETY OF rI'ROPICAL ~'IEDICINE AND tt¥(;IgXt':.
Vol. XXVII. No. 2I. Noveml)cr, 1972f.
VI!RTIIER
S'I'[TDIES IN " I[1.]ATSTROKI:.." IIY
FP, A N K ~%'IARStl, M,])., B.S. (LoNo.), 1).T.M. & I1. ll'2x~;.).
Palllolo,~lsl 1~ I/1~' ..blg/,-P~ rsz'a~t ()//(5,'m,',,:nv L;~.,tit~d *:
[.
]~LOOI) (7III,:MISTRY,
,NtW.MAI, ] " I t ; I R E q
IN PERSIA,
In the A n g l o - P e r s i a n ()il C o m p a n y ' s Medical l(cport for 1,~)3~, the following figures (obtained d u r i n g the cold weather f r o m M a r c h to April) are given for : (a) Normal whole blood chlorides in fifty pcrso,s. Actual m e a n " 494.12 mg/lt)t~ c.c. S t a n d a r d deviation : '38.~18 mg'lt~l) c.c, (b) ,Vormalplasma chlori~gs infifty perso~s'. Actual mean : 564.t)8 m~/l~,) c.c. S t a n d a r d deviation : 3 7 ' 3 rag/101) c.c. (c) Normal plasma bicarbotmt~ i u jifty persom. Actual m e a n : 2 ' 7 8 5 6 millimols/'ll!t) c.c. S t a n d a r d deviation : tl.266 miltimols '1(){) c.c. - ~.... o vols. per (d) Normal plasma C() e i,z fi)ffy persom. Actual m e a n " 63 •'~ cent. S t a n d a r d deviation : 6"21 v,~ls, per cent. (c) ;Vormal limits q/ variatioH. Plasma C() 2 c o m e n t • 55 to 7S vols. per c e n t . " ]LIK?():;" '_'3 t~, 32 millimols per litrc. (PJ,:TI!RS and vax SLYKtC, 19:¢ I.) 'l'hc t e c h n i q u e e m p l o y e d in these estimations is fully described in the above report together w h h certain modifications which ~ere f o u n d necessary in this climate. It was p l a n n e d to p e r f o r m a similar set of cstimati~ms, using n o r m a l people, durin~ the hottest part o1: the SUlmncr lint o w i n g to the e c o n o m i c crisis and c o n s e q u e n t limitation ,4" staff it v, as impossible to carry out this part of the scheme. I l o w c ~ c r , progress was m>t cnti)clv at al standstill and some f u r t h e r i m c s t i g a t i o n s were completed. N o r m a l figures for blood laclic acid, using a slight modification of the m e t h o d of BOYt.aND (1,LS), were obtained in rift)' resting healthy adults of mixed nationality duriniz the cold season (actual m e a n : _4-, , mg;lt)tl c.c.; s t a n d a r d deviation : 6.7 m g / l l ~ c.c,). T h e individual figures and the details of technique arc given in the fo!lox~ing Tables 1£and I i. eThis paper is published by permission of Dr. AI. Y. YOCNG, C.I.E., Chief Nledical ()~eer of the ?~nglo-Persian Oil Company. '['he author is indebted to Mr. t[. A. WILSON, Patholo.gical Assistant, for working out the lcchniquc and, often under conditions of very ;~,ruat difticulty, ipcrformin~ most of the cstilnatiol~s mentioned in this paper.
FUI{THI{P,
256
STUDIES
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'['ABI.E BLOOD LACTIC ACID
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~258
FURTHER STUDIES IN ,i ItEATSTROKE."
II.---URINARY
CHLORIDES IN NORMAL PEOPLE.
A series of u r i n a r y chloride estimations in some 2,7t)0 n o r m a l persons, using fasting urine obtained first t h i n g in the m o r n i n g is described, and the a c c o m p a n y i n g G r a p h I c o n s t r u c t e d to show the relation of variations in the urinary chloride concentration to the seasonal variation in a t m o s p h e r i c and sun temperature. T h e fl~llowing t e c h n i q u e was used : 'I'ECHNIQUE OF ESTIMATION OF URINARY CHI,ORIDE. &
Nolution "A."--29.075 gin. fused AgNOa per 1,000 c.c.
1 c.c. = 0.01 gin. NaC1. ,%'olution "B."---Iron alum (sat. aqueous sol.) 400 c.c.
Concentrated nitric acid Mix.
600 c.c.
( K e e p s indefinitely.)
,S'olution "(L"--Potassium thiocyanate. 1 c.c. - 1 c.c, of solution " A." AIethod :
To 1 ca. of urine add 3 c.c. of solution " A " and 1 c.c. of solution " B." Titrate with solution " C " until red endpoint.
Mix.
Calculation :
3.0 minus c.c. of solution " C " used : = gin. NaCI per cent. e.g. if 1.5 c.c. solution " C " were used, then 3.0-1.5 -, 1.S gin. NaCI per 100 c.c. urine. Bctween six and t w e n t y samples of fasting urine f r o m difl'erent healthy individuals obtained u n d e r identical conditions, were e x a m i n e d cach day. '['he figure for each day on the graph is the a v e r a g e of each day's resuhs. It was t h o u g h t desirable to discover ~xhat was the general t e n d e n c y a m o n g healthy people and since the largest possible g r o u p should be studied in order to get ligures that fairly represented the general herd, obviously there could bc no control of dict or tluid i n t a k e ; urine passed on rising in thc m o r n i n g was considcrcd to bc as near a specimen obtained under basal metabolic conditions us was possible u n d e r the circumstances. 'l'hc g r a p h s h o u s a low s()dimn chloride concentration d u r i n g the cohl m o n t h of !\larch ; this result is p r o b a b l y due to the secretion of large volumes of dilute urine bv the individuals tested. In April the urine is rather more c o n c e n t r a t e d and the b o d y reserves of s o d i u m chloride are p r o b a b l y high so the concentration of u r i n a r \ salt risks. In May the urinary salt concentration begins to fall off a little on a c c o u n t of loss uf sah in the sweat. In June it would a p p e a r that the big decrease in the daily v o h u n e of urine that follo\vs steady s~xcating had increased the concentration ,.ff urinary salt slightly. I n July there is a steady fall in u r i n a r y salt concentration w h i c h is m a i n t a i n e d in August and shou:s only a slight t e n d e n c y to rise in S e p t e m b e r a l t h o u g h by then the ~\Vc regret that owing to the necessity for cconomising in space, tables givin~ the daily urinary chloride estimations from 14th [\]arct~ t~ l,qth September, 1931, have had to he otnitted .----E] ~.
GRAPH I.
i
HEAT STROKEREPORT-1932.
i
i 3 6
. b:,,
I’ASTINC. LJRINI, CONCENTRATIOS
ha<‘,.
i,m,ri w.311 e-,i p”
1,” ii
FRANK MARSI].
:251)
w e a t h e r is very m u c h cooler. D u r i n g the hot m o n t h s of J u l y a n d A u g u s t , w h e n the daily m a x i m u m shade t e m p e r a t u r e i:~ n e v e r below 11{)° F. a n d the n i g h t l y m i n i m u m is rarely bcloxx Sift F., there is a ver~ c o n s i d e r a b l e r e d u c t i o n in the v o l u m e of u r i n e passed b y a n y i n d i v i d u a l d u r i n g the tx~enty-four hours. 'l'his m a r k e d d i m i n u t i o n is a well-kno~vn p h e n o m e n o n in c o u n t r i e s \vith a hot season a n d is r e c o r d e d b v S q u a d r o n - L e a d e r Mol>,'roN (19;~)2), in his p a p e r read before the Royal Societx of M e d i c i n e , b u t hc did n o t find the salt c o n c e n t r a tion depressed very m u c h in his short b u t xvell-rccorded series of o b s e r v a t i o n s . F r o m a s t u d y of o u r tigurcs, it seems as th~mgh the bodily stocks of s o d i u m chloride i n m e n are very low at the e n d of ,,;umnter, a n d thcre is a defini{c la~ period before n o r m a l s o d i u m chloride excretion is rcs:,,med. T h e figures for u r i n a r y salt concentrati~m in ( ; r a p h 1, lend some s u p p o r t to the t h e o r y that the h>ss of salt in the :'~vcat (>f: n o r m a l people d u r i n g hot w e a t h e r m a y not bc c o m p l e t e l y b a l a n c e d (in e v e r \ case) b y sah in~,c, a l:rec choice ()f food. I1].
:~ ('ASI{ ()I: PRODROMAL ]It{ATSTR()I,2[.I.
D u r i n ~ July, 1931, an intercstin~,~ c;~sc ~fi" pr,)drcm~;ti '~ heatstroke " was studied. Mr. A, a European, aged -tS, was admitted to the artificially cooled ward at midday on the 26tb, complaining of malaise and spasmodic cramps of a m o s t painful description in his calves, thighs, buttocks, back, shoulders, arms m~d neck, the paroxysms occurring every few minutes and persisting for from a fraction of a minute up to two minutes. 1luring a (:ramp the muscles affected could be felt ~o contract and remain hard throughout the painful period. He had had no previous illness for some years, the cramps beaan suddenly about 10 o'clock on the day of admission. The patient had had no food si~ce 8 p.m. on the previous day durin~ which he had performed a journey of lS0 mHcs by ear in shade temperature of 118 F. and a sun temperature of 170 ~ F. tie .':tared that lie frequently stopped sweating on the day of the journey and the day bell)re. He had (lot vomited nor had he noticed polyuria. On admission, the patient's mouth temperature was 9 8 . 4 1;., pulse ,$4, respirations ~S. Systolic blood pressure was 1(~0 ram., diastolic 100 mm.ItV, "l'he skin was red and flushed, but not sweating. No abnormal physical signs were noted in chest, abdomen or central nervous system. The knee jerks were accentuated. No si~ns of reran,', ur:emia or strychnine poisoning were present, and n o l l ~ a r k c d vascular chan~es. Laboratow Data.
On admission (26th July, Is>alL *he v:hole blood chloride : '_'(~a.()rag. per 100 c.c. and the blood sugar -- 210 my. per 100 c.c. The blood ure,~ 120 me. per lI)0 c.c., but later on the alst July, it had fallen to 5 0 r a g . p e r I(){) c . c , ~Yhe urine on admission was strongly acid in rcaction ; sugar and acetone were present, but not albumin. 5'licroscopically a few hyaline c a s t s and some red corpuscles were holed. C,hloride was absent in 24-hour specimens collected an '2tgth, 27th and 28th, but it reappcarcd on the 29th July.
q'he plasma bicarbonate estimations in millimols pet" lU0 c.c. were as follows :--27th July ~'3 4th August 2.1 10th August 7.61 29th ,, '2 "7 ,-;th ,, 2.54 24th ,, 2 "~ 2nd August 7.$4 8th ,, E-e; 2Sth ,, 2.1
L),(;O
FURTHER STUDIES IN " tIEATSTROKE."
T h e p a t i e n t was treated w i t h insulin, rectal drips of saline and b i c a r b o n a t e and e n c o u r a g e d to d r i n k w a t e r c o n t a i n i n g s o d i u m b i c a r b o n a t e a n d c o m m o n salt. His cramps ceased in a few h o u r s and did not recur b u t soreness of the muscles persisted for some days. His depressed glucose tolerance was treated b y a series of g r a d u a t e d diets a n d he eventually was able to assimilate a diet of 2,400 calories c o n t a i n i n g protein 132 gm., c a r b o h y d r a t e 1 t2 gm., a n d fat 149 gm. (with b o d y weight 160 lbs.) a n d r e m a i n e d a m i l d diabetic. F r o m the first to the t h i r t e e n t h day of illness the p a t i e n t h a d salt a n d b i c a r b o n a t e in all his drinks, and d u r i n g the first few days he h a d rectal saline as well. As a result blood salt c o n c e n t r a tion rose rapidly a n d salt was excreted in his u r i n e (sec G r a p h II). O n the t e n t h day GRAPH l I.
%
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:~.LL ESTIMATIONS ARE ON ~AMP[,ES I'AKEN\VIIILEI:AS'IING. he w a s m o v e d f r o m the artificially cooled w a r d to a general w a r d w h e r e the air t e m p e r a t u r e n e v e r fell b e l o w 1()0° F. a n d in t h e m i d d l e of the day rose c o n s i d e r a b l y a b o v e this level. F r o m t h e t h i r t e e n t h day to the m i d d l e of the s i x t e e n t h day all salt w a s o m i t t e d f r o m his f o o d a n d d r i n k o w i n g to a m i s i n t e r p r e t a t i o n of o r d e r s . T h e r e s u l t i n g d r o p in his blood c h l o r i d e is clearly s h o w n in t h e g r a p h a n d c h l o r i d e v e r y s o o n d i s a p p e a r e d f r o m his u r i m ' . F r o m the s i x t e e n t h to t h e t h i r t y - f i f t h day of his illness, salt w a s i n g e s t e d b y t h e p a t i e n t at n m a l t i m e s o n l y . H e w a s f r e q u e n t l y e n c o u r a g e d to increase his salt intake b u t salt r e m a i n e d a b s e n t f r o m his u r i n e a n d his b l o o d c h l o r i d e s l o w l y d r o p p e d (sec g r a p h ) . ( ) n the t w e n t y - s e v e n t h day of his illness he w a s w a r n e d to m a k e a v e r y c o n s i d e r a b l e i n c r e a s e
FRANK MARSh.
2(;I
in his salt intake. The result is plainly shown in Graph I1 ; there was an immediate increase in his blood chloride and a return of chloride to his urine. The patient was discharged on the thirty-fifth day feeling very fit : he returned to work and remained well through another summer in Persia. T h e investigation of this patient demonstrates plainly the importance of an ample salt intake. On m a n y occasions, he informed me that he had heen in the habit of taking salt very freely at me:~l times for some years, but it is obvious that the quantity he considered ample was in reality' quite insufficient for his bodily needs during a Persian summer. It is regretted that limitation of staff prevented routine estimations of this patient's blood lactic acid. T h e r e is little doubt that on admission he had some reduction of blood volume and in future attempts will be made to estimate the haemoglobin percentage and to obtain a hmmatocrite readinfz in all cases admitted suffering from heat effects. I think the hypochlormmia and reduction of blood volume so (>ftcn associated with severe diabetic coma was not, in this case, due to diabetes, which existcd only as a mild complication and sequela. T h e high Mood sugar recorded below in the cases of experimental heatstroke in rabbits, causes one to wonder whether prodromal or fully developed heatstroke may not be a starting poinl, hitherto unrecognised, for diabetes. In S q u a d r o n - I , e a d e r ~IoRTON'S series anidrosis i~ m a t ] v cases uas noted, and absent urinary chloride in one case. IV.
BLoor., (;ttEMISTRY IN I:~XI'ERIMENTAL[[EATSTROKE (tIYI'EP,TtH:RMIA).
Some further experiments were carried out with rabbits exposed to the s~m in order to confirm the findings of HALL and \VAKEFIIZ:LI)(1927) who used dogs in a heated chamber. Our results are shown in the Tables l I I , 1 \ and V. \Ve arc in complete agreement with ItALL and \\~AKEFIEI,I), with regard to the increase in blood lactic acid, the decrease of plasma bicarbonate and plasma p I [ ariel the uniformity in the level of blood chloride in animals before and after hyperthermia. We found, however, that there was a marked rise in the blood sugar of rabbits ;dter an attack of h y p e r t h e r m i a : in tlALL and \VAKEFIEIA)'S series o n l \ a slighl and variable alteration in the blood sugar was recorded. We thought it possible that the rabbit results were due to the high carbohydrate diet of the animals. ,\ series of rabbits were accordingly' given water only for some days and then allowed to develop h y p e r t h e r m i a under experimental conditions. In this series a rise of blood sugar also occurred, but not to the marked extent previously noted. It is possible that the rabbit's pancreas is more sensitive to high body t e m p e r a t u r e than is the pancreas of a dog. \Ve could discover no obvious lesions ~f the rabbit's pancreas at atttopsy with naked eve or in sections. T h e normal figures for our various blood cb.emical estimations were <~btained
o 6 o•.,
I [!R'I'IIER STUI)IES IN " IIEAT~'I'I),OI
TAtlLI';
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FRANE MARSII.
26,:;
with blood from the left ventricle obtaincd hv needle puncture, the rabbit being ana~sthetised with ether from a mask. Some days later the animal was allowed to develop hyperthermia in the sun, and its ventricular blood again obtained ; as the animal was unconscious no anaesthetic was necessary for the second operation. A few rabbits were investigated, under the same conditions, 7dthou! an anaesthetic; we found that the anaesthetic raised thc hlood sugar and that in both the anaesthetised and non-anmsthetised rabbit, blood lactic acid volumes were much hi~her than the figures for resting man. The blood bicarbonate did not seem to bc affected by the anaesthetic. Wc als~ performed fifty estimalions of whole blood chloride on normal rabbits (actual mean : $48 mg. in I~tl c.c., standard deviation: 25.1~8 rag. in 1(11} c.c.) as a preliminary to certain experiments on the lines of those of ARMOUR et al. V. -DISCUSSION. Such further investigations as we have been able to make lend additional support to the contention that in non-sweating laboratory animals hyperthermia is accompanied by a rise in blood lactic acid and a fall in plasma bicarbonate (as first pointed out by HALL and WAKEFIELD), which events are accompanied, in the case of sweating man, bv a fall in blood chloride, i feel sure that the fall in blood chloride, which was so marked in the prodromal case described here and which was equally marked in the fully-developed case that I described in a former paper (MARSH, 193o), is responsible for the anidrosis noted in my two published cases and in a n u m b e r of S q u a d r o n - L e a d e r MORTON'S cases and in a series of prodromal heatstroke cases described bv A. K. HEARNE (1932), and a n u m b e r of other observers. ttow hypochloraemia interferes with sweating is not quite clear; it m a \ be that sweat glands are unable to secrete sweat when the blood chloride is low, as [ previously suggested (MARSH, 193~}), or it is possible that a low blood chloride induces a secondary reduction in blood volume. I think it is generally accepted that shrinkage of t;lood volume depresses sweating. T h e work of }lADEN and ORR (1923), GAMBLE and Ross (1925), 'I'm~SLER (192S), and many other observers all goes to show that the extreme hypochlormmia following the prolonged vomiting associated with high intestinal obstruction may cause death with symptoms of weakness, anorexia, ()liguria and profound depression. The " water poisoning " described by *loss (1927), is probably an earlier stage of the same process. Even without the interference with sweating and evidence is accumlllating that this is real--hypochlormmia ~ravely embarrasses all the normal metabolic functions of the bodx. I think a patient with his hlood salt lmv and his bodily salt reserves exhausted will thirstily drink any available water, t|is body is embarrassed
266
FURTttER STUDIES IN ~ tlEATSTROKI'.."
by the necessity for maintaining the physiological tonicity of the blood and tissue fluids and at the same time dealing with the ingested water; hypotonicity is death, so the surplus water is rapidly excreted by the kidneys (polyuria) and perhaps by vomiting and some is lost by a quick burst of sweating. The blood volume then is rapidly restored to its former low level, or slightly lower, since of necessity more salt was lost in the burst of sweating, and the patient is no better off. The vicious circle can only be broken by the ingestion of salt. In the series of cases described by W~LL(:OX (192~i), suppression of sweating was not noticed. The reason, [ think, is that sweating to he effective must be continuous and profuse, anything less will be ineffective and it must have been some such ineffective sweating that was noted in his cases. In acute heatstroke cases, Squadron-I,eader MORTON describes the eflect of the intravenous administration of 1 t~} I 1 pints of '2 per cent. sodium bicarbonate in saline, as dramatic, tle administered s~dimn bicarbonate and glucose (with saline ?) bv month to all his heatstroke cases and the}, rapidly' improved. It is possible that sodium bicarbonate is converted into sodium chloride in the body as he had similar good results with potassium citrate and Professor Moss noted long ago that miners in Pendleton colliery put small amounts of cream of tartar (potassium bitartrate) in their drinkin~ water as a cramp preventive (Moss, 1927). Professor Moss was the first to draw attention to the syndrome ~f " water poisoning " in miners who lost much salt in their sweat while following their occupation in hot mines. APPENDIX.
Technique for Estimation of Blood Lactic Acid. (1) 1~) c.c. blood is obtained from the vein of the patient in an all-glass syringe. (2) This I0 e.c. blood is impelled into 1~t c.c. of 16 per cent. trichloracetic acid (ice cold). (3) The mixture is shaken and filtered through fine paper and the water clear filtrate is kept in the ice chest until the estimation is performed (usually within three hours). (4) A quantitative test with dilute ferric chloride or the ltopkins reaction is usually performed on an aliquot portion of this filtrate. The remainder of the filtrate is measured and then treated in the manner and with the apparatus described by BOYLAND (1928). Steam distillation is employed in the presence of dilute potassium permanganate and sulphuric acid ; this carries over acetaldehyde into a solution of sodium bisulphite, the excess bisulphite being destroyed bv iodine; the acetaldehyde-bisulphite compound is then broken down hy a saturated solution of sodium bicarbonate and the liberated bisulphite carefully titrated with dilute and very accurately
FRANK MARSIf.
2(;7
standardised iodine solution. F r e q u e n t c o n t r o l s are n e c e s s a r y w i t h p u r e l i t h i u m lactate or B.P. lactic acid. W e f ( m n d t h a t it was u n n e c e s s a r y to take m e a s u r e s to r e m o v e the s u g a r in the b l o o d as the t r i c h l o r a c e t i c acid s o l u t i o n d e s t r o y e d it.
REFERENCES.
.\I/MOI I/, J. C., BROWN, 'I'. G., DUNLOP, D. M., MrrcH~;LL, T. C., SEARLS,H. 1t. & STEW.anT, C . P . (1931). Studies on high intestinal obstruction. Brit. ft. Surge~3', xviii (71), 4(57. BOVLANIL E. (1928). Chemical changes in muscle. Biochem. J., xxii, 24{). (;AMnL~:, J. I,. & Ross, S . G . (1925). The factors in the dehydration following colonic obstruction. J. Clin. Invest., i, 403. IlAI)EN, R. L. & OnR, T . G . (1923). Chemical changes in blood of dog after intestinal obstruction. J, Experim. ivied., xxxvii, 365. I la1J., W. W. & \VAKEFIELD, E. G. (1927). Experimental heatstroke. J. Amer. ,lied. Assoc., lxxxix, 179. }h.:AnNE, K. G. (1932). Hyperpyrexial heatstroke: a *lesopotamian experience, with some ~etiological views and a method of prevention arising therefrom. :lied..7. Australia, 19th year, i (7), 226. 3'Iansn, FnANK. (1930). The etiology of heat-stroke and sun ~raumatism. Trans. Roy. Soe. Trop. Med. & Hyg., xxiv (3), 257. MOnTO~,, T. C. ST. C. (1932). The a~tiology and treatment of heat exhaustion and heat hyperpyrexia with special reference to experienee~ in Iraq. Proc. Roy. Soc..'3lied., xxv (8), 1263. 3loss, K. NEVILLE. (1917). Gases, Dust and Heat in 3/lines, p. 190. London : Charles Griffin & Co., Ltd. PFr~ns, J. R. & VAN SLYKE, I). I). (1931). QuantitativeClinicalCkemistrv, col. i, Interpretations, 935. London : Bailli6re, Tindall & Cox. TRUSLEn, H . M . (1928). ttypochlor~emia, ft. dmer. 3lied. Assoc., xci (8), 538. WH~LCOX, W. H. (1920). The nature, prevention and treatment of heat hyperpyrexia. Brit Meal..7., i. 392.
Vol. XXVII. No. 2I. Noveml)cr, 1972f.
VI!RTIIER
S'I'[TDIES IN " I[1.]ATSTROKI:.." IIY
FP, A N K ~%'IARStl, M,])., B.S. (LoNo.), 1).T.M. & I1. ll'2x~;.).
Palllolo,~lsl 1~ I/1~' ..blg/,-P~ rsz'a~t ()//(5,'m,',,:nv L;~.,tit~d *:
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,NtW.MAI, ] " I t ; I R E q
IN PERSIA,
In the A n g l o - P e r s i a n ()il C o m p a n y ' s Medical l(cport for 1,~)3~, the following figures (obtained d u r i n g the cold weather f r o m M a r c h to April) are given for : (a) Normal whole blood chlorides in fifty pcrso,s. Actual m e a n " 494.12 mg/lt)t~ c.c. S t a n d a r d deviation : '38.~18 mg'lt~l) c.c, (b) ,Vormalplasma chlori~gs infifty perso~s'. Actual mean : 564.t)8 m~/l~,) c.c. S t a n d a r d deviation : 3 7 ' 3 rag/101) c.c. (c) Normal plasma bicarbotmt~ i u jifty persom. Actual m e a n : 2 ' 7 8 5 6 millimols/'ll!t) c.c. S t a n d a r d deviation : tl.266 miltimols '1(){) c.c. - ~.... o vols. per (d) Normal plasma C() e i,z fi)ffy persom. Actual m e a n " 63 •'~ cent. S t a n d a r d deviation : 6"21 v,~ls, per cent. (c) ;Vormal limits q/ variatioH. Plasma C() 2 c o m e n t • 55 to 7S vols. per c e n t . " ]LIK?():;" '_'3 t~, 32 millimols per litrc. (PJ,:TI!RS and vax SLYKtC, 19:¢ I.) 'l'hc t e c h n i q u e e m p l o y e d in these estimations is fully described in the above report together w h h certain modifications which ~ere f o u n d necessary in this climate. It was p l a n n e d to p e r f o r m a similar set of cstimati~ms, using n o r m a l people, durin~ the hottest part o1: the SUlmncr lint o w i n g to the e c o n o m i c crisis and c o n s e q u e n t limitation ,4" staff it v, as impossible to carry out this part of the scheme. I l o w c ~ c r , progress was m>t cnti)clv at al standstill and some f u r t h e r i m c s t i g a t i o n s were completed. N o r m a l figures for blood laclic acid, using a slight modification of the m e t h o d of BOYt.aND (1,LS), were obtained in rift)' resting healthy adults of mixed nationality duriniz the cold season (actual m e a n : _4-, , mg;lt)tl c.c.; s t a n d a r d deviation : 6.7 m g / l l ~ c.c,). T h e individual figures and the details of technique arc given in the fo!lox~ing Tables 1£and I i. eThis paper is published by permission of Dr. AI. Y. YOCNG, C.I.E., Chief Nledical ()~eer of the ?~nglo-Persian Oil Company. '['he author is indebted to Mr. t[. A. WILSON, Patholo.gical Assistant, for working out the lcchniquc and, often under conditions of very ;~,ruat difticulty, ipcrformin~ most of the cstilnatiol~s mentioned in this paper.
FUI{THI{P,
256
STUDIES
IN
~' [ I E A T S T P . O K E . "
'['ABI.E BLOOD LACTIC ACID
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[)ETERM1NATIONS
IN F I F T Y
Frequency
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TOTALS
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~258
FURTHER STUDIES IN ,i ItEATSTROKE."
II.---URINARY
CHLORIDES IN NORMAL PEOPLE.
A series of u r i n a r y chloride estimations in some 2,7t)0 n o r m a l persons, using fasting urine obtained first t h i n g in the m o r n i n g is described, and the a c c o m p a n y i n g G r a p h I c o n s t r u c t e d to show the relation of variations in the urinary chloride concentration to the seasonal variation in a t m o s p h e r i c and sun temperature. T h e fl~llowing t e c h n i q u e was used : 'I'ECHNIQUE OF ESTIMATION OF URINARY CHI,ORIDE. &
Nolution "A."--29.075 gin. fused AgNOa per 1,000 c.c.
1 c.c. = 0.01 gin. NaC1. ,%'olution "B."---Iron alum (sat. aqueous sol.) 400 c.c.
Concentrated nitric acid Mix.
600 c.c.
( K e e p s indefinitely.)
,S'olution "(L"--Potassium thiocyanate. 1 c.c. - 1 c.c, of solution " A." AIethod :
To 1 ca. of urine add 3 c.c. of solution " A " and 1 c.c. of solution " B." Titrate with solution " C " until red endpoint.
Mix.
Calculation :
3.0 minus c.c. of solution " C " used : = gin. NaCI per cent. e.g. if 1.5 c.c. solution " C " were used, then 3.0-1.5 -, 1.S gin. NaCI per 100 c.c. urine. Bctween six and t w e n t y samples of fasting urine f r o m difl'erent healthy individuals obtained u n d e r identical conditions, were e x a m i n e d cach day. '['he figure for each day on the graph is the a v e r a g e of each day's resuhs. It was t h o u g h t desirable to discover ~xhat was the general t e n d e n c y a m o n g healthy people and since the largest possible g r o u p should be studied in order to get ligures that fairly represented the general herd, obviously there could bc no control of dict or tluid i n t a k e ; urine passed on rising in thc m o r n i n g was considcrcd to bc as near a specimen obtained under basal metabolic conditions us was possible u n d e r the circumstances. 'l'hc g r a p h s h o u s a low s()dimn chloride concentration d u r i n g the cohl m o n t h of !\larch ; this result is p r o b a b l y due to the secretion of large volumes of dilute urine bv the individuals tested. In April the urine is rather more c o n c e n t r a t e d and the b o d y reserves of s o d i u m chloride are p r o b a b l y high so the concentration of u r i n a r \ salt risks. In May the urinary salt concentration begins to fall off a little on a c c o u n t of loss uf sah in the sweat. In June it would a p p e a r that the big decrease in the daily v o h u n e of urine that follo\vs steady s~xcating had increased the concentration ,.ff urinary salt slightly. I n July there is a steady fall in u r i n a r y salt concentration w h i c h is m a i n t a i n e d in August and shou:s only a slight t e n d e n c y to rise in S e p t e m b e r a l t h o u g h by then the ~\Vc regret that owing to the necessity for cconomising in space, tables givin~ the daily urinary chloride estimations from 14th [\]arct~ t~ l,qth September, 1931, have had to he otnitted .----E] ~.
GRAPH I.
i
HEAT STROKEREPORT-1932.
i
i 3 6
. b:,,
I’ASTINC. LJRINI, CONCENTRATIOS
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i,m,ri w.311 e-,i p”
1,” ii
FRANK MARSI].
:251)
w e a t h e r is very m u c h cooler. D u r i n g the hot m o n t h s of J u l y a n d A u g u s t , w h e n the daily m a x i m u m shade t e m p e r a t u r e i:~ n e v e r below 11{)° F. a n d the n i g h t l y m i n i m u m is rarely bcloxx Sift F., there is a ver~ c o n s i d e r a b l e r e d u c t i o n in the v o l u m e of u r i n e passed b y a n y i n d i v i d u a l d u r i n g the tx~enty-four hours. 'l'his m a r k e d d i m i n u t i o n is a well-kno~vn p h e n o m e n o n in c o u n t r i e s \vith a hot season a n d is r e c o r d e d b v S q u a d r o n - L e a d e r Mol>,'roN (19;~)2), in his p a p e r read before the Royal Societx of M e d i c i n e , b u t hc did n o t find the salt c o n c e n t r a tion depressed very m u c h in his short b u t xvell-rccorded series of o b s e r v a t i o n s . F r o m a s t u d y of o u r tigurcs, it seems as th~mgh the bodily stocks of s o d i u m chloride i n m e n are very low at the e n d of ,,;umnter, a n d thcre is a defini{c la~ period before n o r m a l s o d i u m chloride excretion is rcs:,,med. T h e figures for u r i n a r y salt concentrati~m in ( ; r a p h 1, lend some s u p p o r t to the t h e o r y that the h>ss of salt in the :'~vcat (>f: n o r m a l people d u r i n g hot w e a t h e r m a y not bc c o m p l e t e l y b a l a n c e d (in e v e r \ case) b y sah in~,c,
:~ ('ASI{ ()I: PRODROMAL ]It{ATSTR()I,2[.I.
D u r i n ~ July, 1931, an intercstin~,~ c;~sc ~fi" pr,)drcm~;ti '~ heatstroke " was studied. Mr. A, a European, aged -tS, was admitted to the artificially cooled ward at midday on the 26tb, complaining of malaise and spasmodic cramps of a m o s t painful description in his calves, thighs, buttocks, back, shoulders, arms m~d neck, the paroxysms occurring every few minutes and persisting for from a fraction of a minute up to two minutes. 1luring a (:ramp the muscles affected could be felt ~o contract and remain hard throughout the painful period. He had had no previous illness for some years, the cramps beaan suddenly about 10 o'clock on the day of admission. The patient had had no food si~ce 8 p.m. on the previous day durin~ which he had performed a journey of lS0 mHcs by ear in shade temperature of 118 F. and a sun temperature of 170 ~ F. tie .':tared that lie frequently stopped sweating on the day of the journey and the day bell)re. He had (lot vomited nor had he noticed polyuria. On admission, the patient's mouth temperature was 9 8 . 4 1;., pulse ,$4, respirations ~S. Systolic blood pressure was 1(~0 ram., diastolic 100 mm.ItV, "l'he skin was red and flushed, but not sweating. No abnormal physical signs were noted in chest, abdomen or central nervous system. The knee jerks were accentuated. No si~ns of reran,', ur:emia or strychnine poisoning were present, and n o l l ~ a r k c d vascular chan~es. Laboratow Data.
On admission (26th July, Is>alL *he v:hole blood chloride : '_'(~a.()rag. per 100 c.c. and the blood sugar -- 210 my. per 100 c.c. The blood ure,~ 120 me. per lI)0 c.c., but later on the alst July, it had fallen to 5 0 r a g . p e r I(){) c . c , ~Yhe urine on admission was strongly acid in rcaction ; sugar and acetone were present, but not albumin. 5'licroscopically a few hyaline c a s t s and some red corpuscles were holed. C,hloride was absent in 24-hour specimens collected an '2tgth, 27th and 28th, but it reappcarcd on the 29th July.
q'he plasma bicarbonate estimations in millimols pet" lU0 c.c. were as follows :--27th July ~'3 4th August 2.1 10th August 7.61 29th ,, '2 "7 ,-;th ,, 2.54 24th ,, 2 "~ 2nd August 7.$4 8th ,, E-e; 2Sth ,, 2.1
L),(;O
FURTHER STUDIES IN " tIEATSTROKE."
T h e p a t i e n t was treated w i t h insulin, rectal drips of saline and b i c a r b o n a t e and e n c o u r a g e d to d r i n k w a t e r c o n t a i n i n g s o d i u m b i c a r b o n a t e a n d c o m m o n salt. His cramps ceased in a few h o u r s and did not recur b u t soreness of the muscles persisted for some days. His depressed glucose tolerance was treated b y a series of g r a d u a t e d diets a n d he eventually was able to assimilate a diet of 2,400 calories c o n t a i n i n g protein 132 gm., c a r b o h y d r a t e 1 t2 gm., a n d fat 149 gm. (with b o d y weight 160 lbs.) a n d r e m a i n e d a m i l d diabetic. F r o m the first to the t h i r t e e n t h day of illness the p a t i e n t h a d salt a n d b i c a r b o n a t e in all his drinks, and d u r i n g the first few days he h a d rectal saline as well. As a result blood salt c o n c e n t r a tion rose rapidly a n d salt was excreted in his u r i n e (sec G r a p h II). O n the t e n t h day GRAPH l I.
%
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Period in Ward whereTemp. neyer below 100"F. Sa t ' Salt in FoodOn~.v. .'e,,'imkeid + Y
] ~""*s]'+1 "+| J!
:~.LL ESTIMATIONS ARE ON ~AMP[,ES I'AKEN\VIIILEI:AS'IING. he w a s m o v e d f r o m the artificially cooled w a r d to a general w a r d w h e r e the air t e m p e r a t u r e n e v e r fell b e l o w 1()0° F. a n d in t h e m i d d l e of the day rose c o n s i d e r a b l y a b o v e this level. F r o m t h e t h i r t e e n t h day to the m i d d l e of the s i x t e e n t h day all salt w a s o m i t t e d f r o m his f o o d a n d d r i n k o w i n g to a m i s i n t e r p r e t a t i o n of o r d e r s . T h e r e s u l t i n g d r o p in his blood c h l o r i d e is clearly s h o w n in t h e g r a p h a n d c h l o r i d e v e r y s o o n d i s a p p e a r e d f r o m his u r i m ' . F r o m the s i x t e e n t h to t h e t h i r t y - f i f t h day of his illness, salt w a s i n g e s t e d b y t h e p a t i e n t at n m a l t i m e s o n l y . H e w a s f r e q u e n t l y e n c o u r a g e d to increase his salt intake b u t salt r e m a i n e d a b s e n t f r o m his u r i n e a n d his b l o o d c h l o r i d e s l o w l y d r o p p e d (sec g r a p h ) . ( ) n the t w e n t y - s e v e n t h day of his illness he w a s w a r n e d to m a k e a v e r y c o n s i d e r a b l e i n c r e a s e
FRANK MARSh.
2(;I
in his salt intake. The result is plainly shown in Graph I1 ; there was an immediate increase in his blood chloride and a return of chloride to his urine. The patient was discharged on the thirty-fifth day feeling very fit : he returned to work and remained well through another summer in Persia. T h e investigation of this patient demonstrates plainly the importance of an ample salt intake. On m a n y occasions, he informed me that he had heen in the habit of taking salt very freely at me:~l times for some years, but it is obvious that the quantity he considered ample was in reality' quite insufficient for his bodily needs during a Persian summer. It is regretted that limitation of staff prevented routine estimations of this patient's blood lactic acid. T h e r e is little doubt that on admission he had some reduction of blood volume and in future attempts will be made to estimate the haemoglobin percentage and to obtain a hmmatocrite readinfz in all cases admitted suffering from heat effects. I think the hypochlormmia and reduction of blood volume so (>ftcn associated with severe diabetic coma was not, in this case, due to diabetes, which existcd only as a mild complication and sequela. T h e high Mood sugar recorded below in the cases of experimental heatstroke in rabbits, causes one to wonder whether prodromal or fully developed heatstroke may not be a starting poinl, hitherto unrecognised, for diabetes. In S q u a d r o n - I , e a d e r ~IoRTON'S series anidrosis i~ m a t ] v cases uas noted, and absent urinary chloride in one case. IV.
BLoor., (;ttEMISTRY IN I:~XI'ERIMENTAL[[EATSTROKE (tIYI'EP,TtH:RMIA).
Some further experiments were carried out with rabbits exposed to the s~m in order to confirm the findings of HALL and \VAKEFIIZ:LI)(1927) who used dogs in a heated chamber. Our results are shown in the Tables l I I , 1 \ and V. \Ve arc in complete agreement with ItALL and \\~AKEFIEI,I), with regard to the increase in blood lactic acid, the decrease of plasma bicarbonate and plasma p I [ ariel the uniformity in the level of blood chloride in animals before and after hyperthermia. We found, however, that there was a marked rise in the blood sugar of rabbits ;dter an attack of h y p e r t h e r m i a : in tlALL and \VAKEFIEIA)'S series o n l \ a slighl and variable alteration in the blood sugar was recorded. We thought it possible that the rabbit results were due to the high carbohydrate diet of the animals. ,\ series of rabbits were accordingly' given water only for some days and then allowed to develop h y p e r t h e r m i a under experimental conditions. In this series a rise of blood sugar also occurred, but not to the marked extent previously noted. It is possible that the rabbit's pancreas is more sensitive to high body t e m p e r a t u r e than is the pancreas of a dog. \Ve could discover no obvious lesions ~f the rabbit's pancreas at atttopsy with naked eve or in sections. T h e normal figures for our various blood cb.emical estimations were <~btained
o 6 o•.,
I [!R'I'IIER STUI)IES IN " IIEAT~'I'I),OI
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FRANE MARSII.
26,:;
with blood from the left ventricle obtaincd hv needle puncture, the rabbit being ana~sthetised with ether from a mask. Some days later the animal was allowed to develop hyperthermia in the sun, and its ventricular blood again obtained ; as the animal was unconscious no anaesthetic was necessary for the second operation. A few rabbits were investigated, under the same conditions, 7dthou! an anaesthetic; we found that the anaesthetic raised thc hlood sugar and that in both the anaesthetised and non-anmsthetised rabbit, blood lactic acid volumes were much hi~her than the figures for resting man. The blood bicarbonate did not seem to bc affected by the anaesthetic. Wc als~ performed fifty estimalions of whole blood chloride on normal rabbits (actual mean : $48 mg. in I~tl c.c., standard deviation: 25.1~8 rag. in 1(11} c.c.) as a preliminary to certain experiments on the lines of those of ARMOUR et al. V. -DISCUSSION. Such further investigations as we have been able to make lend additional support to the contention that in non-sweating laboratory animals hyperthermia is accompanied by a rise in blood lactic acid and a fall in plasma bicarbonate (as first pointed out by HALL and WAKEFIELD), which events are accompanied, in the case of sweating man, bv a fall in blood chloride, i feel sure that the fall in blood chloride, which was so marked in the prodromal case described here and which was equally marked in the fully-developed case that I described in a former paper (MARSH, 193o), is responsible for the anidrosis noted in my two published cases and in a n u m b e r of S q u a d r o n - L e a d e r MORTON'S cases and in a series of prodromal heatstroke cases described bv A. K. HEARNE (1932), and a n u m b e r of other observers. ttow hypochloraemia interferes with sweating is not quite clear; it m a \ be that sweat glands are unable to secrete sweat when the blood chloride is low, as [ previously suggested (MARSH, 193~}), or it is possible that a low blood chloride induces a secondary reduction in blood volume. I think it is generally accepted that shrinkage of t;lood volume depresses sweating. T h e work of }lADEN and ORR (1923), GAMBLE and Ross (1925), 'I'm~SLER (192S), and many other observers all goes to show that the extreme hypochlormmia following the prolonged vomiting associated with high intestinal obstruction may cause death with symptoms of weakness, anorexia, ()liguria and profound depression. The " water poisoning " described by *loss (1927), is probably an earlier stage of the same process. Even without the interference with sweating and evidence is accumlllating that this is real--hypochlormmia ~ravely embarrasses all the normal metabolic functions of the bodx. I think a patient with his hlood salt lmv and his bodily salt reserves exhausted will thirstily drink any available water, t|is body is embarrassed
266
FURTttER STUDIES IN ~ tlEATSTROKI'.."
by the necessity for maintaining the physiological tonicity of the blood and tissue fluids and at the same time dealing with the ingested water; hypotonicity is death, so the surplus water is rapidly excreted by the kidneys (polyuria) and perhaps by vomiting and some is lost by a quick burst of sweating. The blood volume then is rapidly restored to its former low level, or slightly lower, since of necessity more salt was lost in the burst of sweating, and the patient is no better off. The vicious circle can only be broken by the ingestion of salt. In the series of cases described by W~LL(:OX (192~i), suppression of sweating was not noticed. The reason, [ think, is that sweating to he effective must be continuous and profuse, anything less will be ineffective and it must have been some such ineffective sweating that was noted in his cases. In acute heatstroke cases, Squadron-I,eader MORTON describes the eflect of the intravenous administration of 1 t~} I 1 pints of '2 per cent. sodium bicarbonate in saline, as dramatic, tle administered s~dimn bicarbonate and glucose (with saline ?) bv month to all his heatstroke cases and the}, rapidly' improved. It is possible that sodium bicarbonate is converted into sodium chloride in the body as he had similar good results with potassium citrate and Professor Moss noted long ago that miners in Pendleton colliery put small amounts of cream of tartar (potassium bitartrate) in their drinkin~ water as a cramp preventive (Moss, 1927). Professor Moss was the first to draw attention to the syndrome ~f " water poisoning " in miners who lost much salt in their sweat while following their occupation in hot mines. APPENDIX.
Technique for Estimation of Blood Lactic Acid. (1) 1~) c.c. blood is obtained from the vein of the patient in an all-glass syringe. (2) This I0 e.c. blood is impelled into 1~t c.c. of 16 per cent. trichloracetic acid (ice cold). (3) The mixture is shaken and filtered through fine paper and the water clear filtrate is kept in the ice chest until the estimation is performed (usually within three hours). (4) A quantitative test with dilute ferric chloride or the ltopkins reaction is usually performed on an aliquot portion of this filtrate. The remainder of the filtrate is measured and then treated in the manner and with the apparatus described by BOYLAND (1928). Steam distillation is employed in the presence of dilute potassium permanganate and sulphuric acid ; this carries over acetaldehyde into a solution of sodium bisulphite, the excess bisulphite being destroyed bv iodine; the acetaldehyde-bisulphite compound is then broken down hy a saturated solution of sodium bicarbonate and the liberated bisulphite carefully titrated with dilute and very accurately
FRANK MARSIf.
2(;7
standardised iodine solution. F r e q u e n t c o n t r o l s are n e c e s s a r y w i t h p u r e l i t h i u m lactate or B.P. lactic acid. W e f ( m n d t h a t it was u n n e c e s s a r y to take m e a s u r e s to r e m o v e the s u g a r in the b l o o d as the t r i c h l o r a c e t i c acid s o l u t i o n d e s t r o y e d it.
REFERENCES.
.\I/MOI I/, J. C., BROWN, 'I'. G., DUNLOP, D. M., MrrcH~;LL, T. C., SEARLS,H. 1t. & STEW.anT, C . P . (1931). Studies on high intestinal obstruction. Brit. ft. Surge~3', xviii (71), 4(57. BOVLANIL E. (1928). Chemical changes in muscle. Biochem. J., xxii, 24{). (;AMnL~:, J. I,. & Ross, S . G . (1925). The factors in the dehydration following colonic obstruction. J. Clin. Invest., i, 403. IlAI)EN, R. L. & OnR, T . G . (1923). Chemical changes in blood of dog after intestinal obstruction. J, Experim. ivied., xxxvii, 365. I la1J., W. W. & \VAKEFIELD, E. G. (1927). Experimental heatstroke. J. Amer. ,lied. Assoc., lxxxix, 179. }h.:AnNE, K. G. (1932). Hyperpyrexial heatstroke: a *lesopotamian experience, with some ~etiological views and a method of prevention arising therefrom. :lied..7. Australia, 19th year, i (7), 226. 3'Iansn, FnANK. (1930). The etiology of heat-stroke and sun ~raumatism. Trans. Roy. Soe. Trop. Med. & Hyg., xxiv (3), 257. MOnTO~,, T. C. ST. C. (1932). The a~tiology and treatment of heat exhaustion and heat hyperpyrexia with special reference to experienee~ in Iraq. Proc. Roy. Soc..'3lied., xxv (8), 1263. 3loss, K. NEVILLE. (1917). Gases, Dust and Heat in 3/lines, p. 190. London : Charles Griffin & Co., Ltd. PFr~ns, J. R. & VAN SLYKE, I). I). (1931). QuantitativeClinicalCkemistrv, col. i, Interpretations, 935. London : Bailli6re, Tindall & Cox. TRUSLEn, H . M . (1928). ttypochlor~emia, ft. dmer. 3lied. Assoc., xci (8), 538. WH~LCOX, W. H. (1920). The nature, prevention and treatment of heat hyperpyrexia. Brit Meal..7., i. 392.