plasma electrolyte changes in hypothermiaplasma samples was confirmed by the benzidine test for...

Thorax (1958), 13, 334.

PLASMA ELECTROLYTE CHANGES IN HYPOTHERMIABY

K. A. MUNDAY, G. F. BLANE, E. F. CHIN, AND E. S. MACHELL

From the Department of Physiology and Biochemistry, Southampton University, and the Surgical Unit,

Southampton Chest Hospital

(RECEIVED FOR PUBLICATION MAY 22, 1958)

Despite the widespread use of hypothermia inclinical surgery, the nature of the plasma electro-lyte changes associated with this state is far fromclear, and little attempt has been made to considerthem in relation to adrenocortical activity.Haemoconcentration has been recorded in

hypothermia by Rosenhain and Penrod (1951),Millar (1954), and Villalobos, Adelson, and Barila(1955), although Segar, Riley, and Barila (1956)and Moyer, Morris, and De Bakey (1957) showedonly slight variations in haematocrits which wereinsignificant but usually indicative of haemo-concentration. This suggests that haemoconcen-tration is a frequent though not consistent resultof hypothermia.The plasma sodium response to hypothermia is

confused. A decrease is reported for hypothermicdogs (Swan, Zeavin, Holmes, and Montgomery,1953), although Segar et al. (1956), also with dogs,found no significant change in the excretion ofsodium. In contrast Moyer et al. (1957) suggesta rise in plasma sodium for both dogs and man asa common occurrence, although they attach nosignificance to this change.Of all the reported changes in blood constituents

in hypothermia a fall in the plasma potassium isthe most consistent (Swan et al., 1953 ; Segar et al.,1956; Moyer et al., 1957), although Elliott andCrismon (1947) and Bigelow, Lindsay and Green-wood (1950) had earlier reported a rise. Theaetiology of this potassium shift is poorly under-stood. The diminished plasma potassium does notrepresent a net loss of body potassium asmeasured by the urinary loss of potassium duringcooling (Swan et al., 1953; Segar et al., 1956;Moyer et al., 1957). Most frequently the move-ment of potassium from the plasma in hypo-thermia is attributed to plasma pH changes.

It has recently been shown (Munday andBlane, 1958) that the electrolyte changes of nor-mal intact animals exposed to cold is compatiblewith the theory of an increased adrenal release ofmineralo-corticoid type hormones in response to

the cold stress. Investigations were carried outand are recorded in this paper on the nature of theplasma electrolyte response of the anaesthetized,cold-exposed animal. Such animals becomehypothermic compared with the unanaesthetizedanimal, which maintains its body tempera-ture. There is also controversy as to the adrenalactivity and responsiveness in the anaesthetizedhypothermic animal, and consequently the investi-gations on the plasma electrolyte response of thehypothermic animal were extended to considerany possible correlation with adrenal corticalactivity.

MATERIALS AND METHODS

ANIMALS.-The rats and rabbits were from depart-mental animal house stocks. The rats were adultmales of the hooded strain and the rabbits adult malelitter mates. The clinical samples were collected frompatients of both sexes and varying ages suffering froma variety of cardiac disorders demanding surgicaltreatment. The majority of cases were repairs ofatrial septal defects of the ostium secundum type.

ANAESTHESIA AND HYPOTHERMIA IN RATS ANDRABBITS.-Since curare type drugs cannot be gener-ally used in animal experimentation, the control ofthe gross shivering necessary for the smooth induc-tion of hypothermia depends entirely on the level ofanaesthesia.

Rats were given 5.0 mg. "nembutal"/100 g. bodyweight intraperitoneally 30 minutes before immersionin the cooling bath and a second dose of 2.0 mg. /100 g. a few minutes before immersion. At this doselevel the control of shivering was adequate and bodytemperature fell smoothly.The rabbits were given 5.0 mg. " nembutal "1

100 g. body weight intraperitoneally two hours beforeimmersion and were maintained on a warm bed at37' C. throughout this period to maintain their bodytemperature. A second dose of 2.5 mg. "'nembutal "/100 g. body weight intraperitoneally was given 30minutes befpre immersion. At this dose level allrabbits shivered on immersion in the cooling bathuntil their body temperature fell to about 25' C. Thiswas unavoidable since administration of higher dosesof anaesthetic were frequently fatal.

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PLASMA ELECTROLYTE CHANGES IN HYPOTHERMIA

The anaesthetized rats and rabbits were cooled byimmersion in a cooling water-bath. The bath temper-ature (37° C. at the start) was lowered by the additionof ice, and when the colonic temperature had reachedthe required minimum (20-24' C.) the bath tempera-ture was raised to that level to prevent a continuedfall in body temperature.For rabbits where serial blood samples were taken

from individuals the animals were slowly rewarmedon a heated bed at 37° C.ANAESTHESIA AND HYPOTHERMIA IN MAN.-lnduc-

tion was by thiopentone after premedication withchlorpromazine and pethidine and sometimes atropineor hyoscine. Shivering was controlled by curare.The patient was surface cooled in an ice-bath to anoesophageal temperature of 32-33° C., and then re-moved and usually maintained at a temperature of29.5 to 30.5° C. during cardiotomy. After cardio-tomy the body temperature was restored to normalby surface rewarming with warm water blankets.BLOOD SAMPLING.-For the rats and rabbits all

blood samples were taken by cardiac puncture usinga paraffined 5 ml. record syringe and a 2 in. (No. V)serum needle. Since blood sampling is itself stressful,rats were rejected after providing one sample, andtook no further part in any experiment.

Serial blood samples of approximately 3 to 4 ml.were taken from individual rabbits to parallel thecontinuous series of the clinical material.The clinical samples were taken at intervals

throughout the operation. Samples were obtainedfrom superficial veins of the arm or leg before andafter thoracotomy, care being taken to sample a limbinto which there was no saline drip, so avoiding anypossible direct dilution effect. While the heart wasexposed samples were always taken by direct rightatrial puncture.

All blood samples were heparinized, and it wasshown that the amount of heparin used introducedno detectable error in the plasma sodium and potas-sium levels. Any blood sample showing a suggestionof haemolysis after centrifugation was discarded forthe plasma potassium value, since correction usingspectrophotometric estimation of the degree ofhaemolysis as suggested by Hunter (1951) proved un-satisfactory. The absence of haemolysis in the clearplasma samples was confirmed by the benzidine testfor haemoglobin.PROCEDURES.-Plasma sodium and potassium levels

were determined using an " EEL" flame photometer.The plasma was routinely diluted, 1 ml. plasma:99 ml. glass-distilled water, I ml. 5°, A.R. HCI. Theacid prevented protein precipitation and gave clearsolutions and was added in similar proportion to astandard containing

145mEq./l. sodium and 5

mEq./l. potassium. This standard was used in theestimation of both sodium and potassium plasma con-centrations and takes account of the radiation inter-ference of large amounts of sodium in determinationsof low concentrations of potassium (Lundgren, 1953).

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K. A. MUNDAY, G. F. BLANE, E. F. CHIN, and E. S. MACHELL

Duplicate whole blood haematocrit determinationswere carried out on well-mixed heparnized wholeblood samples. All pH determinations were carriedout with a Pye "universal" pH meter on wholeblood samples taken under oil. The determinationswere made at the appropriate temperature withinthree minutes of the blood sample being withdrawn.ADRENALECTOMY.-The male rats were bilaterally

adrenalectomized in one stage under nembutal anaes-thesia. They were maintained post-operatively on1% saline drinking water and rat cake (" blue cross "41B). On this rdgime the adrenalectomized animalsmaintained normal plasma sodium levels, but theplasma potassium levels were somewhat lower thanthe controls (see Table V). There was a markedhaemodilution. The completeness of the adrenalec-tomy was confirmed in all animals at necropsy.

RESULTSCLINIcAL.-The plasma electrolyte and whole

blood haematocrit values were determined fromblood samples taken when possible during opera-tions carried out with hypothermia. Thesepatients were in acid-alkali balance. A summaryof the series is given in Table I. "Control"

K

3,1

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values were obtained immediately before induc-tion of anaesthesia and there was good con-sistency between these values and those obtained24 hours earlier before any operative premedica-tion.

Case 3, Table I, is graphically represented inFig. 1. Comparison with other cases in Table Ishows that the trends of change of Case 3 arerepresentative of the series as a whole, and thisis further emphasized by Table II in which thechanges recorded are expressed as a percentageof the control pre-hypothermia values. Thesetrends are briefly:

(1) A consistent tendency for the plasma sodiumlevel to rise throughout the period of surgery andin most cases to continue rising thereafter. Thusin the first seven cases the highest sodium levelswere recorded in post-operative samples takensome three to four hours after the patient had leftthe theatre, by which time normal or almost nor-mal body temperature had been regained. Thesodium levels were normal by the day followingthe operation.

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Time-wFiG. 1.-Plasma sodium and potassium concentration and oesophageal temperature in clinical hypothermia (Case 3). Electrolyte concen-

trations as mEq./l. Patient immersed in cooling bath at 2 p.m.

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TABLE IISUMMARY OF CHANGES IN PLASMA ELECTROLYTESAND WHOLE BLOOD HAEMATOCRITS IN HYPOTHERMIAAT OR NEAR TERMINATION OF SURGERY AS REWARM-

ING BEGAN

Plasma*Patient Haematocrit

Na K

2 +5-6 -33-9 -5-23 +3-3 -31-4 +7-74 +2-8 -1-4 +2-45 +6-2 -30 1 +5-46 +1-2 -34-0 +2-77 +7-2 -38-8 +0-28 +0-6 -35 9 +5-89 +4-6 -25-3 +3-410 +5-1 +5-3 +10-111 +5-7 -32-0 +3-212 +2-4 -35-213 +6-7 -24-6 +11-014 -51-2 -17-515 +2-3 -40-1 -8-816 +2-1 -27-9 +2-6

*Results expressed as % individual pre-hypothermia control values.

(2) A very significant fall in the plasma potas-sium levels, which almost invariably began to fallas soon as cooling commenced before surgery hadbegun. Minimum levels were recorded towardsthe end of the operative period, and invariablywhenever occlusion took place the post-occlusionlevel was markedly below the pre-occlusion value.The onset of rewarming after occlusion appearedto check the decline in plasma potassium concen-tration, and post-operative values, while stillslightly low, were often in the vicinity of thecontrol level. The post-operative value was belowthat of the last surgical sample in only twoinstances (Cases 4 and 9). There was no evidenceof the rise in plasma potassium after thoracotomydescribed by Mavor, Harder, McEvoy, McCoord,and Mahoney (1956) for dogs.

(3) Whole blood haematocrit changes were in-conclusive.

It has been shown that an elevated sodium anddepressed potassium concentration in the plasmais a characteristic feature in unanaesthetized ratsacutely exposed to cold, and further, that in theabsence of the adrenal gland no such changesoccur (Munday and Blane, 1958). The close simi-larity between such an electrolyte response and thepattern observed in patients during and after theinduction of hypothermia suggests that here, too,adrenal hyperactivity with release of mineralo-corticoids could be involved. The continued risein the plasma sodium of most patients, despite thereturn to normal of the body temperature, tendsto contradict any suggestion that the sodiumchange is a purely physical phenomenon depend-ent on body temperature itself, and is more

compatible with a hypothesis of corticoid releasein response to the combined stresses of coolingand major surgical intervention. At the same timethese results alone in no way justify the rejectionof the conclusion reached by earlier workers thatthe potassium shift in hypothermia is principallya result of a metabolic alkalosis induced by hyper-ventilation relative to the reduced needs of theanimal. Nevertheless, this should not negate thepossibility of mineralo-corticoids acting con-

currently and in the same direction as an alkalosisto depress the plasma potassium.

INTACT RATS.-Some questions raised by theseclinical results were then investigated by animalexperiments. It was first established that theplasma electrolyte and whole blood haematocrit

TABLE IIIPLASMA ELECTROLYTES AND WHOLE BLOOD HAEMATOCRITS OF INTACT RATS BEFORE AND AFTERNEMBUTAL ANAESTHESIA, DURING INDUCTION OF HYPOTHERMIA, HYPOTHERMIA, AND ON REWARMING

Time Colonic Plasma Na Plasma K HaematocritPeriod from Temperature ('C.) (mEq./l.) (mEq/1.) (%)

Immersion(min.) Mean Level Mean Level Mean Level Mean

Control, not anaesthetized 0 38-0 145-6 4-88 42-6±0-21 ±0-08 -0-41

Control, " nembutal " anaesthesia 0 38-2 145-8 4-53 40-038-2 38-1 145-6 145-7 4-61 4-75 44-0 41-937-8 145-9 4-80 42-538-2 145-5 5-06 41-0

Anaesthetized, cooling (0-40 min.) 15 34-0 151-5 4-17 44-520 33-5 153-5 3-62 47-525 29-6 155-0 2-92 48-530 26-0 155-9 3-02 49-0

Anaesthetized, cold (40-80 min.) 40 22-5 153-0 3-54 52-355 20-0 23-2 152-5 153-0 3-82 3-81 51-3 51-975 24-0 152-5 51-980 26-0 153-8 4-06 52-0

Rewarming 100 min. after removal 180 37-5 150-9 4-46 52-0from bath. Body temperature 180 38 5 38-0 149-2 150-9 4-34 4-44 55-9 52-3normal 180 38-1 152-5 4-51 49-0

280 min. after removal from bath 360 37-8 148-1 4-61 51-0360 36-6 37-3 148-4 148-5 4-69 4-66 51-5 51-3360 37-5 149-0 4-69 51-5

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0

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FIG. 2.-Plasma sodium and potassium and whole blood haematocrit changes in intact rats during, andimmediately after, hypothermia. Baselines in figure represent control means. A = Net change fromthese means.

levels remained normal in "nembutal " anaes-

thetized rats which were not cooled (Table III).Other rats were anaesthetized and cooled as

described earlier, and blood samples were

obtained and analysed at various stages (Table IIIand Fig. 2).A consistent record was obtained of rapidly

rising plasma sodium and whole blood haemato-crit values as hypothermia was induced. At thesame time plasma potassium fell to low levels.

The haematocrits remained high throughoutthe period of deep hypothermia (30-80 min. afterimmersion in the cooling bath) and were still highwhen the last rat was sampled 260 minutes afterrewarming had begun. By this time the bodytemperature had been normal for approximately180 minutes. This clearly defined haemoconcen-tration of the rat in hypothermia agrees withthat recorded by certain earlier workers butcontrasts with the haemodilution which occurs in

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cold-exposed normothermic rats (Munday andBlane, 1958). It may represent fluid shiftscaused specifically by hypothermia, and takingsome time to adjust.

Plasma sodium reached a high maximum levelwithin 30 minutes after cooling began and thenfell somewhat but remained high until after theanimals were rewarmed. In contrast the potas-sium, while reciprocating the early sodium pictureand reaching very low values after 25 to 30minutes of cooling, climbed steadily throughoutthe " cold " period. By the end of the six-hourexperimental period potassium levels were almostnormal.The hypothermic rats of this experiment

received no artificial respiration and were ventilat-ing at a very slow rate. It seemed possible, there-fore, that a metabolic acidosis might be presentdue to inadequate disposal of CO2. Sufficientblood for pH determination, as well as electrolyteanalysis, could not be obtained from an individualrat and consequently a second group of rats wereused to test the blood pH changes in hypothermia.The rats were anaesthetized and half their number(five) cooled as before. The other five were keptat body temperature (370 C.) to act as controls.Blood samples were taken from both sets ofanimals over a period when electrolyte changes inthe hypothermic rats were known to be maximaland the pH determined in each case immediatelyafter withdrawal. The results from control andhypothermic animals are detailed in Table IV,together with the respiratory rates of the animalsimmediately before sampling.

TABLE IVBLOOD pH AND RESPIRATORY RATE OF NORMAL ANDHYPOTHERMIC MALE RATS ANAESTHETIZED WITH

NEMBUTAL

Time from ColonicRat nauctio Pf Temperature Blood Respiratory(a )

Iahes ('C.) pH Rate'Minute

Normal (Control)1 50 37 0 7 50 902 50 370 748 923 65 37 6 7 60 924 85 37 4 7 60 535 90 37.3 754 85

Mean 68 37-3 7 54 82

Hypothermic6 30 22-5 7 27 247 40 23 0 7 05 368 50 210 7 18 239 55 23*0 7-09 Irregular10 80 228 720 30

Mean 51 22 5 7 16 28A -17 -148 -038 -54

A Change from control means.

It is seen that a marked acidosis was present inthe hypothermic animals, significant at the 1-0.1 %level (t=8.10). While the rate of ventilation wasdepressed in these rats to one third of the controllevel it does not necessarily follow that CO2retention was the cause of the acidosis, althoughthis is the most probable explanation. The possi-bility remains that impairment of kidney functionat least contributes to the conditions.

This finding of an acidosis in hypothermic rats,concomitant with a low plasma potassium level,renders the more necessary some other interpreta-tion than that previously put forward for this well-established electrolyte change in hypothermia,since an acidosis alone is known to favour thedevelopment of hyperkalaemia (Fenn and Asano,1956; Tobin, 1956). Axelrod and Bass (1956) andBoere (1957) had also reported low plasmapotassium levels in acidosed hypothermic subjects.These results again direct attention to the hypo-thesis that a sudden release of mineralo-corticoidsdue to adrenal hyperactivity in response to hypo-thermia may be responsible for the rapid fall inplasma potassium concentration.ADRENALECTOMIZED RATS.-TO test this hypo-

thesis eight bilaterally adrenalectomized rats werecooled using an identical procedure to that forintact animals. The body temperature of alladrenalectomized animals was found to beslightly subnormal initially (average 36.5° C.).There was little gross shivering during the induc-tion of hypothermia and the rats cooled rapidlyto below 250 C. Thereafter they were maintainedat body temperatures similar to those reached inthe earlier investigation using intact rats (TableIII) until the last one had been sampled. Plasmaelectrolytes and haematocrits were determined forsix anaesthetized adrenalectomized controls aswell as for the adrenalectomized animals subjectedto hypothermia (Table V).There was no significant change in the level of

plasma sodium or potassium on either " nem-butal" anaesthesia or hypothermia of the adrenal-ectomized rats, although there was some haemo-concentration, particularly in hypothermia. Sincepost-experimental necropsies, performed on allanimals participating in this experiment, showedthat adrenalectomy had been complete in everycase, it is concluded that the sodium and potas-sium shifts seen in intact rats are, in fact, bothdependent on the presence of the adrenal gland,the hormones of the mineralo-corticoid groupprobably being the responsible agents.

INTACT RABBITS.-A series of small bloodsamples was taken from individual rabbits. They

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TABLE VPLASMA ELECTROLYTES AND WHOLE BLOOD HAEMATOCRITS OF NORMAL, ADRENALECTOMIZED, ANAESTHETIZED

ADRENALECTOMIZED, AND ANAESTHETIZED ADRENALECTOMIZED RATS RENDERED HYPOTHERMIC

Time Colonicfrom Tempera- Na (mEq. '.) K (mEq.!l.) Haematocrit (%)

Immersion ture(min.) (OC.) Level Mean Level Mean Level Mean

Normal, intact, non-anaesthetized rats .. 38-0 145-6 4-88 42-6±0-21 ±0 08 ±0-41

(30) (22) (12)Adrenalectomized, non-anaesthetized rats .. 368 1461 448 3015

(5) ±0-42 ±0-16 ±0-64

Nembutal anaesthetized controls (adrenalecto- 37 0 144-3 4-28 34 5mized) 38-0 1450 4-76 33 0

36-5 145-8 145-8 4-84 4-51 33-1 31-736 5 147-6 ±0 45 4-35 ±0-15 31-0 ±0-9235 4 145-9 3-96 28-835-7 145-9 4-86 29 5

Nembutal anaesthetized hypothermic 20 27-0 146-0 4-40 34-4(adrenalectomized) 30 18*5 144-3 4-17 37-3

35 22-5 146-8 4 51 38 540 250 143-5 145-4 4-30 4-47 37 9 35-645 22 0 1459 ±0-37 4 05 ±0 08 33-5 ±0 7355 19-0 1459 4-71 32-565 23-0 145-6 4-48 35*480 23-0 145-3 4-61 35 0

Means ± Standard errors. Number of animals in brackets.

were anaesthetized with " nembutal" and acontrol blood sample obtained at normal bodytemperature. The animals were then cooled forperiods from 75 to 160 minutes and severalblood samples taken at intervals during coolingand rewarming.The changes occurring at the end of cooling as

rewarming began are summarized in Table VI,and the general pattern of results confirms thatalready reported in detail for rats. Again amarked fall in plasma potassium was associatedwith a respiratory acidosis produced as a result ofthe anaesthesia.

DISCUSSIONThese results show that a marked fall in plasma

potassium and a rise in plasma sodium occurs in

TABLE VISUMMARY OF CHANGES IN PLASMA ELECTROLYTES OFRABBIT AT THE BEGINNING OF REWARMING AFTER

PERIODS OF HYPOTHERMIA

ColonicTem- Chang

Length of perature Plasma* Respira- inRabbit Cooling ('C.) as tory -Blood(min.) Re- Rate* pH*

warmiingBegan Na K

1 75 21-0 +3-35 -24-62 75 20-5 +3-2 -I1-8 -47-53 80 23-5 +4-4 -20-3 -72-54 80 24-3 +3-1 -29-4 -79-0 7-55-7 205 80 28-5 +0-8 -28-0 -62-5 7-48-7-385 Maintained 29-0 +0-8 -40-6 -56 2 7-38

(cont.) at body sI.eadytempera-ture 29°C.for further80 min.

* Results expressed as % individual pro-hypothermia control value.

rats, rabbits, and humans anaesthetized anddeliberately rendered hypothermic. The per-centage fall in plasma potassium is markedlygreater than the rise in plasma sodium in allanimals. There is also a discrepancy in timebetween the smaller, more sustained rise in plasmasodium and the faster adjustment of the fall inplasma potassium. There was marked haemo-concentration in the hypothermic rats. The ex-planation of these electrolyte and fluid changes issomewhat problematical.As the body temperature falls there is a pro-

gressive reduction in renal activity, as measured bythe renal blood flow and glomerular filtration rate(Andersen and Nielsen, 1955; Page, 1955; Segaret al., 1956; Moyer et al., 1957). Yet both Segarand Moyer and their co-workers show no con-comitant fall in urine output but rather a diuresis.The haemoconcentration, a characteristic

feature in intact hypothermic rats, also developedin adrenalectomized animals, confirming theearlier suggestion that this may be a purelyphysical phenomenon, specifically resulting fromthe hypothermia.No theory has been advanced to account for the

plasma sodium shifts, probably because of theirvariability as recorded by earlier workers. Theplasma potassium changes have been correlatedwith the blood pH changes. In hypothermia mostworkers artificially ventilate at normal rates, yetthe metabolic rate and therefore CO2 productionare depressed. Consequently such animals arefrequently relatively hyperventilated and thereforealkalosed. It has been shown in normal animals

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that elevated potassium levels occur in acidosis(Fenn and Asano, 1956; and Tobin, 1956) and lowpotassium levels in respiratory alkalosis (MacKay,1947). This correlation is emphasized by Segaret al. (1956) in attributing the fall in plasma potas-sium of their hypothermic dogs to hyperventila-tion resulting in a respiratory alkalosis. Theirfigures show a close inverse relation betweenplasma potassium level and pH, potassium levelsfalling during cooling and rising again onrewarming with reciprocal pH changes. Withcontinued hyperventilation Mavor et al. (1956)found the fall in plasma potassium reversed afterthoracotomy in 31 out of 45 dogs despite a furtherfall in temperature. They related this rise inserum potassium to increased hepatic glycogeno-lysis.

In hypothermic animals not receiving artificialrespiration an acidosis frequently develops due torespiratory depression despite the falling metabolicrate. Such a "cold-acidosis" was reported byAxelrod and Bass (1956) in hypothermic dogs andby Boere (1957) in humans. These acidosedanimals did not show the high plasma potassiumlevels expected, but instead there was a slight fallin potassium paralleling falling pH in the dogs(Axelrod and Bass, 1956) and low plasma levelsoccurred in the acidosed humans (Boere, 1957).By contrast Bigelow, Lindsay, Harrison, Gordon,and Greenwood (1950) had found high potassiumin the plasma of hypothermic dogs which werepresumably extremely acidosed since they wereallowed to continue natural ventilation until itceased.A respiratory alkalosis known to develop in

artificially ventilating hypothermic animals willtherefore contribute to any hypokalaemia. How-ever, the results reported in this paper show lowplasma potassium levels with a highly significantacidosis in rats. Preliminary observations in thehumans and rabbits also indicate no markedalkalosis developing during hypothermia althoughsignificant hypokalaemia. Consequently somealternative explanation to pH variation isrequired to account for these plasma potassiumshifts.

Barbitone anaesthetics were employed in allcooling experiments in which low potassium levelshave been recorded, and Millar (1954) suggeststhat barbitone anaesthetized animals, whethercooled or not, may be refractory to stressfulstimuli which normally cause release of A.C.T.H.This contention is supported by Masserman's(1937) finding that "nembutal" and other barbi-turates have a selective inhibitory effect on

hypothalamic nuclei and in consequence adecreased eosinopenic response to trauma innormal cats so anaesthetized. In contrast anincreased 17-hydroxycorticosteroid secretion fromthe adrenal vein of "nembutal "-anaesthetizeddogs has been recorded in response to suchstressors as scalding (Egdahl and Richards, 1956)and exposure to 20% CO2 (Richards and Stein,1957). In the experiments recorded in this paper" nembutal " anaesthesia alone also failed to affectmarkedly the plasma potassium level, and it is,therefore, doubtful if the low potassium levelsare related to the barbitone anaesthetics.

It has also been suggested that the hypothermicanimal is unresponsive to all forms of stresspossibly through complete autonomic block(Millar, 1954), and supporting evidence for this isprovided by Sayers and Sayers' (1948) report thatbarbitone anaesthetized rats do not exhibitadrenal ascorbic acid depletion after exposure to+ 30 C. for one hour. The Sayers suggest that areduction in cellular activity normally associatedwith the homoeostatic adjustment to cold isresponsible for the action of barbiturates inpreventing any increase of adrenocortical activityin stress.

Direct evidence that adrenal activity isdecreased in hypothermic dogs is provided byEgdahl, Nelson, and Hume (1955). They show asteady fall in the 17-hydroxycorticosteroid levelof adrenal venous blood with cooling to 75%below the control level at 210 C. and a rise incorticoid output on rewarming. Continuous in-fusion of A.C.T.H. did not prevent this fall, indi-cating a direct suppression of adrenal activity bycold. In contrast to these findings Egdahl andRichards (1956) and Boulouard (1957) reported amarked increase in 17-hydroxycorticosteroid out-put in unanaesthetized animals exposed to severecold.While these limited results on the activity of

the adrenal cortex in hypothermic anaesthetizedanimals suggest that corticoid output is depressedin the hypothermic subject, this level may notnecessarily be low relative to tissue requirements,which will also be depressed. A state of relativehypercorticoidism might still therefore exist, and,further, Richards and Stein (1957) have shownthat changes in the CO2 content of the blood canstimulate 17-hydroxycorticosteroid release throughthe ALP. Consequently hyper- or hypo-ventilat-ing animals might themselves cause increasedcortical activity.More recent work on aldosterone suggests its

likely implication in the aetiology of the electro-

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lyte shifts in hypothermia. Aldosterone is knownto be released in response to body fluid electrolyteimbalances (Leutscher and Axelrad, 1954; Rosen-feld, Rosemberg, Ungar, and Dorfman, 1956)rather than A.C.T.H. secretion (Farrell, Banks,and Koletsky, 1956; Rauschkolb, Farrell, andKoletsky, 1956). It is therefore quite possible thataldosterone may be released in the hypothermicanimal in response to increased demand fromeither the fluid shifts that seem to occur in hypo-thermia or from electrolyte irregularities.The pattern of the plasma electrolyte response

reported in this paper for the intact hypothermicanimal is compatible with the hypothesis of a sud-den release of mineralo-corticoid type hormonesdue to adrenal hyperactivity resulting from hypo-thermia. It is also established that the hypo-kalaemia developed during hypothermia in therats is not due to the development of an alkalosis.This theory of adrenal participation is furthersubstantiated by the failure of adrenalectomizedhypothermic rats to give the plasma electrolyteresponse typical of intact hypothermic animals.

Churchill-Davidson (1954) has remarked on theabsence of evidence that patients rendered hypo-thermic suffer less from the reactions of stress thanduring other forms of anaesthesia, and he hasadded that the induction of cooling itself may beanother form of trauma.The suggestion in this paper of a possibly

adrenally controlled change in the electrolytepattern of the hypothermic mammal could there-fore imply that the pituitary-adrenal axis ofanaesthetized animals may not be as refractory tostressful stimuli as many earlier workers havesupposed.

SUMMARYIn hypothermic rats, rabbits, and humans there

is a small sustained rise in plasma sodium levelsand a marked fall in plasma potassium levels.

Haemoconcentration occurs in hypothermicrats. This electrolyte response does not occur inhypothermic adrenalectomized rats, althoughthere is some haemoconcentration.

It is suggested that the plasma electrolyteresponse of hypothermia may be attributable toadrenal cortical hyperactivity, presumablythrough hormones of the mineralo-corticoid type.The marked hypokalaemia of hypothermia is

not due to the development of a respiratoryalkalosis.

REFERENCES

Andersen, M., and Nielsen, K. C. (1955). Acta med. scand., 151,191.

Axelrod, D. R., and Bass, D. E. (1956). Amer. J. Physiol., 186, 31.Bigelow, W. G., Lindsay, W. K., and Greenwood, W. F. (1950).

Ann. Surg., 132, 849.- Harrison, R. C., Gordon, R. A., and Greenwood, W. F.

(1950). Amer. J. Physiol., 160, 125.Boore, L. A. (1957). Anaesthesia, 12, 299.Boulouard, R. (1957). C.R. Soc. Biol. (Paris), 151, 913.Churchill-Davidson, H. C. (1954). Postgrad. med. J., 30, 394.Egdahl, R. H., Nelson, D. H., and Hume, D. M. (1955). Science,

121, 506.- and Richards, J. B. (1956). Amer. J. Physiol., 185, 239.Elliott, H. W., and Crismon, J. M. (1947). Ibid., 151, 366.Farrell, G. L.. Banks, R. C., and Koletsky, S. (1956). Endocrinology,

58, 104.Fenn, W. O., and Asano, T. (1956). Amer. J. Physiol., 185, 567.Hunter, F. R. (1951). J. biol. Chem., 192, 701.Leutscher, J. A., and Axelrad, B. J. (1954). Proc. Soc. exp. Biol.

(N. Y.), 87, 650.Lundgren, P. (1953). J. Pharm. (Lond.), 5, 511.MacKay, J. L. (1947). Amer. J. Physiol, 151, 469.Masserman, J. H. (1937). Arch. Neurol. Psychiat. (Chicago), 37, 617.Mavor, G. E., Harder, R. A., McEvoy, R. K., McCoord, A. B., and

Mahoney, E. B. (1956). Amer. J. Physiol., 185, 515.Millar, R. A. (1954). Brit. J. Anaesth., 26, 380.Moyer, J. H., Morris, G., and De Bakey, M. E. (1957). Ann. Surg.,

14 ,26.Munday, K. A., and Blane, G. F. (1958). J. Endocrinol., 16, 13.Page, L. B. (1955). Amer. J. Physiol., 181, 171.Rauschkolb, E. W., Farrell, G. L., and Koletsky, S. (1956). Ibid.,

184, 55.Richards, J. B., and Stein, S. N. (1957). Ibid., 18, 1.Rosenfeld, G., Rosemberg, E., Ungar, F., and Dorfman, R. I. (1956).

Endocrinology, 58, 255.Rosenhain, F. R., and Penrod, K. E. (1951). Amer. J. Physiol., 166,

55.Sayers, G., and Sayers, M. A. (1948). Recent Progr. Hormone Res.,

2, 81.Segar, W. E., Riley, P. A., and Barila, T. G. (1956). Amer. J.

Physiol., 185, 528.Swan, H., Zeavin, I., Holmes, J. H., and Montgomery, V. (1953).

Ann. Surg., 138, 360.Tobin, R. B. (1956). Amer. J. Physiol., 186, 131.Villalobos, T. J., Adelson, E., and Barila, T. G. (1955). Proc. Soc.

exp. Biol. (N.Y.), 89, 192.

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plasma electrolyte changes in hypothermiaplasma samples was confirmed by the benzidine test for...

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