Experimental studies on differential hypothermia of the liver

" at a' I S t u d m' s E7x, p m , ""1me1 Hypothermia

of the

on

Differential

Liver

MICHIO MITO, M.D., AKIRA TAMAKI, M.D., T A D A M A S A KON, M.D., SEIJI OI~tlRA. M.D., and JIRO MIKAM1, M.D.,

tlokkaido University School of Medicine For the purpose of pert%rming hepatic resection under a dry operative field and the reconsir'action of lhe portal triad after complete removal, temporary interruplion of hepatic blood flow has been required. It is generally agreed that under normothermia the maximum safe period of hepatic artery occlusion is 20 to 30 minutes,~'* and that this period may be prolonged to 60 minutes under hypothermia of about 26 ° C, rectally. ~"a. ,~,,~ Surface cooling as reported at present, however, has several shortcomings. These a,"~. complexity of management, necessity for a longer period of cooling, and the fact that indications for radical operation for hepatic or hilar cancer are now determined after laparof omy. Furthermore, there is considerable discrepancy in the findings relating to the maximum safe period of occlusion and hepatic temperature. An attempt has been made and is ~eported in this paper to develop a new method of "differential hypothcrmia of the liver," so that even after laparotomy the liver may be cooled satisfactorily within a brief period. The safety and clinical applicability of this method was demonstrafed by studies of hemodynamics, histology, liver function tests and oxygen consumption of the liver during and after the procedure. Oxygen uptake of the liver was measured in vivo and in vitro at temperatures between 37 and 15° C.

Cooling

Group A,

l~errupting

Group 8

A~V P : Pump

A'-* P0rl~ P0rl; --, V H.E :Heat Exchanger

Figure 1. Extracorporeal circuit for cooling.

GROIJP A. This group underwent interruption of hepatic blood supply under general hypolhermia by means of blood stream cooling to determine the hepatic temperature necessary tbr 90 minutes' occlusion. GP,OUP B. In this group, the interruption was performed under differential hypothermia of the liver m or below the temperature attained in the experiments in Group A. A closed extracorporeal circulation was employed in cooling and rewarming, consisting of a pump of the DeBakey type and a heat exchanger, both of which were connected with polyethylene robes. Priming blood vNume was approximately 200 co. Cooling was performed through portal and arterial systems. Oxygen consumption of the liver was measured u n d e r the arterial shunt (Fig. 1).

MATERIALS AND METHODS

OPERATION

Adult mongrei dogs weighing I5 to 17 kg. were t~sed and were divided into two groups.

Atropine 0.2 to 0.3 rag. intramuscularly and thiamylal sodium 20 to 25 mgJkg, were administered as premedication prior to inmbation. Anesthesia was mNntained with ether to stage ! II, plane II before cooling; Group A Was cooled to 25 Io 30° C. rectal temperature b y means of the shunt belween 207

From the Fiest Department of SurgerY, Hokkaido Untversit)' School of Medicine, Sapporo, Japan. Dr. MRo is Resealx:h Fellow in Surgery, Harvard Medical Schoo! arid Boston City HospRaL 8oston. Massachusetts. Submitted for publication D e c e m ~ r 15, ! 964. JSR -- VoI. V, Ne, 5 - May 1965

208

MITO

JSR -

ET AL.

N0.32 19kg RoomTemp. 2 I" C

"C 35

Vol. V, No. 5 -- May 1965

'%~

Het~a!ic Blo,o~ Flaw

interrupteo for 90 rain,

30 25

Coolin,

Rewarming

Rectal

8.P,

mmHg

~,

50

,,'~ Pulse/rain

TO0

|

, b"

"' "-o--.~'-'~

40 F i g u r e 2,

t30

rain

Operative course (Group A): 19 kg. male; room temperature - 21 ° C.

Flow rate Time Perfusate

'C

Cooling

Rewarmtng

t 20-40 cc,/mflz. 42 rain. 4-5 C~

140 cc,lmin~ 30 rain. 38-40 C,

!.to.39 t5.5kg ~ RoomTemp 20"C

35

.

•

interrupted

~ "

30

•

20

J. I

Rectal

a |', I

,, . . . . .

tb".-"'HeP"ti:

Coo~i~g } mrnHgl o.., •] 150t t,,,~, !"

i /

Portal P,

Operative course (Group B): 15.5 kg. male;

Flow rate Time Perfusate

j j [i

o 20 F i g u r e 3.

i Rewarming

I

V'-~P l

• o.; tO(It ~

1,

Pulse _

.,,, o,,' 0~" rQ.~ ~,.,,~

.'w~'''~-''''

p" 1 0

rain

roomteraperature

-

20 ° C.

General cooling

Hepatic cooling

Rewarmtng

140 CeJmin. 10 rain. 4 - 5 C.

60 co./rain. I0 rain. 4,-5 C.

I20 c¢./rain. 43 rain, 3 8 - 4 0 C.

,ISR -- Voh V. No. 5 -- May 1965

DIFFERENTIAL

femoral artery and vein, while Group B was similarly cooled to 32 ° C. The liver was cooled differentially by pouring the cooled blood into the splenic vein. As an adjunct, direct intraperitoneal cooling was performed on both groups by filling the abdominal cavity with sterile saline at a temperature of 5 to 8 ° C. Hepatic blood flow was inlermpted when the hepatic temperature became less than 26 ° C. During the occlusion, sp!anchnic pooling of venous blood was prevented by the ~plenicfemoral bypass by which the pooled blood was returned to the systemic venous circulation. After the interruption of hepatic blood flow for 90 minutes in both groups, blood stream rewarming was continued with the femoral arteriovenous shunt until rectal temperature became 35 ° C. (Figs. 2, 3). In each group, hemodynamic stfidies and hematochemical examinations were followed until three weeks postoperatively. After dead~ or sacrifice, livers and other organs were examined histologically. For the purpose of determining the relation of hepatic temperature and oxygen consumption of hepatic cells, Eck fistulas were prepared initially in dogs. The livers of these dogs were cooled differentially through a femoral-hepatic artery shunt. (A~eriat blood from the femoral adery was diverted into the hepatic artery after cooling through an extracorporeal circuit.) Inflow rote into the liver and oxygen content of hepatic artery and vein were measured. Total hepatic oxygen uptake was calculated as the product of the blood flow and the difference in oxygen content of the inflowing and outflowing blood determined by Van Slyke's method. Oxygen consumption of liver slices was measured by Warburg*s apparatus at temperatures of 37, 30, 25 and 20 ° C. RESULTS 1. G ~ u p A (rectal temperature 30 to 25 ° C., 90 minutes' occlusion). a. In two dogs in Group A which received 90 minutes" occlusion under rectal tempe~ture of 30 to 29* C., no abnormal findings were observed in the circulatory system before and after the occlusion. However, the dogs died on the first and third postoperative days, showing remarkable increase in S G O T and S G P T and a definite decrease in serum pmteim Histologic examination of the livers revealed congestion,

HYPOTHERMIA

OF

LIVER

2t19

cloudy swelling, atrophy and necrosis of hepatic cells. b. On the other hand, all five dogs in which hepatic blood flow was i n t e ~ p t e d under rectal temperature of less than 26 ¢' C. survived for a long term. All through the inter~ption, the circulatory system showed no significant changes and only the electrocardiogram revealed changes that could be explained by hypothermic influences. Biochemically, slight elevation of S G O T and S G P T was seen on the first and third postoperative days, but it returned to normal one week posto~ratively. The animals became aroused when the body temperature returned to normal, and they ambulated a few hours after the extubation. Histologic studies were normal except for slight cloudy swelling of hepatic cells and minimum disorder of hepatic architecture. The conclusion was reached that hepatic temperature required for 90 minutes occlusion of hepatic blood flow is less than 26 ° C. 2, Groul) B (occlusion under differential hypothermia of the liver). Since the experiments o~ Group A revealed that hepatic tempez~attmre should be less than 26 ° C, in order to obtain 90 minutes' safe occlusion, Group B underwent interruption of hepatic blood supply with hepatic temperatures of less than 26 ° C. a. COOIANG~ It took 40 m 45 minutes to cool Group A to 26* C., while in Group B c ~ l i n g via the hepatic artery necessitated 15 minutes and via the portal vein, 17 to 18 minutes. At that time, rectal temperatures were 32 and 29 ° C. respectively. b. C I R C U L A S O I t Y CIt_ANGES. Pulse and blood pressure gradually decreased in parallel with the cooling process and the changes were well correlated with rectal tempm~ature, but not with hepatic temperature. D u r i n g the rewarming process, both the pulse and blood pressure returned gradually t o the previous level, but the pulse gradient was larger than during cooling (Fig. 4). During the cooling p r ~ e s s , the prolongation of P-Q, R-R and Q-T imervNs, high voltage of QR~q complex and depression of T wave were observed; but they returned m normal after rewan-ning, tn both groups there was no significam difference in the electrocardiogram, and, moreover, it was considered that the above mentioned changes were not due to hepatic perfusion but rather 1o h y ~ t h e r m i a itself. All through the Procedure, neither atrial nor ventricuIar fibN1lation was observed (Fig. 5). C. H E M A T O B I O C t t E M I C A L

EXAMINATIONS.

210

MITO

JSR -- Vol. V, No. 5 -

E T AL+

cootin9

gm/dl

rewarrnin9

May t965

Group B

lO0

serum protein ++

90 80

.~.++..0-~

70

b It)o++ sugar

50 +++"+

"

¢eetal Figure 4, pulse +rate.

Rectal

+

+mr

temp

temperature

+ and

reduction

Serum protein decreased slightly on the first to third postoperative days but began to increase a week later. It returned to normal by the third week without any difference between the two groups. Blood sugar in both A and B dropped to about 50 my. per 100 ml+ immediately after 90 minutes" occlusion regardless of the ternperature of the rectum and liver, but returned to the previous level after rewarming. No substantial changes occurred in serum bilirubin, thymol turbidity test and icterus index, but there was some degree of change in alkaline phosphatase, S G O T and SGPT, all of which became normal a week postoperatively. Comparing A with B. S G O T was higher in the ++:+ i+ +i+ii i++::+~+++ ;+

Pro

I

33 31 29 llccl 30mie Figure 5+ Elecmocardiogmm of dog in Group B.

II

~

GPT

t~f

/"

Gi3,f+~',,

50

days

wks

Figure 13. Biochemical examination (Group B)+

former group, which had the longer perfusion of the liver (Fig. 6). d. H I S T O L O G I C FINI)IN(L;S, The livers in which the blood flow was occluded under rectal temperature or hepatic temperature of tess than 26 ° C. showed slight congestion, cloudy swelling and disto~ion of hepatic architecture. All returned to normal by the third week postoperatively. Histologicatty, there was no significant difference between the two. Based upon these findings, it became clear that differential hypothermia which cooled the I+ver to 26 + C+ and kept the body under only moderate hypothermia decreased the adverse effects of hypothermia, and with this procedure interruption of hepatic blood flow could be possible for 90 minutes. It is noteworthy that the data obtained by Warburg's method coincided with van+t H o ~ s law (Q~,~ = 2)+ According to the data. oxygen consumption of liver slices decreased to 36 per cent at hepatic temperature of 26 + C+ when compared with that at 37 ° C. (Fig. 7)+ CAsE RF.POI:tT, This techniqtte was later applied to a clinical case, A 54 year old male was diagnosed by preoperative examinations as having cancer of the right lobe of the liver. Laparotomy revealed cancer of the right Iobe which was approximately 20 cm+ in diameter. Total removal of the right lobe was undertal~*en. Initially, the liver was cooled selectively by a shunt between the femoral artery and the splenic vein. Femoral artery blood was cooled

JSR -

DIFFERENTIAL HYPOTHERMIA OF LIVER

V o L V , No. 5 -- May 1965

splanchnic pooling as previously described. Hepatic circulation was occluded for 45 minutes, during which tinie the removal of the total right lobe was successfully accomplished. After reopening the hepatic circulation, the blood stream rewarming was carried out by femoral arteriovenous shunt, Rectal temperature returned to 35 ° C. in about 40 minutes when the extracorporeal circulation was discontinued (Fig. 8). The patient was covered with blankets. He regained consciousness at a temperature of 36 ° C. and the postoperative course was unevenffutJ

80

60

,, ---.--., "".

\".V

211

S

DISCUSSION 37

30

20

75

15

Temp "C

Figm'e 7, Relation between |emperature and O2 consumptitm of liver, ( ) ~ -~2: ~lNe curve shows decreased O~ uptake in accordance wi~h van't HotVs law. W: O= uptake of liver slices measured by Warbt~rg's method, V,S,: ()~ uplake converted f~om the measuremenl with Van Slyke's meth~d.

to 5° C. -while passing through the extmcorporeal circuit and was returned to the splenic vein. After 15 minutes, rectal temperature dropped to 32 ° C. and hepatic temperature to 20 ° C,, and the hepatic blood flow was interrupted, During the interruption, bypass of the splenic-femoral vein was done to prevent 8,P.

S,Y. 54 Y/0 X 57 kg.

10C a0 letup,

"C

Coal ~nlerfuption at H!tus

t Rewa~m =

35

j4,,t

30 J Hepatic

25 20:

I5 F'i~ure. 8, Operalive c o u p e under hypothermia,

60 during hepatec~omy

According to previous studies on interruption of hepatic circulation, the maximum safe period for interruption is 30 minutes under normothermia and 60 minutes under" hypothermia with a rectal temperature of 26 ° C?- :~"~'''' Because of differences in anesthesia, methods of cooling and rewarming and the operative procedures to occlude hepatic circulation, accurate comparison of the dala is difficult; however, it wilt be summarized as follows: a. It takes a few hours with surface cooling to obtain a rectal temperature of 25 to 26 ° C, b. The maximum safe period for the interruption of hepatic circulation is 60 minutes by the method already reported. c. Splanchnic pooling is inevitable during the occEusion, d. The correlation between hepatic temperalure and hepatic anoxia remah~s obscure, Befieving that the relation between hepatic temperature and the length of the interruption ~ r i o d would never be clear until sphmchnic pooling was excluded by bypass, the experiments of Group A were performed. The resultant data proved that interruption for 90 minutes would be possible under hypothermia of hepatic tempmature 26 ° C. As a second stage, difli~ren6al hypothermia of liver was investigated, the purpose of which was to decrease the disadvantages following hypothermic procedures and to prolong the period of occlusion, with the following results: as in Group A, the interruption for 90 minutes was possible under hypothermia with a hepatic temperature of 26 ° C, even if the body temperature remained in the neighborhood of 30 ° C. Cooling via portal vein is better in clinical

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