Br. J. Surg. Vol. 64 (1977) 819-821
Total hepatic ischaemia in the Rhesus monkey PAUL MCMASTER A N D R I C H A R D MEDD* SUMMARY
During operations for major hepatic trauma it may he necessary temporardy ro deprive the liver of its blood supply by occlusion of the hepatic artery and portal vein. The maximum ‘safe period‘ of total hepatic ischaemia in man is unknown. In the monkey the ischaemic liver ‘leaks’ potassium, and levels of this element in the hepatic veins rise during ischaemia reaching a peak immediately after blood supply to the liver is restored. However, critical systemic levels of potassium are never reached and severe biochemical disturbance does not occur until 2 h following revascularization in animals having experienced ischaemic periods of longer than 20 min.
INrecent years there has been a steady increase in the incidence of major hepatic trauma associated with high speed road traffic accidents (Morton et al. 1972). In severe injury massive haemorrhage may be encountered at operation and it may be necessary to occlude the blood supply to the liver in order to gain control of haemorrhage or to facilitate hepatic resection (Little, 1971). Since the technique of clamping the hepatic vessels was described (Pringle, 1908), it has generally been considered that up to 20min of total hepatic ischaemia is safe (Raffucci, 1953) but that beyond 30 min severe ischaemic damage of the liver will have occurred (Drapanas et al., 1955; Peacock et al., 1969). Nevertheless, patients have survived more prolonged periods of ischaemia and cases in which the portal vein and hepatic artery were both clamped for as long as 78 min have been reported (Anastasia et al., 1967; Waltuck et al., 1970). Thus the maximum ‘safe period of time that the total blood supply to the liver in man may be interrupted at normal temperatures remains uncertain. Experimental studies have previously demonstrated that total occlusion of the afferent blood supply to the liver in animals is poorly tolerated because of the apparent susceptibility of the liver to anoxic damage (Bernhard et al., 1955; Jolly and Foster, 1963; Backlund et al., 1965). In the dog, hepatic necrosis due to hypoxic damage has been considered to be responsible for death after only 20min of total ischaemia (Raffucci and Wangensteen, 1951 ; Hyndman et al., 1957). Yet this susceptibility of the liver to normothermic ischaemic damage has recently been questioned, and quite marked extension of liver ischaemic times has been achieved in dogs with splanchnic decompression by portacaval shunting (Jolly and Foster, 1963; Mackenzie et al., 1975). Splanchnic decompression by portacaval shunting in man during surgery for severe hepatic injury is, however, rarely feasible. Factors other than hepatic necrosis have been considered responsible for the high mortality following complete hepatic ischaemia. These have included endotoxic shock (Battersby et al., 1971), hypovolaemia (Brunschwig, 1955), hepatic outflow block syndrome (Starzl et al., 1960) and the release of vasoactive substances (Joseph et al., 1968). In acute liver damage
potassium is released from hypoxic liver cells (Stewart et al., 1953) and high values have been recorded during total hepatic ischaemia (Backlund et al., 1965). Severe cardiac arrhythmias due to hyperkalaemia during total hepatic ischaemia have also been observed in the dog (Hall, 1972). However, the dog has disadvantages as a model for hepatic ischaemia which make interpretation of such results difficult. The problem of hepatic congestion and outflow block syndrome (Starzl et al., 1960) and the liver’s susceptibility to endogenous bacterial colonization leading to infection and endotoxic shock are well known (Ford, 1900; Battersby et al., 1971). In order to overcome some of these difficulties the Rhesus monkey was used in the present study which was undertaken to clarify the potassium changes occurring during total hepatic ischaemia without portal decompression. An assessment was made of the maximum ‘safe period’ for total normothermic hepatic ischaemia in the monkey. Materials and methods Six female Rhesus monkeys (Mucucu muluttu) weighing from 3.5 to 5 kg were used during this study. Anaesthesia was induced with intravenous thiopentone and maintained by an oxygen/halothane mixture. A cannula was introduced into the right side of the heart via the internal jugular vein and advanced into the pulmonary artery. The femoral vein was exposed and a second cannula was fed up into the inferior vena cava. A 5 per cent dextrose infusion was commenced in one of the upper limbs. A n upper midline incision was made and the liver was exposed. The structures in the free edge of the lesser omentum were identified and completely freed of the surrounding tissues. The hepatic artery was cleared as far as the gastroduodenal branch and the portal vein as far as its coronary tributory. The common bile duct was exposed along its supraduodenal segment, and all associated lymphatics and nerves in the porta hepatis were divided. The liver was then completely skcletonized with division of the left triangular ligament permitting complete mobilization of the left lobe. All branches of the left gastric artery running to the left lobe were divided and in 2 animals a major branch of the left lobe was discovered. The infrahepatic inferior vena cava was then exposed, acting as a guide for the division of the peritoneal attachments to the right lobe, and the right triangular ligament was divided. The whole right lobe was mobilized until the retrohepatic cava was exposed and the right phrenic veins identified. The falciform ligament was divided and the dissection above the liver exposed thc suprahepatic inferior vena cava. The cannula within the inferior vena cava was then advanced further and introduced into the opening of the middle hepatic vein. A small cannula was introduced into the coronary branch and advanced into the portal vein. Thus skeletonized, the liver remained attached only by its major vessels and the common bile duct. In order to allow continuous monitoring of pulse and blood pressure an aortic cannula was introduced via the right femoral artery and continuous ECG recordings were made.
* P. McMaster, University of Cambridge, Department of Surgery, Addenbrooke’s Hospital ; R. Medd, Department of Experimental Surgery, Huntingdon Research Centre. Correspondence to: P. McMaster.
820
Paul McMaster and Richard Medd
l‘ahle I: SERUM POTASSIUM LEVELS IN ALL ANIMALS DURING AND FOLLOWING TOTAL HEPATIC ISCHAEMlA Portal Pulmonary Hepatic vein vein artery Before occlusion 4.3 +0.5 3.9f0.7 4.0+0.8 After 15 min 5.6 0.6 4-1k 0 . 7 4.310.3 ischaemia 6.2+0.8*** 4.1 f 0 . 8 4.1 t O . 8 Immediately before release of clamp 3.940.6 4.140.4 20 s after release 7.4&0.6** 4.1 f 0 . 4 4.5+0.6 40 s after release 5.6+0.7*** 4.0h0.7 4.210.5 60 s after release 4.7*0.5 2 rnin after release 4.2+0.5 4.1 i0.5 4.010.6 10 min after release 4.1 +0.6 4.0+0.6 4.1 t0.8
+
All values are in mmol/lts.d. * * P = .CO.Ol; *** P =
Total hepatic ischaemia in the Rhesus monkey PAUL MCMASTER A N D R I C H A R D MEDD* SUMMARY
During operations for major hepatic trauma it may he necessary temporardy ro deprive the liver of its blood supply by occlusion of the hepatic artery and portal vein. The maximum ‘safe period‘ of total hepatic ischaemia in man is unknown. In the monkey the ischaemic liver ‘leaks’ potassium, and levels of this element in the hepatic veins rise during ischaemia reaching a peak immediately after blood supply to the liver is restored. However, critical systemic levels of potassium are never reached and severe biochemical disturbance does not occur until 2 h following revascularization in animals having experienced ischaemic periods of longer than 20 min.
INrecent years there has been a steady increase in the incidence of major hepatic trauma associated with high speed road traffic accidents (Morton et al. 1972). In severe injury massive haemorrhage may be encountered at operation and it may be necessary to occlude the blood supply to the liver in order to gain control of haemorrhage or to facilitate hepatic resection (Little, 1971). Since the technique of clamping the hepatic vessels was described (Pringle, 1908), it has generally been considered that up to 20min of total hepatic ischaemia is safe (Raffucci, 1953) but that beyond 30 min severe ischaemic damage of the liver will have occurred (Drapanas et al., 1955; Peacock et al., 1969). Nevertheless, patients have survived more prolonged periods of ischaemia and cases in which the portal vein and hepatic artery were both clamped for as long as 78 min have been reported (Anastasia et al., 1967; Waltuck et al., 1970). Thus the maximum ‘safe period of time that the total blood supply to the liver in man may be interrupted at normal temperatures remains uncertain. Experimental studies have previously demonstrated that total occlusion of the afferent blood supply to the liver in animals is poorly tolerated because of the apparent susceptibility of the liver to anoxic damage (Bernhard et al., 1955; Jolly and Foster, 1963; Backlund et al., 1965). In the dog, hepatic necrosis due to hypoxic damage has been considered to be responsible for death after only 20min of total ischaemia (Raffucci and Wangensteen, 1951 ; Hyndman et al., 1957). Yet this susceptibility of the liver to normothermic ischaemic damage has recently been questioned, and quite marked extension of liver ischaemic times has been achieved in dogs with splanchnic decompression by portacaval shunting (Jolly and Foster, 1963; Mackenzie et al., 1975). Splanchnic decompression by portacaval shunting in man during surgery for severe hepatic injury is, however, rarely feasible. Factors other than hepatic necrosis have been considered responsible for the high mortality following complete hepatic ischaemia. These have included endotoxic shock (Battersby et al., 1971), hypovolaemia (Brunschwig, 1955), hepatic outflow block syndrome (Starzl et al., 1960) and the release of vasoactive substances (Joseph et al., 1968). In acute liver damage
potassium is released from hypoxic liver cells (Stewart et al., 1953) and high values have been recorded during total hepatic ischaemia (Backlund et al., 1965). Severe cardiac arrhythmias due to hyperkalaemia during total hepatic ischaemia have also been observed in the dog (Hall, 1972). However, the dog has disadvantages as a model for hepatic ischaemia which make interpretation of such results difficult. The problem of hepatic congestion and outflow block syndrome (Starzl et al., 1960) and the liver’s susceptibility to endogenous bacterial colonization leading to infection and endotoxic shock are well known (Ford, 1900; Battersby et al., 1971). In order to overcome some of these difficulties the Rhesus monkey was used in the present study which was undertaken to clarify the potassium changes occurring during total hepatic ischaemia without portal decompression. An assessment was made of the maximum ‘safe period’ for total normothermic hepatic ischaemia in the monkey. Materials and methods Six female Rhesus monkeys (Mucucu muluttu) weighing from 3.5 to 5 kg were used during this study. Anaesthesia was induced with intravenous thiopentone and maintained by an oxygen/halothane mixture. A cannula was introduced into the right side of the heart via the internal jugular vein and advanced into the pulmonary artery. The femoral vein was exposed and a second cannula was fed up into the inferior vena cava. A 5 per cent dextrose infusion was commenced in one of the upper limbs. A n upper midline incision was made and the liver was exposed. The structures in the free edge of the lesser omentum were identified and completely freed of the surrounding tissues. The hepatic artery was cleared as far as the gastroduodenal branch and the portal vein as far as its coronary tributory. The common bile duct was exposed along its supraduodenal segment, and all associated lymphatics and nerves in the porta hepatis were divided. The liver was then completely skcletonized with division of the left triangular ligament permitting complete mobilization of the left lobe. All branches of the left gastric artery running to the left lobe were divided and in 2 animals a major branch of the left lobe was discovered. The infrahepatic inferior vena cava was then exposed, acting as a guide for the division of the peritoneal attachments to the right lobe, and the right triangular ligament was divided. The whole right lobe was mobilized until the retrohepatic cava was exposed and the right phrenic veins identified. The falciform ligament was divided and the dissection above the liver exposed thc suprahepatic inferior vena cava. The cannula within the inferior vena cava was then advanced further and introduced into the opening of the middle hepatic vein. A small cannula was introduced into the coronary branch and advanced into the portal vein. Thus skeletonized, the liver remained attached only by its major vessels and the common bile duct. In order to allow continuous monitoring of pulse and blood pressure an aortic cannula was introduced via the right femoral artery and continuous ECG recordings were made.
* P. McMaster, University of Cambridge, Department of Surgery, Addenbrooke’s Hospital ; R. Medd, Department of Experimental Surgery, Huntingdon Research Centre. Correspondence to: P. McMaster.
820
Paul McMaster and Richard Medd
l‘ahle I: SERUM POTASSIUM LEVELS IN ALL ANIMALS DURING AND FOLLOWING TOTAL HEPATIC ISCHAEMlA Portal Pulmonary Hepatic vein vein artery Before occlusion 4.3 +0.5 3.9f0.7 4.0+0.8 After 15 min 5.6 0.6 4-1k 0 . 7 4.310.3 ischaemia 6.2+0.8*** 4.1 f 0 . 8 4.1 t O . 8 Immediately before release of clamp 3.940.6 4.140.4 20 s after release 7.4&0.6** 4.1 f 0 . 4 4.5+0.6 40 s after release 5.6+0.7*** 4.0h0.7 4.210.5 60 s after release 4.7*0.5 2 rnin after release 4.2+0.5 4.1 i0.5 4.010.6 10 min after release 4.1 +0.6 4.0+0.6 4.1 t0.8
+
All values are in mmol/lts.d. * * P = .CO.Ol; *** P =
