Thermpregulatory mechanisms and ethanol hypothermia

~r~n ~um~ ~P~rm~o~, ©~ / N o ~ h ~ d ~om~

~ E R M O ~ G ~ ~ Y

71 (1981) 4 8 3 ~ ~e~

MECHAN~MS AND ET~OL

PETER LOMA~ JOSEPH G. BAJOREK, T E R R ~ N N E D~m~t Los A n ~

483

~ ~m~o~, School of M ~ e ~H~& 90024, ~ A .

HYPOTHERMIA

B ~ O R E K ~ d ROWAND R ~ CHAFFEE

and the B~in Research Ins~tut~ ~ W e ~

of C a ~

Recdved 27 Novemb~ 1980, reused MS ~ce~ed 3 March 1981, accepted 4 M~ch 1981

P. LOMA~ J.G. BAJOREK, ~ A . B ~ O R E K ~ d R.R~. CHAFFEE, ~ e ~ o r ~ u ~ mechan~ms and ethanol h~o~m~ E ~ o p ~ n J. ~ ~ . 71 (1981) 4 8 3 ~ 8 7 . The mecha~sms u ~ the h y p o t h ~ m ~ effect of ~ h a n ~ h ~ e been h v ~ d h ra~. At an a m ~ e ~ ~mp~u~ of 26°C, at w~ch ta~ s~n blood flow will ~ y be expected to ~ a y a role in reguhting ~ r e ~mp~u~, no change in ta~ cutaneous t e m p ~ u ~ occu~ed during the p ~ o d ~ w~ch the core ~ m p ~ u ~ was ~ l ~ g aRer a d m i n ~ n of ~ h a n ~ . ~ the drug e ~ c t waned t~l skh ~ m p ~ e ~H b~ow the ~ M ~mp~u~ ~ ~ e h y p o ~ m h w ~ co~e~ed. ~ l~t o b ~ r ~ t ~ n ~ s eafli~ ~ s ~ ~ c a ~ n g a shiR h the th~momg~atory ~ t p o h t aRer a d m h ~ n of ~ h a n ~ . There was no ~ g n ~ change in oxygen consump~on rehted to the ~ h a n ~ hduced hfi in core ~ m p ~ u ~ so ~ heat ~oduc~on wo~d ~ t appe~ to be a h c t o r in the th~mM imb~an~. N d t h ~ was t h e e any change ~ r ~ m t o r y rate or m~ute v~ume to account ~ r an ~ e ~ e ~ convect~e or e ~ p ~ e heat ~ ~a the hngs. From these ~ s ~ R ~ n ~ d e ~ by what mecha~sm the enthanol hduced ~we~ng of the set p~nt leads to a ~ 1 ~ core t e m p ~ u ~ . Oth~ avenues of heat ~ , ~ r exam~e from other cutaneous s u r h c ~ , and h r t h ~ deta~ed t h ~ m ~ bMance ~u~es will be needed to resolve th~ ~ o ~ e m .

Ethanol

H~o~a

Oxy~n consum~n

1. h t m d u ~ n

Sk~ ~ m p ~ e

Resp~ation

H~t loss

A~ adm~~n of ~coh~ ( e ~ ~cohoL ~ ~ h ~ ) ~ s to a d o ~ depem dent ~ l ~ body ~ ~ e ~ ~ce, ~ , g~bfls (Lomax ~ d B~orek, 1980) ~ d ~ e a p~s ( H ~ ~ d Hu~enen, 1977). The

w~d ~ g of ~ e ~ n ~ ~mos~s (Lom ~ et ~., 1980). The ~ w ~ g of ~ e set p~ m ~ be o~y one ~ o n ~ r ~ e ~ l ~ ~mp~e, ~ c ~ ff ~ h ~ ~ ~min~md under a d v ~ ~ m ~ cond~ ~ons. The ~ w ~ s e ~ g wffi, h o w ~ reduce the p h y ~ o ~ c ~ responses to c~d

m ~ d e ~ ~e ~ of body ~mp~e ~ a function of the ~ o n m ~ ~mp~e (Freund, 1~3; H ~ ~d Hu~enen, 1977; L o m ~ et ~ . , 1 9 8 1 ) ~ ~ e s e s p e d e s ~ d ~ h ~ led t o ~ h e r s~y o f ~ e responses ~ deve~p~g ~ ~ model to ~ g ~ e the ~n~ome ~ e ~ i ~ ~ n ~ hp poth~mh ~ m~. ~ h ~ ~ e ~ e ~ h ~ ~ud~s ~ ~ e d th~ ~e ~ s ~ a he~ ~ at t h e ~ m e ~ e b o d y ~ m p ~ e w~ ~fing, ~ d ~ g th~ the hypoth~m~ e~ct of ~h~ was due, ~ least ~ p ~ , to a d o w m

~p~e ~d ~ ~ ~ e ~ e ~ ~a~ c o u l d d e ~ o p in w h ~ h t h e ~ i m ~ ~ u n ~ ~ ~c~e ~s h e a t p r o d u c t i o n . C ~ y , ~ deve~p~g p m ~ ~ ~d ~apeufic ~ e m s for ~h~ induced ~ c ~ hp poth~mia ~ ~ ~ s ~ to con~der the ~ h ~ l ~ sys~ms me~g ~e response. The u n d e f l y ~ g m ~ h ~ m s by wh~h ~h~ ~we~ body ~ ~ ~ un~e~. In~e~ed ~ e ~ b l o o d flow, w ~ h a u p men~d convect~e ~d ~ t he~ ~s~ a p p e ~ s t o be ~ e d ~ ~e in~i~ ~tor

484

precipitat~g hypotherm~, ~ t h o u g h the p ~ h o g e n e ~ s of the va~ular change has not been explained. In ~ u d i ~ ~ humans ~ven moderate d o ~ s of ethanol ( ~ o o d ethanol ~ 1 0 0 m g - ~ - ~ ) during immer~on ~ c o ~ w ~ e r no ~ c r e a ~ s ~ cutaneous blood flow w ~ e d e ~ c t e d ( M a r t ~ and C o o p e h 1978; Fox ~ ~., 1979). N o r w e ~ w e a b ~ to d e m o n s t r a ~ changes ~ t ~ l s k ~ ~ m p e r a t u r e ~ prelim~ary s t u d i ~ ~ r a ~ i n j e c ~ d with ethanol (1 g . k ~ ~ i.p.) ~ an ambient ~ m p e r ~ u r e of 18°C (Lomax and B~orek, 1980). During cold exposure the ethanol ~ d u c e d f ~ l in b o d y ~ m p e r a t u r e ~ associated with d e p ~ t i o n of blood ~ u c o ~ leve~ ( H ~ g h t and K e ~ g ~ 1973) and ~ has been suggested t h ~ a f a r ~ h a n ~ heat loss ~ n o t m a s h e d by heat production ~ s ~ of carbohydrate m o b ~ zation (Hirvonen and H u ~ e n e n , 1977). A~hough H ~ g h t and K e a t ~ g e (1973) d e ~ m ~ e d the e f f e ~ of e t h a n ~ on the m e ~ b ~ response to cold (14.5°C) them do n o t appear to have been any ~ p o ~ s of ~ u d ~ s in w h ~ h the metabofic response to ethanol has been measured under n o r m o t h e r m ~ cond~ions. Thus, ~ t h o u g h e t h a n ~ appears to have a d ~ e c t ~c~on on the t h ~ m o r e g u l a t o r y c e n ~ , ~ ~ n o t ~ear w h ~ e f ~ o r mechan~ms m e , a t e the subsequent f ~ l h b o d y ~ m p ~ rature. The p o ~ f l i t i e s t h ~ might be cons~ed ~ude decreased m e ~ b ~ h e ~ ~rodu~n or ~ e a s e d resp~atory e v a p o r a t e h e ~ loss. Cutaneous h e ~ loss ~ o m the taft ~ s o needed ~ a s ~ m e n t s ~ c e tail b ~ o d flow ~ m i n i m ~ at ambient ~ m p e r ~ u r e s below 24°C and m a x i m ~ above 28°C (Hells~Sm, 1975). Between these ~ m p e r ~ u r ~ the t ~ l skin ~ m p e r a t u r e shows the ~ e a ~ responses to ~ t e ~ d ambient ~ m p ~ a t u ~ s with a h ~ steresis loop c h a r a ~ e ~ z ~ g the ~ l ~ n s ~ p (Dawson and K e b ~ , 1979). These c o n s ~ tions rendered ~ p o s ~ e that p r e ~ o u s s t u d , s of cutaneous heat loss (Lomax and B~orek, 1980) w ~ e c a r t e d o u t ~ t o o l o w a n a m ~ e n t ~ m p e r a t u r e (18°C) so t h ~ vasodflation was suppressed ~ sp~e of the change ~ the set po~t.

P. L O M A X E T AL.

2. M a t e r , s and m e t h o d s M ~ e Sprague-Daw~y r ~ s w ~ h an ~ i ~ b o d y weight of 2 0 0 ~ 2 0 g w ~ e used. The an~ m ~ s w ~ e m a ~ m ~ e d ~ an ambient ~ m p ~ rature of 18 ± I°C up to the time of the e x p e ~ m e n ~ . During the e x p e ~ m e n ~ the anim ~ s w ~ e ~ghfly ~ s ~ n e d ~ ~ c cag~ or u n r e s ~ n e d in the s p ~ o m e ~ r chambe~

2.1. T e m p e ~ t u ~ measu~men~ Body ~ m p e r a t u r e w ~ m e ~ u r e d w ~ h a t h ~ m ~ t o r probe ~ r ~ d a p p r o x i m a ~ 6 cm into the colon. The probe was e ~ h ~ taped lightly to the base of the ~fl (for c o n t ~ u o u s ~ c o r d ~ g ) or ~ s ~ d ~rm~ntly. Sk~ ~ m p e r ~ u r e was measured w ~ h a d~c therm ~ t o r attached tightly, so as n o t to impede b ~ o d flow, to the d o ~ surface of the taft 1 cm ~ o m the b ~ e .

~2. Measu~ment and ~spiration

of oxygen

consumption

These m e ~ u ~ m e n ~ w ~ e made with the a ~ m ~ s ~ a sp~ometer chamber c o n ~ e c ~ d to a 500 ml c a p a ~ t y sm~l a n i m ~ s p ~ o m e ~ The e n t r e s y ~ e m was f i l e d with oxygen and the m o v e m e n t of the s p ~ o m e ~ r drum, which was recorded on a k y m o g r a p ~ was suffid e n f l y ~ n s i t ~ e to ~ w m e ~ u r e m e n t of oxygen c o n s u m p t ~ n , respiratory r a ~ and m~u~ resp~atory v ~ u m e simu~aneou~y. A ~ v o h m e s a r e c o ~ e c ~ d to standard ~ m p ~ t u ~ and p ~ u r e , dry. The mean r e ~ g oxygen c o n s u m p ~ o n of 10 c o n ~ o l animus ~ 25°C was 3.16 ± 0.24 ml • min -~ • 100 g-~ compared to a v ~ u e of 3.10 ± 0.08 ml • min -~ • 100 g-~ in earlier studies ( L o t ~ et ~., 1966). The ambient ~ m p e r a t u r e was that of the w ~ e r sump forming the gas s e ~ ~ the s p ~ meter c h a m b ~ and, ~ a room ~ m p e r a t u r e of 22°C, t h ~ stabilized ~ 25 ± l°C. A ~ m ~ s w ~ e cond~ioned to the chamber on the day p ~ o r to measurement.

ETHANOLHYPOTHERMIA 2.3. Drugs

Ethanol was dissolved in steele NaC1 (0.9%) solufion to a concentration of 20% (w/v). The pH was checked, adjusted to 7.0 with NaHCO3 ~ necessary, and the solu~on was passed through a Mfllipore fi~er into a sterile vial. Control injec~ons were NaC1 (0.9%) solution subjected to the same treatmen~ 3. Results 3.1. E f f e c ~ o f ethanol on core and ta~ skin temperature

Two groups of 8 rats w~re conditioned to an ambient temperature of 26 ± I°C for 120 min (08:00--10:00 h) by which time the 2c°rt ehi~vdnJeect ti'38"1o Eae7thean S d wit rthespectively~ " a i°s 0Cki i tehntlehicla hent 'anOv l edmperat r ee6"( 91. SU50.(on9~%ggr°u0 2 p'CNack 2-h 3°" 1,g lad wS astabflizeL d)mPean. 7.5(thna~i em

485 a mean faU in core temperature of 0.65 ± 0.08°C over the ensuing 30 min which was ~gn~icanfly greater (P = 0.0022; Mann Whitney U-test) than the slight (0.1 ± 0.05°C) decline in the control animals over the same period (fig. 1). During the 30 min interval over which the core temperature was falling there was no change in taft skin temperature (fig. 1). However, at the time the ethanol induced fall reached its maximum (at 30 min) the tail temperature in these animals then declined and remained at a level approximately I°C below the initial temperature during the pe~od of recovery. Th~ change was ~gn~icant compared to vehicle injected animals {P = 0.0149; Mann Wh~ney U~est).

P -~ co~ T E M ~

kg-~ Lp.). The ethanol injected animals had

-~ ~

OXYGEN CONSUMPTION

0_

i

~

,

i

i

0

minute s

Fig. 1. Ef~ct of ethanol (1.5 g • kg-~ i.p.) (unfilled c ~ ) cr ve~i~e (0.9% NaCl, 7.5 ml • kg-1 i.p.) (tiffed c~es) on core and taft sk~ ~mp~ure in two ~oups of 8 ra~. I~ec~ons were made at 0 mira V~cM Hn~ represent 1 ~E.M.

m in u te s

Fig. 2. Effect of ethanol (2 g • kg-i i.p.) injected at 0 mh on core temp~ature, oxygen consumpt~n and r e s p ~ n in a ~oup of 10 r~s. Ve~ical fines represent 1 S.E.M. Initi~ mean core ~mper~ure was 37.8 ± 0.08°C.

486 3.2. E f f e c ~ o f ethanol on oxygen consump~on and respiration Two groups of 10 rats were injected w~h either ethanol (2 g • kg -1 i.p.) or vehicle {0.9% NaC1, 10 ml" kg -1 i.p.).As illus~ated ~n f~. 2 there was a ~ h t gradu~ fa~ in oxygen consumpfion over the recording pe~od. Admin~ a t i o n o f e t h a n o l ( 2 g • kg -~ i & . ) l o w e r e d t h e core temperature 1.69 ± 0.28°C over 30 min {core temperature was measured at the time of i n j e c f o n of ethanol and 30 min ~ter) but there was no associated change in oxygen con~umpfon. In c o n ~ o l a n i m u s the temperature and oxygen c o n s u m p f o n remained ~ e a d y throughout the recording pe~od, N e t h e r the resp~atory rate nor the minute volume showed any s~nificant changes fo~ lowing injection of ethanol (fig. 2) or vehicle {not illus~ated).

4. D ~ c u s ~ o n The earliest studies suggesting that the taft of the rat f u n c f o n s as a heat d~sipating organ appear to be those of K n o p p e ~ (1942). Gemmel and H~es {1977) d e m o n s ~ a t e d histologic ~ l y the existence of ante~ovenous anastomoses in the rat taft which would be C O h e r e n t w~h such a role. Dawson and Keber (1979) concluded that the rat tail has the characte~ ~ f c s of an o n / o f f controller and that the taft skin temperature increases as a resu~ of an act~e n e u r o l o ~ c ~ process at r~sed ambient temperatures. Rand et ~. {1965) estimated t h a t up to 20% of t o t ~ heat p r o d u c f o n in the rat could be l o ~ ~ o m the taft. In ear5er studies carried out an ambient temperature of 18°C the fa~ in b o d y temperature induced by ethanol w~s not a c c o m p a n ~ d by any ~se in. tail temperature (Lomax and B~orek, 1980). R ~ f i k ~ y that at t h ~ a m b ~ n t temperature the a c t u a t i o n of increased tail blood flow ~ inhib~ed (Hels~Sm, 1975). Howeve~ as ~ clear ~ o m fig. 1, even at ambient t e m p e r ~ tures at which this response would be active there was no e~dence of increased flow

P. LOMAX ET AL during the ~me the core temperature was falfing, ind~ating that the tail does n o t cont ~ b u t e to increased heat l o ~ after a d m i n ~ w f o n of ethanol. T h ~ conclu~on ~ cons~tent w ~ h an~ogous resu~s in human studies (Martin and Coope~ 1978; Fox et ~., 1979). There ~, nonethdess, an intere~ing observm f o n in f ~ . 1. Our pre~ous s t u d , s (Lomax et ~., 1980) indicated t h a t ethanol causes a downse~ing of the regulated temperature. As the drug effect subsides the set point will revert to ~s normM v~ue. Under the cond~ fions ~ading to the changes in fig. 1 t h ~ occurred 30 m~n after drug a d m i n ~ a t i o n . The coze temperature at t h ~ point ~ now b d o w the set temperature and heat conservm fion mechan~ms are actN~ted, including a decrease in tail skin blood flow. This is man~ fest by the f ~ l in taft temperature at t h ~ f m e . Conversely, t h ~ observation tends to c o n f ~ m that a set point change had occurred. Since a stable body temperature involves a balance between heat production and heat loss a reduction in metabol~m could result in a fall in temperature if heat loss were unchanged. Th~ would be reflected by a fa~ in oxygen c o n s u m p f o n ; as seen in fig. 2 there was no s~nificant change in oxygen cons u m p f o n during the 30 m~n fall ~n b o d y temperature induced by ethanol. A~hough such a m e c h a n ~ m has ~ e q u e n f l y been suggested as unde~ying the h y p o t h e r m ~ ac~on of various drugs (e.g. LoCi et ~., 1966) gmple assumpfive c ~ c u ~ f o n s render t h ~ u n l i k d y in the present instances. According to Brody {1945) in the adu~ ~bino rat 1 ~ e of oxygen ~ e q u N ~ e n t to 4.9 kc~. Thus, in the present e x p e ~ m e n ~ , at a steady oxygen c o n s u m p f o n of 3 ml • min -1 - 100 g-~, the animus are producing 850-900 c ~ in 30 min. A f ~ l ~n body temperature of 1.69°C invokes an e n ~ o p ~ r e d u c f o n of approximately 350 c ~ on the bas~ of a net specific heat of 1 for the w h o ~ animM. Therefore, to ach~ve t h ~ fall in body temperature by m e t a b o l ~ means ~ o n e the animal would need to reduce i~ heat production by 40% and there was no e~dence of a change o f t h ~ m a g n ~ u d e (fig. 2).

ETHANOL HYPOTHERMIA Another source of heat loss in homeotherms ~ that from convective heat exchange and evaporative cooling du~ng resp~ation. After injection of ethancl there was no ~gn~icant change in either resp~atory rate or tidal volume (fig. 2) indicating that the pulmonary tree is unlikely to be cont~buting to add~ fional heat loss. Under normobaric conditions resp~atory heat loss ~ usually less than 10% of total b o d y heat exchange (Grayson and Kuehn, 1979) so that minor changes in respkatory rate or volume are unHkely to resu~ in a sign~icant fall in core temperature. The results o f t h ~ study still leave unanswered the question of the route of heat 10~ cau~ng the lowering of b o d y t e m p e r a t u r e after a d m i n ~ t r a t i o n of ethanol. Sweating probably does n o t occur in the rat b u t sa~va spreadin~ w ~ h consequent evaporative heat loss, m a y be observed u n d e r certain condi~ons of heat stress or drug induced hypothermia (e.g. during opioid withdrawal hypothermia). Howeve~ t h ~ behavioral response was n o t observed after ethanol. The remaining possibilities are that ethanol induces altered metabolic p a t h w a y ~ t h a t do n o t involve heat produc~on, or heat l o ~ other than via the taft skin. There are no desc~bed m e c h a n ~ m s lending credence to the former. As to the latter, although the tail ~ widely regarded as a heat loss organ in the rat (Rand et al., 1965) the bared skin of the feet may const~ute an equally effective avenue (Thompson and Stevenson, 1965). Clearly m o r e detailed heat balance studfes will be requ~ed to resolve t h ~ question. And, although the problem has much theoretical interest in the rat, the elucidation of the mechan~ms in man is of considerable relevance to the m a n a g ~ ment of ethanol induced accidental hypothermia,

Acknowledgements Th~ ~udy was supposed by ONR con~a~ N 0 0 0 1 4 ~ 5 ~ 5 0 6 and by USPHS grant AAO 3513-03.

487 References

Br°dys 'pe~"Referencl 945' eBi°energet~t S the o Effi~ena ndcyGr°wtc hom~e:~n Dom~tic A~m~s (R~nh~d, New York City) p. 451. Dawso~ N.J. and A.W. KebeL 1979, Phy~Aogy of heat lo~ ~om an ex~emity: the taft of the rat, Cl~. Exp. PharmacA. P h y ~ . 6, 69. F°x~f~cG t'R'~fJ'Sal'cohH:lYwao nrdth~ma nd ~G'Nb"~ancH e°bS°no f 'maln979~n cad watt, Can. J. P h y ~ . PharmacY. 57,860. Freund, G., 1973, Hypoth~mh a~er acute ~hanA and benz~ ~cohA administration, Life S~. 13, Gemini_ ,45.3 R.T. and &R.S. H~es, 1977, Cutaneous ~ o v e n o u s anastomoses present in the ~ but absent ~om the ear of the rat, & Anat. 124, 355. Grayson, J. and L.A. Kueh~ 1979, Heat transfer and he~ lo~, ~: Body Temp~ature, eds. P. Lomax H~ghta, nd E~s.jS .chbnbaum (D ' e nkW.R. k ~da KeatingeN, ew 1973Y ,°rk)'Fa~ur~ 71"e of th~moregulat~n h the cad during hypo~ycaemh induced by exerdse and ~han~, & P h y ~ . London 229, 87. Hells~bm, B., 1975, Heat vasod~atat~n of the rat H~vonent , a ~ Can~J~nP~ysiA. , P .h Hu~ene~ arm . a c o l p 19775, 3' 202T "he ef~ct of ~hanA on the ab~ty of gu~ea ~gs to w~h~and severe cold exposure, in: Drug~ Bioge~c Amines and Body T e m p ~ u r e , eds. K.E. Coop~, P. Lomax and E. Schbnbaum (Karger, Bas~) p. 230. Knopp~s, A.Th., 1942, La queue du rat, ~ m ~ n de h r~g~n th~miqu~ Arch. Need. PhylA. 26, 364. Lomax, P. and J.G. B~o~k, 1980, C o m p l i N e th~moreg~atory effects of ~hanA in rats, mice and gerb~s, Proc. We~. PharmacA. Soc. 23, 219. Lomax, P., J.G. B~orek, T.-A. B~orek and R.RJ. th~mC haffee' ic ef~l ~t981'o~hana~C~im~i n nthe rata,ndproct .he hyP°W "e~. PharmacA. Soc. 24 (~ pm~). Lomax, P., J.G. Ba~orek, W.A. Che~rek and R.RJ. Chaffee, 1980, EthanA-~duced hypoth~mh in the rat, Pharm~col. 21,288. L°ttid'u~Vn~" anPd " L°mah Xea t losas nd iRn" thGe e°rg~ 1' 9 a6fo~owi~gea~ntraP, 6tr r°" c~eb~al and sy~emic a d m i ~ r a t i o n of mo~ p~ne, Int. J. NeuropharmacA. 5, 75. M~t~, S. and K.E. Coop~, 1978, A~ohA and respkatory and body temp~ature changes during Randt ,eP~R2.w,ate;.ci?m~si°nB ' u r t o nan~ T~P~I "ng,PhY~°l 1"965,Th~4~a~83o'f the rat, in t e m p ~ u r e reguh~on and acdimat~m tion, Can. J. PhylA. Pharmacol. 43, 257. Thompson, G.E. and J.A.F. Stevenson, 1965, The t e m p ~ u r e response of the male rat to ~eadm~ e x ~ s e , and the effect of ante~or hypothMamic lemons, Can. J. P h y ~ . Ph~mac~. 43, 279.