Changes in arterial ketone body ratio in the phase immediately after hepatectomy. Prognostic implications

Postoperative fluctuations of the ketone body ratio in arterial blood (acetoacetate/3-hydroxybutyrate), reflecting hepatic mitochondrial redox potential, were analyzed in 266 hepatectomized patients in relation to their prognosis. Changes in ketone body ratio were classified into the following two types: a primary decrease at the end of operation and a secondary decrease after transient recovery. Patients were classified into three groups by the primary decrease of ketone body ratio: group 1 (183 cases) with ketone body ratio above 0.7, group 2 (49 cases) between 0.7 and 0.4, and group 3 (34 cases) below 0.4 Ketone body ratio was restored to above 0.7 in 2.5 +/- 0.2 days (mean +/- SE) in all group 2 patients. However, though it was restored within 4.5 +/- 0.4 days in 26 group 3 patients, the other 8 died of multiple organ system failure in 7.4 +/- 2.8 days without recovery of ketone body ratio. This was followed by a secondary decrease in ketone body ratio to below 0.7 in 94 patients, concomitant with complications. The degree of the secondary decrease was positively correlated with that of the primary decrease. In the secondary decrease, of 42 patients with ketone body ratio below 0.4, 28 died of multiple organ failure. Total mortality was 7% in group 1, 12% in group 2, and 50% in group 3. It is suggested that the primary decrease in ketone body ratio at the end of operation is a decisive factor in the prognosis for hepatectomized patients.     

Effect of prostaglandin E1 on arterial ketone body ratio in hepatectomy

We evaluated the effect of prostaglandin E₁ (PGE₁) administration during hepatectomy on arterial ketone body ratio (AKBR), which is an indicator of liver function, and on other liver functions in the postoperative period. Eighteen patients were divided into two groups: Continuous intravenous administration of PGE₁ (0.02 μg·kg⁻¹·h⁻¹) was started immediately before hepatic resection and ceased at the end of operation in nine patients (PGE₁ group); the other nine did not receive PGE₁ (control group). After hepatic resection, a significant increase in AKBR was observed in the PGE₁ group. However, no change was observed in the control group. In the PGE₁ group, total bilirubin and SGOT recovered more rapidly to the preoperative level than in the control group. These findings suggested that PGE₁ might have a protective effect on the liver.     

Clinical study of arterial ketone body ratio (ACAC/beta-OHCS) during hepatectomy

The changes in arterial ketone body ratio (acetoacetate/beta-hydroxybutyrate) were investigated in 7 patients undergoing hepatectomy under epidural anesthesia with nitrous oxide and oxygen. The plasma levels of glucose, insulin, glucagon, lactate, pyruvate and non-esterified free fatty acid (NEFA) were measured during the operation. The plasma level of insulin activity increased significantly during surgery. The secretory capability of insulin against glucose load was relatively preserved. Arterial ketone body ratio also increased during the operation. The plasma insulin activity was positively correlated significantly with the arterial ketone body ratio (Y = 0.98 + 0.76X; r = 0.76). Both lactate and pyruvate increased significantly during surgery. No remarkable changes of L/P ratio reflecting the redox state in cytoplasma were found in both groups. Our results suggest that the quantity of glucose load and insulin activity should be considered when arterial ketone body ratio is measured during the operation.     

Prognostic implications of postoperative suppression of arterial ketone body ratio: time factor involved in the suppression of hepatic mitochondrial oxidation-reduction state

To determine the tolerance limit of the liver in the critically suppressed mitochondrial oxidation-reduction state, the arterial ketone body ratio (acetoacetate/3-hydroxybutyrate), which reflects hepatic mitochondrial oxidation-reduction potential, was measured 1319 times in 161 patients during the postoperative critical period. Because patients who showed arterial ketone body ratios between 0.40 and 0.25 had a higher incidence of postoperative complications than had those who showed ratios above 0.40, this was designated as the critical zone of the arterial ketone body ratio. When duration in the critical zone was less than 2 days, 90% of the patients were able to tolerate the condition and survive. By contrast, when an arterial ketone body ratio below 0.40 was prolonged for more than 5 days, there was a high incidence of multiple organ failure and a 100% mortality rate, with the average survival period after a 5-day suppression being estimated as 5.7 +/- 2.4 days. It is suggested that the arterial ketone body ratio in the critical zone must be returned to normal values within 2 days to obtain a good prognosis.     

Change in arterial ketone body ratio during gastrectomy and mastectomy]

We evaluated the influence of operative procedure on arterial ketone body ratio (AKBR), which indicates the function of the liver cells, in patients undergoing gastrectomy or mastectomy. AKBR during the stomach resection was significantly lower than that during the breast resection. A significant reduction in AKBR due to induced hypotension was observed in mastectomy group. SGOT and SGPT increased significantly in gastrectomy group, but unchanged in mastectomy group on the first and the seventh postoperative days. On the first post-operative day, SGOT and SGPT in gastrectomy group were significantly higher than those in mastectomy group. These findings suggest that influence of operative procedure on the liver during gastrectomy is more serious than that during mastectomy.     

Significance of arterial ketone body ratio measurement in human liver transplantation

Arterial ketone body ratio (KBR), which reflects the NAD+/NADH ratio of hepatic mitochondria, was measured sequentially in 39 liver transplantations. In 22 cases, KBR was increased to above 0.7 within 6 hr after reperfusion (group A). In 11 cases, restoration of KBR was delayed until the first postoperative day (group B) and in 6 cases, KBR failed to recover (group C). The patients in group A survived liver transplantation without complications. By contrast, morbidity and mortality were significantly higher in groups B and C. In 2 cases in group C, the livers were clinically diagnosed as initially nonfunctioning grafts and the patients underwent retransplantation. Another two died of hepatic failure soon after the operation. It is suggested that delayed recovery of KBR is an early indicator of metabolic overload in the liver allograft, and that a delay exceeding 24 hr may imply the need for retransplantation.     

Effects of glucagon and insulin on poly(ADP-ribose) polymerase activity and blood ketone body ratio after partial hepatectomy in rats

The effects of glucagon and insulin on liver nuclear poly(ADP-ribose) polymerase activity and blood ketone body ratio after rat partial (68%) hepatectomy were examined. Liver weight regeneration rate was enhanced by glucagon and insulin after 5th posthepatectomy day. The maximal value of poly(ADP-ribose) polymerase activity without glucagon and insulin was revealed as 368 +/- 64 pmole/mg/min on 5 days after the hepatectomy. In contrast, the enzyme activity with glucagon and insulin reached to the peak value as 253 +/- 42 pmole/mg/min on 2 days after the hepatectomy. The amounts of DNA per nuclear protein showed similar changes with the changes of poly (ADP-ribose) polymerase activity after the hepatectomy. Blood ketone body ratio showed almost similar changes in both groups, except transitional decrease in the group without glucagon and insulin on 5th postoperative day. It is suggested that, to promote remnant liver regeneration, the combined therapy of glucagon and insulin may act directly to nucleic acid metabolism through the changes of poly(ADP-ribose) polymerase activity and preserve energy charge level by the suppression of NAD consumption by massive poly(ADP-ribose) formation.     

Clinical and biological significance of arterial blood ketone body ratio in hepatic surgery

In a recent study from our laboratory, 372 patients were classified into 4 groups according to the postoperative changes in the arterial blood ketone body ratio: Group A without decrease below 0.7 (greater than 0.7 in control), Group B with transient decrease to 0.4, Group C with progressive decrease to below 0.4, and Group D, the terminal stage, with decrease to below 0.25. Groups A and B patients tolerated operation well. In the 28 Group C patients, 24 of them died of multiple organ failure. The metabolic liver support designed by us (an ex vivo pig or baboon liver cross-hemodialysis with an interposed cuprophan membrane) has been applied for the patients with both blood ketone body ratio below 0.4 and grade IV hepatic coma. All Group C patients became fully alert after liver support concomitant with the restoration of the blood ketone body ratio. By contrast, in Group D patients, there was no restoration of consciousness and no improvement in their blood ketone body ratios by this liver support. It has been suggested that blood ketone body ratio level serves as an excellent indicator of the deranged metabolic process and mortality in critically ill patients.     

The fundamental factor determining the clinical prognosis of prolonged jaundice--relation to the arterial ketone body ratio

Factors related to the prognosis of patients with hyperbilirubinemia were investigated in 16 highly jaundiced patients. Patients who died within 3 weeks showed a deterioration of the hepatic energy status, measured by the arterial ketone body ratio, but patients who did not die within 3 weeks after the measurement of the ketone body ratio had a ratio within the normal range, despite high total bilirubin levels (18 mg/0.1 L). C3, C4 and CH50 in the former were also significantly lower than those in the latter. However, endotoxin and high fever occurred to the same extent, in the both groups. Thus, hepatic energy balance is the most pertinent factor related to prognosis, and is concerned with both the hepatocyte and reticuloendothelial systems. On the other hand, infection or endotoxin, when the energy balance is disturbed, becomes an aggravating but not a fundamental factor.     

Decrease in arterial ketone body ratio indicating graft dysfunction after liver transplantation.

In 3 cases of living related liver transplantation, arterial ketone body ratio (AKBR) showed secondary decrease in the early postoperative period, indicating the graft dysfunction more rapidly and sensitively than other liver function tests. Significance of AKBR for monitoring the graft function in postoperative management after liver transplantation is discussed.     

Relationship between insulin response to oral glucose load and creatinine clearance.

In order to investigate the relationship between insulin response to oral glucose load and renal function, a 100-gm. oral glucose tolerance test was performed in twenty-two patients with chronic glomerulonephritis, whose creatinine clearances ranged form 5 to 96 ml. per minute. Glucose areas during oral glucose load were little affected by the creatinine clearance in this study. Insulin area during oral glucose load increased in proportion to the decrease in creatinine clearance. The ratio of insulin area to glucose area correlated closely with creatinine clearance and a linear relationship was obtained (y = 1.46 - 0.01x, r = -0.82, p less than 0.001). There were also significant correlations with serum creatinine, blood urea nitrogen, and PSP (r = 0.6, 0.63, and -0.62, respectively). These results show that the impaired renal function has a significant influence on the plasma insulin levels, and it seems likely that such influence becomes manifest below approximately 60 ml. per minute of creatinine clearance.     

Effects of sevoflurane and isoflurane anesthesia on arterial ketone body ratio and liver function

BACKGROUND: The purpose of this study was to compare the effect on arterial ketone body ratio (AKBR), which indicates hepatic mitochondrial energy charge in relation to hepatic blood flow, and liver function test (serum levels of liver enzymes) between sevoflurane and isoflurane anesthesia. METHODS: Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBil), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GTP), and lactate dehydrogenase (LDH) were measured before and 1,2,3,7, and 14 days after anesthesia in each of 60 patients receiving either sevoflurane or isoflurane anesthesia for neurosurgery (tumor resection). In 13 patients of both groups, arterial concentrations of acetoacetate and 3-hydroxybutyrate were also measured before, during and after (up to 12 h) anesthesia and the AKBR was calculated. RESULTS: AST, ALT and GTP increased, peaking 7 days after anesthesia, especially in the isoflurane group. There was a significantly greater number of patients with abnormal AST and ALT values in the isoflurane group than in the sevoflurane group. The increase of TBil had its peak 1 day after anesthesia in both groups. AKBR decreased after anesthesia induction and recovered to the control value 12 h after anesthesia in both groups. There was no difference between the two anesthetic groups in AKBR. CONCLUSION: Isoflurane induced an elevation of serum levels of liver enzymes more frequently than did sevoflurane 3 to 14 days after anesthesia, while AKBR until 12 h after anesthesia did not show any significant difference between sevoflurane and isoflurane anesthesia.     

Superoxide production by liver macrophages in a septic rat model--relation to arterial ketone body ratio.

The relationship between superoxide production by liver macrophages and arterial ketone body ratio (AKBR), which reflects the oxidation-reduction state in the mitochondrial compartment of hepatocytes, was studied in rats with lethal and sublethal septicemia induced by intravenous injection of live Escherichia coli 014. In the sublethal model, AKBR decreased transiently (p < 0.01) and superoxide production by isolated liver macrophages increased significantly after opsonized zymosan (OZ) stimulation (p < 0.05). On the other hand, in the lethal model, AKBR decreased markedly (p < 0.01) to below 0.4 without recovery, and superoxide production was not activated by OZ stimulation. Thus, when AKBR decreases to an irreversible level, below about 0.4, superoxide production by liver macrophages is impaired, while as long as AKBR remains reversible, more than about 0.4, it is enhanced. It is suggested that superoxide production by the Kupffer cells is related to the intrahepatic oxidation-reduction state in the septic model.     

Effect of induced hypotension on arterial blood ketone body ratio (AKBR)

Arterial blood ketone body ratio (AKBR; acetoacetate/beta-hydroxybutyrate) is known as a parameter to indicate the function of the liver cells. We evaluated the effects of induced hypotension with prostaglandin E1 (PGE1) or trimetaphan (TMP) on AKBR in patients without liver disease undergoing mastectomy. Almost no change was observed in AKBR before, during and after hypotension with PGE1, but slight diminution was observed during hypotension with TMP. No hepatic dysfunction, however, developed in these patients postoperatively. These findings suggest that usual hypotension with TMP may provoke no postoperative hepatic dysfunction in patients without liver disease. For the patient who required either hypotension of long duration or hypotension with other factors affecting function of liver (surgical procedures, drugs and others), we prefer PGE1 to TMP as a hypotensive drug. We should also adopt PGE1 when cardiovascular control with hypotensive drug is necessary in patients with liver disease.     

Effect of prostaglandin E1 on arterial ketone body ratio during gastrectomy]

We evaluated the effect of prostaglandin E1 (PGE1) on arterial ketone body ratio (AKBR), which is a parameter to indicate the function of the liver cells, in the patients undergoing total or subtotal gastrectomy. Twenty patients were divided into two groups: continuous intravenous administration of PGE1 (0.02 micrograms.kg-1.min-1) was started from 30 minutes after the beginning of the operation in 10 patients, and the remainders did not receive PGE1. AKBR levels at 30 minutes after the beginning of the operation (during the resection of stomach) were significantly lower than those after the resection of stomach in both groups. A significant increase in AKBR caused by the administration of PGE1 was observed during the resection of the stomach in PGE1 group. However, almost no change was observed in AKBR during the resection of the stomach in control group. These findings suggest that the administration of PGE1 has a protective effect on liver which is due mainly to the increase in hepatic blood flow during the resection of stomach.     

The fundamental factor determining the clinical prognosis of prolonged jaundice—Relation to the arterial ketone body ratio

Factors related to the prognosis of patients with hyperbilirubinemia were investigated in 16 highly jaundiced patients. Patients who died within 3 weeks showed a deterioration of the hepatic energy status, measured by the arterial ketone body ratio, but patients who did not die within 3 weeks after the measurement of the ketone body ratio had a ratio within the normal range, despite high total bilirubin levels (18 mg/0.1 L). C3, C4 and CH50 in the former were also significantly lower than those in the latter. However, endotoxin and high fever occurred to the same extent, in the both groups. Thus, hepatic energy balance is the most pertinent factor related to prognosis, and is concerned with both the hepatocyte and reticuloendothelial systems. On the other hand, infection or endotoxin, when the energy balance is disturbed, becomes an aggravating but not a fundamental factor.     

Contribution of the arterial blood ketone body ratio to elevate plasma amino acids in hepatic encephalopathy of surgical patients

To clarify the role of hepatic metabolic derangements in elevated plasma amino acid levels, the patterns of plasma amino acids in 17 surgical patients with hepatic failure were analyzed in relation to the blood ketone body ratio (acetoacetate to beta-hydroxybutyrate), which reflects the mitochondrial redox potential. The blood ketone body ratios were 0.49 in eight alert patients with hepatic failure and 0.28 in nine patients with grade IV hepatic coma, compared with values of 0.79 to 6.42 in patients with healthy livers. The plasma concentrations of alanine, proline, phenylalanine, and tyrosine were negatively correlated with the blood ketone body ratio. Elevations of alanine, phenylalanine, tyrosine, and glutamate were greater in comatose patients than in alert patients. Also, the molar ratios between the plasma concentrations of the branched-chain amino acid and the aromatic amino acids were positively correlated with the blood ketone body ratio (r = 0.78, p less than 0.0001). We suggest that a reduced mitochondrial redox potential, coupled with enhanced muscle breakdown, results in inhibition in the entrance of the amino acids into the Krebs' cycle and then the characteristic changes in the free amino acid patterns which result in hepatic coma.     

Relationship of deranged energy metabolism in liver and kidney to arterial ketone body ratio following liver ischemia in rats

Changes in energy metabolism in the liver and kidney in liver ischemia induced in rats were simultaneously studied, in terms of energy charge (EC) and mitochondrial oxidoreduction state. Mean arterial blood pressure, glucose and lactate, total ketone bodies (acetoacetate+β-hydroxybutyrate) and the ketone body ratio in arterial blood (KBR) were also investigated. During and after liver ischemia, both organs showed similar patterns of reversibility, and KBR, which reflects the mitochondrial oxidoreduction state, correlated well with EC, in both organs. Referring to the mortality and changes in substrates above mentioned, KBR is a pertinent parameter for detection of viability following induced liver ischemia. It was also suggested that KBR may indicate a regulation role by the liver, in kidney energy metabolism.     

Hepatic tolerance to hypotension as assessed by the changes in arterial ketone body ratio in the state of brain death

Hepatic tolerance to hypotension was assessed by changes in arterial ketone body ratio (KBR) and hepatic energy charge levels in experimental brain death induced by epidural ballooning in dogs, and compared with the hemorrhagic shock model. Systolic arterial blood pressure was significantly decreased from 182 mmHg to 67 mmHg after completion of brain death (P less than 0.01), but KBR was maintained at near the control value of 1.098 +/- 0.051 in spite of marked hypotension. Hepatic energy charge was 0.846 +/- 0.016 and remained at normal level. No significant changes were observed in lactate level, total bilirubin, SGPT, and LDH. SGOT was slightly elevated but was still within normal limits (P less than 0.05). Light microscopic examination revealed no apparent ischemic change in the centrilobular region under hematoxylin and eosin staining. By contrast, KBR decreased from 0.975 +/- 0.054 to 0.273 +/- 0.060 following hypotension in the Wiggers' shock model (P less than 0.01). Lactate levels were gradually elevated significantly (P less than 0.05), but no significant increases were observed in total bilirubin, SGOT, SGPT, and LDH. It is suggested that the hepatic energy status is well maintained in the state of brain death, in which state the liver has high tolerance to marked hypotension until shortly before stoppage of the heart.     

Changes in blood glucose levels in relation to blood ketone body ratio following hypertonic glucose infusion in 70% hepatectomized rabbits

The effects of postoperative infusion of a hypertonic glucose solution on the blood glucose level, blood ketone body ratio (acetoacetate/beta-hydroxybutyrate), and plasma alanine and proline levels were studied in 70% hepatectomized rabbits (group A) and in rabbits 70% hepatectomized and, in addition, subjected to bile duct obstruction at 12 h after hepatectomy (group B). Glucose infusion was started at the end of hepatectomy and continued for 20 h. The blood glucose level in group A remained at approximately 300 mg/dl throughout the study; however, it reached 789 mg/dl in group B at 20 h. The blood ketone body ratio, which reflects hepatic mitochondrial redox potential, decreased from 0.90 +/- 0.09 in untreated rabbits to 0.38 +/- 0.05 in group A, and to 0.19 +/- 0.03 in group B at 20 h. As the blood ketone body ratio decreased, plasma proline and alanine levels increased rapidly (proline, r = -0.601, p less than 0.02; alanine, r = -0.640, p less than 0.001). In addition, the blood ketone body ratio was positively correlated with the hepatic energy charge level [(ATP + 0.5 ADP)/(ATP + ADP + AMP)] (r = 0.57, p less than 0.001). It is suggested that the entry of glucose and amino acids into the Krebs cycle is inhibited as the blood ketone body ratio decreases, and under such conditions the infused glucose tends to accumulate, resulting in severe hyperglycemia.