K. Ozawa

Arterial ketone body ratio as a predictor of donor liver viability in human liver transplantation

The viability of the donor liver was assessed with regard to early postoperative survival in human liver transplantations from 40 brain-dead donors at Hannover Medical College and 13 living donors at Kyoto University by measuring the arterial ketone body ratio (AKBR). Of 40 grafts harvested from brain-dead patients in Hannover, 35 survived the first week after operation, but 5 developed initial nonfunction of the transplanted graft within the first week. The mean AKBR values were 1.11±0.11 for grafts that survived and 0.44±0.10 for grafts that failed (P<0.01). The AKBR values of the 5 initially nonfunctioning cases were all below 0.7. Of 13 grafts harvested from the living donors in Kyoto, all survived the first week. The AKBR values of the donors were all above 1.0, with a mean value of 1.87±0.23. Among all 53 cases, the survival rate of the grafts with AKBR above 0.7 was significantly higher than that of the grafts with AKBR below 0.7 (100% vs. 62%, P<0.01). NO other donor parameters, including age, dose of dopamine administered, and clinical laboratory findings, were significantly related to differences in graft survival rates. AKBR is a useful index for the evaluation of donor liver viability. Grafts used from donors with AKBR of less than 0.7 have a significantly increased risk of early nonfunction. Grafts from donors with AKBR of greater than 1.0 have, in our experience, always been viable after transplantation.

Postoperative prognosis as related to blood ketone body ratios in hepatectomized patients

20 hepatectomized patients, both cirrhotic and noncirrhotic, were studied for the postoperative changes in the arterial blood ketone body ratio and standard liver function tests. It was found that serum enzyme activities, total protein, albumin, total bilirubin, total cholesterol and prothrombin time were less reliable direct indicators of the onset of postoperative hepatic insufficiency than the arterial blood ketone body ratio, which reflects the oxidoreduction state of liver mitochondria. The hepatectomized patients were classified into three groups according to the postoperative changes in the blood ketone body ratio. In the 8 patients of group A, the blood ketone body ratio did not decrease to below 0.7. In the 7 patients of group B, the blood ketone body ratio decreased transiently to 0.4-0.7 and then increased to over 0.7. In the 5 patients of group C, the blood ketone body ratio decreased irreversibly to below 0.4. There were few postoperative complications in group A. In group B, while a variety of complications occurred, they were ameliorated concomitantly with the restoration of the blood ketone body ratio. All group C patients died of multiple organ failure. It is proposed that the arterial blood ketone body ratio is a new and practical approach which enables more effective postoperative management by the accurate evaluation of hepatic functional reserve after hepatectomy.

Evaluation of the liver graft before procurement : Significance of arterial ketone body ratio in brain-dead patients

Hepatic energy metabolism was assessed by measuring the blood ketone body ratio (KBR), that is, the ratio of acetoacetate to β-hydroxybutyrate in the arterial blood, in 31 brain-dead patients in an intensive care unit (ICU) in Japan and in 25 donors just before procurement of the liver for transplantation in Germany. In the study in Japan, 7 of the 12 brain-dead patients treated with highdose catecholamine showed significantly decreased KBRs, revealing the detrimental effect of catecholamine on livermmetabolism. In contrast, 8 of the 9 untreated patients with blood pressure below 80 mm Hg showed almost normal KBRs. In the 25 donors in Germany, KBR was maintained within the normal range. Based upon conventional criteria, 21 livers were selected for use and the other 4 were discarded. Nineteen of the grafts were able to normalize KBR within 24 h after reperfusion, while 2 failed to function and required a second transplantation. It was suggested that a KBR in the normal range in donors is a prerequisite to immediate recovery of metabolic function of the liver graft after transplantation, and that hypotensive donors as a potential source of liver grafts may warrant further study.

Hepatic mitochondrial redox state in hypotensive brain-dead patients and an effect of dopamine administration

Arterial blood ketone body ratio, reflecting hepatic mitochondrial redox state, was measured in 26 brain-dead patients who were hypotensive but hemodynamically stable. All of them had substantially normal hepatic function. In 18 of the patients, blood ketone body ratio was maintained within the normal range in spite of hypotension. This was in marked contrast to the markedly decreased blood ketone body ratio often observed in patients in shock. This phenomenon was especially conspicuous in those who had not received exogenous dopamine infusion. It is suggested that hepatic mitochondrial redox state can probably be maintained despite systemic hypotension in brain-dead patients. Dopamine administration, on the other hand, is suggested to be a contributing factor to the reduction of hepatic mitochondrial redox state in hypotensive brain-dead patients. This study may provide a guideline for effective preservation of hepatic function in the body of brain-dead patients.

Four stages of mitochondrial deterioration in hemorrhagic shock

SummaryIt is of great importance to define the manner in which cells are damaged and how intracellular derangement becomes irreversible during shock. When supply of both oxygen and substrates to cells is limited during shock, cellular energy metabolism of vital organs is severely depressed. In this experiment, the relationship was clarified between the reversibility of shock and the cellular energy status, from the viewpoint of hepatic energy charge, mitochondrial redox state, ATP synthesis of isolated mitochondria, and fragility of mitochondrial membrane in rat livers. The derangement of energy metabolism passed through a series of four stages during hemorrhagic shock. At Stage I (initial stage), the cellular energy level decreased greatly due to marked energy consumption, without any organic damages in the mitochondria. Stage II (cell distress stage) showed that cellular energy imbalance occurred due to the depressed mitochondrial activity in vivo, although it was reversible when the blood supply was restored. Stage III (transitional stage) was the phase at which mitochondrial fragility increased severely. At Stage IV (terminal stage), mitochondria were markedly damaged organically and cellular energy metabolism was not remedied by any intensive therapies, which inevitably meant the death of vital organs.

Is the deterioration of liver viability due to hepatic warm ischemia or reinflow of pooled-portal blood in intermittent portal triad cross-clamping?

SummaryThe effects of hepatic warm ischemia and portal pooling on the viability of the liver were investigated with respect to hepatic energy metabolism by performing intermittent portal triad cross-clamping (Pringles maneuver) on dogs with or without portosystemic shunt. The dogs were divided into two groups of five: Group 1, non-shunt group, underwent Pringles maneuver performed for 30 min and declamping for 30 min, a process that was repeated five times; and Group 2, shunt group, underwent the same procedure as Group 1, except for portosystemic shunt using a heparinized hydrophilic catheter between the splenic and jugular veins. The shunt was opened during Pringles maneuver and was closed immediately at declamping. In the non-shunt group, portal pooling increased and systemic blood pressure decreased when Pringles maneuver was performed, but in the shunt group portal and systemic blood pressures remained within the normal range. In the non-shunt group, the initial velocity of arterial blood ketone body ratio (KBR) recovery after each declamping significantly (P < 0.01) decreased from 0.122 ± 0.016 (per min) after the first declamping to 0.028 ± 0.017 (per min) after the fifth declamping. Hepatic energy charge [= (ATP + 1/2 ADP)/(ATP + ADP + AMP)] decreased from 0.840 ± 0.003 before ischemia to 0.749 ± 0.003 30 min after the fifth declamping (P < 0.001). The concentrations of lactate and total amino acids in arterial blood increased. On the other hand, in the shunt group, the initial velocity of KBR recovery and hepatic energy charge showed little change even after the fifth declamping (0.081 ± 0.016 per min and 0.851 ± 0.009, respectively). The concentrations of lactate and total amino acids showed almost no increase. The impairment of hepatic energy metabolism by intermittent portal triad cross-clamping is mainly due to reinflow of pooled-portal blood to the previously ischemic liver, rather than hepatic warm ischemia. The KBR may be useful for determining the degree of impairment of hepatic energy metabolism.

Effect of Gabexate Mesilate on Thrombin and Plasmin Generation after Hepatic Resection in Cirrhotic Patients

The effect of the gabexate mesilate (Gab) on thrombin and plasmin generation following liver resection in cirrhotic patients was studied. Six cirrhotic patients received an infusion of Gab after liver resection (Gab group), and another 6 patients did not receive such treatment (Con group). The parameters measured were thrombin-antithrombin complex (TAT), plasmin-antiplasmin complex (PAP) and D-dimer. The real increases of D-dimer and PAP were significantly higher in Con group after surgery while no significant difference was observed in the increase of TAT. These results show that Gab suppresses plasmin generation and following D-dimer production more effectively than thrombin generation after hepatic resection.

Ketogenesis during sepsis in relation to hepatic energy metabolism.

SummaryThe concentrations of acetoacetate,β-hydroxybutyrate, and adenine nucleotides, and the mitochondrial phosphorylative activities, induced by cecal ligation and punctured in the liver of septic rats, were determined. The concentrations of glucose, free fatty acids (FFA), and free amino acids in arterial blood were also studied along with ketone body concentrations. Hepatic energy charge levels decreased from 0.84 to 0.77 at 12h after the induction of sepsis (P<0.01) and to 0.60 at 18h (P<0.001). Mitochondrial phosphorylative activity was enhanced at 6h (P<0.001) and decreased at 18 h later. Ketone body concentrations in the liver and the arterial blood decreased concomitant with the decrease in hepatic energy charge. The mitochondrial redox state increased significantly at 12 and 18h after the induction of sepsis (P<0.01) concomitant with a marked decrease in the concentrations of ketone bodies (P<0.01). Blood glucose levels remained within normal limits except for a transient increase at 6h, but plasma FFA levels decreased (P<0.01). The plasma concentrations of aromatic amino acids (P<0.001), proline, and alanine (P<0.05) increased slightly at 18h. It is suggested that the ketogenic capacity of the liver is inhibited during sepsis, but that the liver maintains gluconeogenesis at relatively normal levels until a more advanced stage of sepsis.

Changes in Energy Metabolism of Allografts after Liver Transplantation

To evaluate the function of energy metabolism in allografts after liver transplantation, changes in hepatic energy charge levels, oxidative and phosphorylative activities of mitochondria and arterial blood ketone body ratio (acetoacetate/3-hydroxybutyrate; KBR) were studied in piglets. Hepatic energy charge levels decreased to 0.831 +/- 0.010 at 3 days and 0.836 +/- 0.009 at 3 weeks after operation compared to the preoperative value of 0.868 +/- 0.006 (p less than 0.01), and returned to 0.856 +/- 0.007 at 6 weeks. Mitochondrial oxidative and phosphorylative activities were moderately enhanced to 19.14 +/- 2.07 (10(-10) mol ATP/mg of mitochondrial protein/s) at 3 days and 20.89 +/- 1.72 at 3 weeks compared to the preoperative value of 16.74 +/- 2.36, and returned to 16.65 +/- 1.54 at 6 weeks. There was no significant difference in the concentrations of mitochondrial respiratory components, except in cytochrome c + c1. KBR decreased immediately at the beginning of the anhepatic phase and rapidly recovered to the preoperative level within 60 min after revascularization of allografts. There was no change in KBR during the postoperative course except in cases with clinical deterioration. From these results, it is suggested that the mitochondrial capacity for ATP synthesis was enhanced to compensate for the decreased energy charge level and that a decreased KBR is a sign of a critically deranged metabolic function in allografts.

Functional deterioration of the liver by elevated inferior vena cava pressure: A proposed upper safety limit of pressure for maintaining liver viability in dogs

ObjectiveAbnormally elevated central venous pressure is considered to be an etiological factor in the onset of acute hepatic failure following modified Fontan operation. This paper hypothesises that an increase in inferior vena cava pressure (IVCP) after such an operation has adverse effects on hepatic energy status.DesignVarious degrees of venous hypertension were produced in 10 mongrel dogs by clamping the thoracic IVC with an active veno-venous shunt and varying its flow rate from 60–2.5 ml/min/kg. Arterial ketone body ratio (KBR), reflecting the hepatic mitochondrial redox state, was measured as an index of hepatic energy status.Measurements and results: The lower the flow rates of the shunt, the higher the pressures of IVC and portal vein, while systolic blood pressure was maintained above 100 mmHg. CO significantly decreased when the pump speed was less than 30 ml/min/kg. KBR showed a negative correlation to IVCP as well as a positive correlation to portal blood flow (p<0.05).ConclusionFrom the simple regression line obtained between IVCP and KBR, it was determined that an upper safety limit of IVCP may lie at about 27 cmH2O (20.5 mmHg), and that a IVCP of 35 cmH2O (26.6 mmHg) seems to be the critical level for maintaining liver viability.