Arterial Blood Ketone Body Ratio Research Articles

MEDICAL EFFECT OF SPORTS ON IMPROVING THE MAXIMUM OXYGEN

ABSTRACT Introduction: Maximum oxygen uptake is an effective indicator of the level of human cardiopulmonary function and aerobic work capacity. Observing the effects of aerobic training and formulating scientific training plans are of considerable value. Objective: To observe the effect of physical exercise on the human body's maximum oxygen uptake and arterial blood ketone body ratio. Methods: Before and after 4 weeks of physical exercise, the maximum oxygen uptake, blood lactic acid and heart rate changes, and ketone body content in the incremental load exercise experiment was measured in the human body. Results: The subjects’ maximum oxygen uptake, maximum exercise load, heart rate, and blood lactic acid levels increased significantly after physical exercise. Conclusion: The human body's maximum oxygen uptake is enhanced under sports. Level of evidence II; Therapeutic studies - investigation of treatment results.

Influence of Normothermic Cardiopulmonary Bypass on Body Oxygen Metabolism During Lung Transplantation

Studies have demonstrated that cardiopulmonary bypass (CPB) adversely affects pulmonary circulation, which is involved in metabolism in the lung, and that pulmonary circulation after CPB can restore the prostaglandin E2 (PGE2) level mainly standing for levels of key vasostimulators augmented during CPB, which may influence systemic tissue perfusion and body oxygen metabolism. However, in lung transplantation (Lx), pulmonary circulation is restored to the graft, which might induce another CPB reaction. We prospectively examined the influence of CPB on body oxygen metabolism in Lx. Left Lx was successfully performed on 10 dogs (group-on: with normothermic CPB without cardiac arrest, group-off: without CPB; n = 5 vs. 5). At 30 minutes after graft perfusion, the right pulmonary artery and bronchus were clamped. Body weight, donor-to-recipient body weight ratio, and clinical parameters were comparable between the two groups, except for the hematocrit level during CPB. At 90 minutes after graft perfusion, mixed venous oxygen saturation (SvO2) was lower (p < 0.01) and O2 extraction rate (p < 0.01), PGE2 (p = 0.025), and arterial blood ketone body ratio (KBR) (p < 0.01) were higher in group-on than in group-off, whereas these parameters were comparable before graft perfusion between the two groups. O2 consumption and acetic acid were higher in group-on than in group-off, whereas O2 delivery and 3-hydroxy propioic acid were comparable between the groups. In conclusion, Lx during CPB may induce a new inflammatory reaction and influence body oxygen metabolism, contrary to the restoration of pulmonary circulation after CPB.

Comparative study of artifical circulation for the liver after cardiogenic shock: Pulsatile or nonpulsatile?

Because of multiple organ failure (MOF), the survival rate of patients with mechanical circulatory support has not been satisfactory, The purpose of this study is to estimate the effects of pulsatile and nonpulsatile artificial circulation on hepatic microcirculation and function. Cardiogenic shock was induced experimentally by ligating of left anterior descending branch in pigs. For the right ventricular assist device, a nonpulsatile pump (Nikkiso HPM-15) was employed. The left ventricular function was supported by either a nonpulsatile pump (Nikkiso HPM-15: NP group) or a pulsatile pump (Zeon Medical: P group). NP group was further divided into 80% support (NP-1 group) and 100% support (NP-2 group) of the control cardiac output. All groups were maintained at an equivalent mean aortic pressure of 3 hours. We measured the hepatic artery blood flow, portal vein flow and hepatic regional blood flow. For the metabolic and hepatic oxygen metabolic data, GOT, GPT, arterial blood ketone body ratio (AKBR), lactate/pirubic acid (L/P), and hyaluronic acid were evaluated. The mean aortic pressure was higher in the NP-2 group than in the other groups. The hepatic arterial blood flow was significantly higher in the P group than in the others. The AKBR and hepatic oxygen metabolism showed significant improvement in the P group in comparison with others. The regional blood flow in the liver showed improvements in the P and NP-2 groups. These findings suggested that pulsatile circulation may be beneficial for microcirculation of the liver; and the augmented nonpulsatile flow had effects similar to those of pulsatile flow in hepatic circulation.

Hepatic adenylate energy charge levels in patients with hepatoma after hepatic artery embolization.

AIM:To evaluate hepatic energy charge levels of the patients with hepatoma after hepatic artery embolization and its relation to postoperative complications.METHODS:Sixty-nine patients with hepatoma were continuously measured for their arterial blood ketone body ratio (AKBR) and compared with their postoperative clinical course or conventional liver function test after various hepatic artery embolization.RESULTS:AKBR in high radiation dose or jaundice group drastically decreased at 1-3 days and recovered slowly. Patients were classified into three groups according to the value of AKBR: group A (35 cases), AKBR remained higher than 0.7; group B (31 cases), AKBR had transiently dropped to 0.4-0.7 and then increased to preoperative value; and group C (3 cases), AKBR decreased steadily to below 0.4.The occurrence rate of various complications were 5.7%, 32.3% and 100% in the three groups, respectively (P < 0.005).CONCLUSION:The AKBR which reflects hepatic mitochondria redox state is more reliable as a direct indicator to assess hepatic tolerance for embolization than routine liver function test.

Assessment of hepatic function by blood ketone body ratio

The arterial blood ketone body ratio is a non-invasive means of evaluating mitochondrial ATP synthesis and the related energy status of the liver, in which arterial blood is used, instead of the sampling of liver tissue or the isolation of mitochondria. We discuss AKBR in relation to: ATP synthesis, the rationale of using AKBR for assessment of the intramitochondrial redox state, factors affecting the intramitochondrial redox state, regulation of the speed of ATP synthesis by the oxidized/reduced form of pyridine nucleotid (NAD+/NADH) ratio, and the clinical applications of AKBR.

Ketone body ratios of the superior and inferior vena cava and of pulmonary arterial blood compared to that of arterial blood: central venous ketone body ratio as a substitute for the arterial ketone body ratio

To investigate the ketone body ratio (acetoacetate/3-hydroxybutyrate) of central venous blood compared to that of peripheral arterial blood, the acetoacetate and 3-hydroxybutyrate concentrations in paired peripheral arterial and central venous or pulmonary arterial blood were measured. The ketone body concentrations in superior and inferior vena cava blood were significantly ( P < 0.0001) lower than those in peripheral arterial blood, whereas those in pulmonary arterial blood were almost the same as those in peripheral arterial blood. These results indicate that ketone bodies were metabolized in the muscles, which reduced their levels in vena cava blood, but ketone bodies newly produced by the liver were transported to the right side of the heart via the hepatic vein, giving concentrations in pulmonary arterial blood that were almost the same as those in peripheral arterial blood. On the other hand, the correlation coefficients ( r 2) of the arterial blood ketone body ratio to the ratio of superior and inferior vena cava and pulmonary arterial blood were 0.897, 0.767 and 0.882, respectively. The ratios of central venous ketone body ratio/arterial blood ketone body ratio were 0.89 ± 0.15 in the superior vena cava, 0.64 ± 0.18 in the inferior vena cava and 1.01 ± 0.15 in the pulmonary artery.

Enzymatic method for determining ketone body ratio in arterial blood

We have developed a new, sensitive, and rapid method for measuring the ketone body concentration in arterial blood and determining the arterial blood ketone body ratio. The procedure involves the sequential use of the enzymes 3-hydroxybutyrate dehydrogenase (3-HBDH; EC 1.1.1.30) and NADH oxidase, followed by a color-generating reaction with the hydrogen peroxide produced by the oxidase reaction. The amount of oxidized chromogen produced is proportional to the 3-hydroxybutyrate (3-HBA) concentration. The acetoacetate (AcAc) concentration is obtained after complete conversion of the AcAc to 3-HBA, in the presence of 3-HBDH. The total 3-HBA concentration is measured and then subtracted from the total ketone body concentration to give the AcAc concentration. This procedure may be applied to plasma samples and the absorbance change measured with an automated chemistry analyzer. Ketone body concentration may be determined over the range 0 to 400 mumol/L. The analysis takes approximately 12 min and requires only 30 microL of plasma.

Expanding the donor pool

Expanding the donor pool

The arterial ketone body ratio and serum alpha-fetoprotein level in patients with acute hepatic failure.

Hepatocyte regeneration is essential for recovery in acute hepatic failure, although it requires a large amount of energy. The ratio of acetoacetate to beta-hydroxybutyrate in arterial blood has been reported to reflect the cellular energy charge of hepatocytes, and we proposed that the recovery of the ratio in the early days of acute hepatic failure is essential for survival. However, there is no report on any marker of regeneration to confirm this hypothesis. In this study, we have assessed this ratio and the serum alpha-fetoprotein level sequentially in 26 patients with acute hepatic failure. Ten patients recovered and 16 died. The arterial blood ketone body ratio 3 days after the onset of hepatic encephalopathy of grade II or more was below 0.6 in 15 of the 16 nonsurvivors, whereas that in the 10 survivors was above 0.6. There was a positive correlation between the arterial blood ketone body ratio and the maximal concentration of alpha-fetoprotein (r = 0.465, p < 0.02 by Student's t-test). These data indicate that the arterial blood ketone body ratio is a marker for the capacity of the liver to regenerate and for the prognosis in patients with acute hepatic failure: effective hepatocyte regeneration may be impossible if these metabolic changes in acute hepatic failure impair the hepatocyte energy charge severely.

Evidence that portal vein decompression improves survival of canine quarter orthotopic liver transplantation.

The minimum graft volume still remains unclear in reduced-size liver transplantation (RLT). This study reports the improved survival of canine RLT using a quarter graft with the aid of a portahepatic vein shunt (PHVS). In beagles, the donor liver was reduced to the right lateral and caudate lobes (quarter graft) with or without provision of PHVS, and transplanted orthotopically in the recipient. The PHVS was established by an end-to-end anastomosis of the portal vein branch and the hepatic vein in the resected left lateral lobe. Liver chemistries including arterial blood ketone body ratio (AKBR) were serially measured during and after surgery. All seven animals with PHVS survived more than 3 days (mean +/- SD; 5.3 +/- 1.7 days), whereas all six without PHVS died within 3 days (1.8 +/- 0.8 days, P < 0.01). Portal vein pressures immediately after recirculation in animals with and without PHVS were 8.5 +/- 1.2 mmHg and 16.9 +/- 3.1 mmHg, respectively (P < 0.01). Regardless of the presence or absence of PHVS, AKBR dropped to a level lower than 0.7 during the anhepatic period and returned promptly to above 1.0 as early as 30 min after recirculation. Thereafter, the AKBR values in animals with PHVS remained higher than 1.0, whereas those in animals without PHVS showed a progressive decrease, showing a statistically significant difference between the two groups after 12 hr (P < 0.05). Graft function, as assessed by AKBR, was well correlated with survival and other liver chemistries. These results indicate that, in an extreme RLT, portal hypertension is a risk factor predisposing to graft failure, most likely by increasing microvascular injury after recirculation.

The Effect of a Bolus Injection of TNF-α and IL-1β on Hepatic Energy Metabolism in Rats

The effects of intravenous bolus injection of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) on hepatic mitochondrial energy metabolism were investigated in rats. The rats were injected with 15 μg/kg body wt of human recombinant TNF-α and IL-1β. The hepatic energy charge decreased to 0.794 ± 0.005 and 0.789 ± 0.006 in comparison with the sham control value of 0.838 ± 0.007 and 0.835 ± 0.011 at 12 and 24 hr after the treatment. The mitochondrial redox state (NAD +/NADH) increased from 17.4 ± 1.9, 16.6 ± 1.4, and 19.2 ± 2.1 to 33.5 ± 3.5, 27.8 ± 2.8, and 30.9 ± 2.6 concomitant with an increase in arterial blood ketone body ratio (acetoacetate/β-hydroxybutyrate) from 0.49 ± 0.04, 0.34 ± 0.04, and 0.44 ± 0.09 to 1.00 ± 0.16, 0.69 ± 0.13, and 0.86 ± 0.15 at 3, 12, and 24 hr after the treatment. Total ketone body concentration in liver tissue and arterial blood was significantly lower at 24 hr after the treatment. State 3 respiration rate of isolated mitochondria increased by 29.2, 30.3, and 19.2% concomitant with an increase in oxidative phosphorylation rate by 26, 33.7, and 24.3% at 3, 12, and 24 hr after the treatment. These results showed that the administration of TNF-α and IL-1β in rats induced a hypermetabolic state in hepatic mitochondrial energy metabolism, which is a pattern similar to sepsis and presumably a compensatory reaction to the increased energy consumption.

Surgical Approach for Maintaining Nonischemic Conditions of the Liver in Acute Hepatic Vein Obstruction

To establish a possible surgical approach for preventing warm ischemic injury to the liver followed by hepatic vein occlusion (HVO), the hepatic hemodynamics and energy metabolism were investigated in an acute canine HVO model with and without hepatic arterial blood flow. Arterial blood ketone body ratio (AKBR; acetoacetate/3-hydroxybutyrate) and adenylate energy charge potential (ECP = [ATP + 1/2 ADP]/[ATP + ADP + AMP]) of the liver tissue were measured during and after 60 min of HVO. In the group with hepatic arterial blood flow, in which arterial blood was drained by hepatofugal portal flow via the venovenous bypass, total hepatic blood flow, portal vein pressure, ECP, and AKBR were maintained at almost normal level after the termination of HVO, resulting in the survival of all animals for 3 days or longer. By contrast, in the group without hepatic arterial blood flow (warm ischemic group), total hepatic blood flow was maintained at less than 60% of preischemic value, and portal vein pressure gradually increased up to twice the preischemic value. ECP decreased from 0.81 ± 0.06 to 0.71 ± 0.07 along with increasing portal venous pressure, and AKBR also decreased from 1.23 ± 0.12 to 0.63 ± 0.23, resulting in no survival longer 6 hr. It was concluded that hepatic arterial blood flow during HVO, if drained as hepatofugal portal flow, could maintain nonischemic conditions in the liver, despite vena cava obstruction, by providing an alternate outflow via reversed flow in the portal vein.

A new experimental model of specific liver hypoxia using membrane oxygenator.

The present study introduces a new experimental canine model of hepatic arterial deoxygenation using a membrane oxygenator to investigate the influence of hepatic arterial hypoxia on hepatic hemodynamics and energy metabolism. Eighteen mongrel dogs weighing 10 kg each were randomly divided into three groups: group A served as a control (118.0 +/- 9.0 mmHg of hepatic arterial O2 content), group B as a moderately deoxygenated group (40 mmHg of hepatic arterial O2 content), and group C as a severely deoxygenated group (25 mmHg of hepatic arterial O2 content). Deoxygenation was achieved by perfusion of a gas mixture of O2 and N2 through the membrane oxygenator, which was interposed between the femoral artery and the proper hepatic artery, for 60 min. In group C, hypoxia decreased the mean systemic arterial blood pressure and hepatic arterial blood flow. Arterial blood ketone body ratio (AKBR = acetoacetate/3-hydroxybutyrate), which reflects the hepatic mitochondrial redox state, rapidly decreased prior to the significant increase of glutamate oxaloacetate transminase, glutamate pyruvate transminase, and lactate dehydrogenase after the initiation of hypoxia. Hepatic arterial deoxygenation to 25 mmHg for 60 min induced injury to hepatic hemodynamics, resulting in the deterioration of systemic hemodynamics even after the termination of liver hypoxia. This in vivo temporal hepatic arterial hypoxic model without alteration of inflow volume might be useful for investigating the mechanism of hypoxic injury and the critical point of liver hypoxia on hepatic and/or systemic hemodynamics and liver viability.

The arterial blood ketone body ratio as a possible marker of multi-organ failure in patients with alcoholic hepatitis.

The arterial blood ketone body ratio (AKBR: acetoacetate/3-hydroxybutyrate) within 48 h of admission is reported to be an excellent prognostic indicator for acute hepatic failure. In this study, we assessed the AKBR in 63 patients receiving supportive medical therapy for alcoholic hepatitis, in order to investigate its efficacy for predicting complications and the prognosis. Twelve patients (19%) died and 51 patients (81%) survived. Hepatic encephalopathy, severe coagulopathy, and renal failure were the critical complications (P < 0.01), and the AKBR at 72 h of hospitalization was closely correlated with these complications (P < 0.01), although they could not be predicted in any other way during the early admission period. The AKBR of normal individuals ranged from 1.0 to 2.1 (1.54 +/- 0.26, mean +/- SD), so an AKBR > 1.0 (mean-2SD) was defined as normal. The AKBR value at 48 and 72 h of hospitalization showed a significant difference between survivors and non-survivors (P < 0.01). All survivors showed an increase of the AKBR to above 0.7 at 72 h, with subsequent maintenance of the ratio over 1.0, while eight of the 12 non-survivors had sustained suppression of the AKBR below 0.7 at 72 h. Seven of these eight patients subsequently developed multiple organ failure. These findings suggest that the AKBR could be a possible marker of potentially fatal complications and a poor prognosis in patients with alcoholic hepatitis.

Plasma exchange and the arterial blood ketone body ratio in patients with acute hepatic failure

Hepatocyte regeneration in acute hepatic failure is essential for recovery, but requires a large amount of energy. One problem with plasma exchange as supportive therapy in these cases is that massive citrate infusion has an adverse effect on the hepatic energy charge, which may be a serious risk in these patients. The ratio of acetoacetate to beta-hydroxybutyrate in arterial blood has been reported to reflect the cellular energy charge of hepatocytes. In this study, this ratio was assessed before and after plasma exchange in 19 patients with acute hepatic failure. Eight patients recovered and 11 died. The arterial blood ketone body ratio was below 0.6 in all 11 nonsurvivors. It fell to below 0.4 in 10 of them during the first plasma exchange session, and remained below 0.4 for over 12 h in seven of them. On the other hand, the arterial blood ketone body ratio returned to above 0.6 in four of eight surviving patients within 12 h after the first plasma exchange and remained below 0.4 for over 12 h only in two of eight patients. These data indicate that plasma exchange may cause suppression of the arterial ketone body ratio in patients with severe acute hepatic failure. These metabolic changes impair liver metabolism and may make effective hepatocyte regeneration impossible.

Hemodynamics and Hepatic Energy Metabolism in Canine Model of Acute Hepatic Venous Occlusion with Mesocaval Shunt

The relationship between portal hemodynamics and the energy metabolism of the liver with acute hepatic venous occlusion (HVO) was investigated by assessing the changes in the hepatic blood flow, arterial blood ketone body ratio (AKBR) and adenylate energy charge potential (ECP) of the liver tissue in canine model. Acute HVO was induced by the ligation of both the supra- and infrahepatic inferior vena cava (IVC) over the protruding ends of a heparin-coated polyethylene cannula inserted into the IVC. All dogs with only HVO (n = 5) died within 30 min. HVO dogs with additional mesocaval (MC) shunt (n = 10) survived longer than 7 days, during which time their AKBR were maintained in the normal range (over 1.0). ECP was also maintained above the normal level (over 0.850) during the 28-day period. Along with increasing portal pressure caused by the narrowing of the shunt anastomosis, the hepatic blood flow decrease gradually, resulting in a sudden decrease in AKBR and ECP when the portal pressure increased over 11 mm Hg. It is suggested that the normalization of portal pressure is one of the most important factors for maintaining the hepatic energy metabolism and that MC shunt is an effective therapy for maintaining the function of the liver with HVO, as long as portal pressure can be kept within normal range.

Long-latency event-related potentials in acute hepatitis patients with severe coagulopathy

In 19 acute hepatitis patients with severe coagulopathy who were fully alert and oriented without any changes of mood or behavior, the P300 latency and the arterial blood ketone body ratio (KBR) were assessed as predictors of fulminant hepatitis. All 5 patients developing fulminant hepatitis had a corrected P300 latency longer than 345 msec and 4 of them had a KBR below 0.6. There was a significant negative correlation between the KBR and the blood ammonia level and between the KBR and the corrected P300 latency, while there was a positive correlation between the blood ammonia level and the corrected P300 latency. These data suggest that hepatic encephalopathy develops when loss of hepatic detoxifying activity allows toxic substances to reach the brain and induce cerebral edema. Our findings also suggest the clinical value of using the P300 latency combined with the KBR as predictors of fulminant hepatitis.

Encapsulated Hepatocyte Transplantation for the Treatment of D-Galactosamine-lnduced Acute Hepatic Failure in Rats

Intraperitoneal transplantation of hepatocytes encapsulated with calcium alginate gel produced a marked improvement in the survival rate (75%) of rats with D-galactosamine (D-gal)-induced acute hepatic failure (AHF) when compared to the rate of 50% in rats undergoing free hepatocyte transplantation (HCTX). The viability of encapsulated hepatocytes was still 70% at 36 h after transplantation, and a gradual improvement in the serum glutamic oxaloacetic transaminase (GOT) and total bilirubin values was observed after encapsulated HCTX. Moreover, the arterial blood ketone body ratio (AKBR) remained within the normal range for the whole period of the investigation (60 h after transplantation), and histological investigation of the liver at 36 h demonstrated only slight inflammatory cell infiltrates without hepatocellular necrosis. The phagocytic index rose immediately after encapsulated HCTX and remained high subsequently. A prostaglandin inhibitor, indomethacin, blocked the improvement in survival rate, serum GOT, and AKBR of rats with D-gal-induced AHF despite encapsulated HCTX. Furthermore, no increase in the phagocytic index was observed. Indomethacin apparently suppressed the activation of Kupffer cells by encapsulated HCTX, which then failed to improve the survival of rats with D-gal-induced acute hepatic failure. Our results indicate that the reticuloendothelial system seems to play an important role in the efficacy of encapsulated HCTX in rats with D-gal-induced AHF.

Preserved mitochondrial function by allopurinol despite deteriorated hemodynamics in warm ischemia-damaged canine liver

To investigate the pathophysiology of warm ischemia (WI) of the liver, the changes in hemodynamics and energy metabolism were studied during and after 60-min complete WI induced by total hepatic vascular exclusion (HVE) in the canine model. Hepatic arterial blood flow after WI was maintained at 76% of the pre-ischemic level, while portal blood flow was only 27% of the pre-ischemic level associated with increased portal vein pressure, which was twice the pre-ischemic level, resulting in a decrease of total hepatic blood flow to 46% of the pre-ischemic level. Concentration of tissue lipid peroxide increased after WI. Arterial blood ketone body ratio (AKBR), which reflects the hepatic mitochondrial redox state, could not recover to the pre-ischemic level after termination of WI. However, when 100 mg/kg of allopurinol (xanthine oxidase inhibitor) was administered intravenously 10 min prior to initiating WI, AKBR was restored to the pre-ischemic level at 30 min after WI in spite of the fact that allopurinol administration to one group produced no remarkable changes in the hepatic hemodynamics compared with the group without allopurinol treatment. Concentration of adenine nucleotides was significantly higher for the treated group at the end of and after WI than for the group without allopurinol treatment and was maintained at a higher level even after WI. Lipid peroxide production was suppressed. Electron microscopic examination revealed that allopurinol treatment could not prevent mitochondrial swelling. It is suggested that WI causes injury primarily to the portal sinusoidal circulation, resulting in portal congestion concomitant with high portal pressure after the release of WI. Allopurinol could prevent the deterioration of mitochondrial ATP metabolism, and was able to inhibit lipid peroxide production, resulting in the rapid recovery of mitochondrial redox state in spite of the fact that it produced no amelioration of hepatic hemodynamics and morphological alterations.

Arterial blood ketone body ratio as a possible indicator for predicting fulminant hepatitis in patients with acute hepatitis.

Encephalopathy and severe coagulopathy in patients with acute hepatitis (AH) are good markers for the diagnosis of fulminant hepatitis (FH), which occurs in only about 1% of AH patients. However, even if patients show severe coagulopathy, it is quite difficult to predict FH before the onset of encephalopathy. The ratio of acetoacetate/beta-hydroxybutyrate in arterial blood (KBR) has been reported to reflect the cellular energy charge level in hepatocytes. In our previous report, KBR was quite low in FH patients and was an excellent marker for predicting the prognosis. KBR of normal subjects is distributed in a range of 1.0-2.1 (1.54 +/- 0.26, mean +/- SD). In this study, we assessed KBR serially in 15 AH patients with severe coagulopathy (hepaplastin test (HPT) < 40%), including seven patients who developed FH, to see if we could predict FH by using KBR as a marker. Seven patients with KBR < 0.6 of long duration (4 days or more) were complicated with hepatic encephalopathy (HE) and it took 3 or more days of KBR below 0.6 before HE appeared. The other eight patients with KBR < 0.6 of short duration (less than 4 days) were not complicated with HE. These data suggest that AH patients with HPT < 40% and a 3-day duration of KBR < 0.6 are at serious risk of FH.