Factor VII levels as a guide to prognosis in fulminant hepatic failure

Levels of clotting factors II, V, and VII were measured on admission and then daily in 12 patients with grade IV hepatic coma due to fulminant hepatic failure. Factor VII levels obtained within 36 hours of the development of grade IV coma were not of value in predicting which patients would subsequently recover consciousness. Four of the latter group had levels below 9% at this time while the levels in three of the seven fatal cases were higher. Serial determinations were of more value and levels rose rapidly in those patients who ultimately made a complete recovery.     

Living-related liver transplantation and neurological outcome in children with fulminant hepatic failure

In vivo, endothelial cells (ECs) are subjected to a complex mechanical environment composed of shear stress, pressure, and circumferential stretch. The aim of this study was to subject bovine aortic ECs to a pulsatile pressure oscillating from 70 to 130 mm Hg (mean of 100 mm Hg) in combination with pulsatile shear stresses from 0.1 to 6 dyne/cm2 (1 dyne/cm2=0.1 N/m2) with or without a cyclic circumferential stretch of 4% for 1, 4, and 24 hours. The effect of highly reversing oscillatory shear stress (range -3 to +3 dyne/cm2, mean of 0.3 dyne/cm2) typical of regions prone to the development of atherosclerotic plaques was also studied at 4 and 24 hours. Endothelin-1 (ET-1) and endothelial constitutive nitric oxide synthase (ecNOS) mRNA expression was time and mechanical force dependent. ET-1 mRNA was maximal at 4 hours and decreased to less than static culture expression at 24 hours, whereas ecNOS mRNA increased over time. Pressure combined with low shear stress upregulated ET-1 and ecNOS mRNA compared with static control. Additional increase in expression for both genes was observed under a combination of higher shear stress and pressure. A cyclic circumferential stretch of 4% did not induce a further increase in ET-1 and ecNOS mRNA at either low or high shear stress. Oscillatory shear stress with pressure induced a higher expression of ET-1 mRNA but lower expression of ecNOS mRNA compared with unidirectional shear stress and pressure. We have shown that the combination of pressure and oscillatory shear stress can downregulate ecNOS levels, as well as upregulate transient expression of ET-1, compared with unidirectional shear stress. These results provide a new insight into the exact role of mechanical forces in endothelial dysfunction in regions prone to the development of atherosclerosis.     

Prognostic evaluation of early indicators in fulminant hepatic failure by multivariate analysis

Results of eight multicenter, randomized, placebo-controlled, double-blind, parallel-group studies were pooled to assess the efficacy of the angiotensin II-receptor blocker irbesartan over the dose range of 1 to 900 mg. A total of 2955 adults with a seated diastolic blood pressure of 95 to 110 mm Hg were randomized to treatment with oral irbesartan once daily or placebo for 6 to 8 weeks. Office blood pressure was measured at trough (24+/-3 hours after the last dose) and peak (3+/-1 hours after the last dose) by mercury sphygmomanometry. Demographic characteristics (mean blood pressure; 151/101 mm Hg; mean age, 54 years; 63% male; and 82% white) were similar across all dose groups. After the groups were pooled, antihypertensive efficacy was assessed by therapeutic response (trough seated diastolic blood pressure <90 mm Hg or a reduction from baseline of > or = 10 mm Hg) and by modeling of the maximum reductions in trough and peak seated diastolic and systolic blood pressure. Antihypertensive effects increased with increasing doses and reached a plateau at > or = 300 mg. Irbesartan 150 mg provided placebo-subtracted reductions in trough seated systolic and diastolic blood pressure of approximately 8 and approximately 5 mm Hg, respectively, with 56% of patients displaying a favorable response. In conclusion, irbesartan provides clinically significant blood pressure lowering, with a clear relationship between (log) dose and antihypertensive effect.     

Kinetics of [14C]cholic acid in fulminant hepatic failure: a prognostic test

The kinetics of intravenously injected [14C]cholic acid have been investigated in 14 patients with fulminant hepatic failure, 24 to 36 hr after the development of grade IV encephalopathy. Radioactivity was measured in plasma samples and in the individual plasma bile acid fractions after separation by thin layer chromatography. Plasma disappearance curves of the free [14C]cholic acid were calculated by an iterative nonlinear least squares fitting procedure using a computer. The disappearance of total plasma radioactivity was similar in all patients and greatly prolonged compared with healthy subjects. However, the plasma disappearance of free [14C]cholic acid was significantly faster in the 8 patients who recovered consciousness than in the 6 who did not. Plasma disappearance of free [14C]cholic acid correlated highly significantly with the proportion of conjugated [14C]cholate in plasma. All patients in whom more than 70% of plasma radioactivity was in the conjugated fraction 3 hr after injection survived and left hospital, whereas all of those in whom less than 55% was conjugated died. Measuring the percentage conjugation of [14C]cholate 3 hr after injection may therefore be a useful test of residual liver function in hepatic failure, as a guide to prognosis and in evaluating new forms of treatment.     

The distribution of HBV, HCV and HGV among livers with fulminant hepatic failure of different aetiology

BACKGROUND/AIMS: The aim of the study was to assess the impact factor of HCV and HGV in fulminant hepatic failure. METHODS: The 5'-untranslated regions of HCV RNA and HGV RNA and a segment of the core antigen sequence of HBV were amplified after extracting the nucleic acids from snap-frozen tissue aliquots from explanted livers of 26 consecutive patients undergoing orthotopic liver transplantation for fulminant hepatic failure preoperatively diagnosed as either autoimmune (n=2), HAV/HBV (n=8), toxic (n=4) or aetiologically unknown (n=12). RESULTS: HCV RNA was detected in five of 26 (19.2%) livers with fulminant hepatic failure. All five HCV RNA-positive livers belonged to the group of non-toxic, non-autoimmune liver failure (n=20), three of them were found in the group of liver failure with unknown aetiology (n=12) and two in the group of HBV-associated liver failure (n=7), making an HCV incidence of 25%, 25% and 28.6%, in the different groups, respectively. HGV RNA was detected in 10 of 17 (58.8%) explants and in all four groups of fulminant hepatic failure as defined preoperatively. HBV DNA was identified in six livers of 26 patients (23.1%) with fulminant hepatic failure. Neither HCV RNA nor HBV DNA was detected in the livers of patients with toxic or autoimmune fulminant hepatic failure. CONCLUSIONS: These results indicate that HBV and HCV, but not HGV, play an aetiologic role in fulminant hepatic failure. HCV-positive cases were concentrated either in the group of otherwise unexplained fulminant hepatic failure or in the group of HBV fulminant hepatic failure. HGV-positive cases, on the other hand, were found within all four preoperatively defined groups, indicating a role as cofactor rather than as single aetiologic agent.     

Changes in endogenous benzodiazepine-like compound levels during the course of fulminant hepatic failure: potential effects of decreased renal function

The pathogenetic agents which cause encephalopathy due to fulminant hepatic failure are still under debate. Ammonia and benzodiazepine-like compounds are two of the most important agents considered, so far. Herein, we report the levels of benzodiazepine-like compounds in serum and in urine and of venous ammonia measured during the course of the disease (30 days). The patient rapidly developed stage IV encephalopathy with high levels of ammonia and with only a slight increase of benzodiazepine-like compounds. At that moment, the levels of these compounds were similar to those recorded in the blood when the patient regained full consciousness 28 days later. During the course of the disease, there was a 10-fold increase of benzodiazepine-like compounds in serum which was recorded in parallel with an impaired excretion due to oliguria. This observation seems to indicate that encephalopathy may develop in the absence of significantly increased levels of these compounds and that their episodic increase during fulminant hepatic failure may be an epiphenomenon linked with several factors such as impaired renal function.     

Detection of hepatitis C virus with RNA polymerase chain reaction in fulminant hepatic failure

The role of hepatitis C virus (HCV) infection in fulminant hepatic failure is controversial. The frequency of serum HCV RNA positivity in previously reported patients with fulminant hepatic failure (FHF) of indeterminate cause ranged from 0 to 12% in the United States and Europe and from 43% to 59% in Asia. We assessed serum HCV RNA using polymerase chain reaction (PCR) and oligoprimers from the 5'UTR of the HCV genome in 26 consecutive patients with FHF. Another laboratory independently performed PCR on 21 of the serum samples using different oligoprimers from the 5'UTR and NS3 region of the HCV genome. Serum HCV RNA was detected in two of seven (28%) patients with hepatitis B, 9 of 15 (60%) with an indeterminate cause, and in none with hepatitis A (n = 2) or drug-induced hepatotoxicity (n = 2). HCV RNA PCR results were concordant between both laboratories in 17 of 21 (81%) of samples. In patients with an indeterminate cause, HCV RNA positivity was significantly associated with the transmission risk factor of low socioeconomic status and Hispanic ethnicity. Eighteen patients underwent liver transplantation (LT) and 15 (83%) survived. Among patients with FHF of indeterminate cause, recurrent or acquired HCV infection after transplantation occurred in three of five (60%) and one of four (25%) patients, respectively. Three of four (75%) patients with hepatitis C virus infection post-LT also developed histologic hepatitis. HCV appears to be the causative agent of a substantial number of cases of FHF classified as indeterminate in the Los Angeles area. Differences in patient populations or risk factors may explain the discordant incidences of HCV infection in FHF observed among different programs.     

Comparison of the effects of ischemic preconditioning and surgical delay on pedicled musculocutaneous flap survival in a rat model

Both surgical delay (SD) and ischemic preconditioning (IP) have been shown to be effective in improving the survival of pedicled musculocutaneous flaps. The goal of our study was to determine the effects of IP and SD, separately and together, on the survival of pedicled transverse rectus abdominis musculocutaneous (TRAM) flaps in a rat model. Thirty-two male Sprague-Dawley rats were divided into four groups of 8 rats each: (1) control, (2) 2-week SD, (3) IP, and (4) SD plus IP. A TRAM flap was elevated in each rat. Flap viability was assessed on the fifth postoperative day by computerized video planimetry. Mean area of flap survival was compared between the control, IP, SD, and SD plus IP groups using analysis of variance and Student's t-test. Improvement in surface area survival was seen in musculocutaneous flaps subjected to IP, SD, and SD plus IP compared with the control. IP and SD improved survival 1.3 and 1.4 times the control area respectively. Differences between treatment and control flaps were statistically significant (p < 0.04). In addition, the combination of SD plus IP improved survival by 1.8 times, which is statistically different from controls and from either technique individually (p < 0.002). IP and SD have similar efficacy in improving survival in this musculocutaneous flap model. The effects of IP and SD appear to be additive. The advantage of IP over SD is that IP can be performed during the same operative session as the flap elevation and only adds 1 hour to the surgical procedure.     

Prolonged beneficial effects of a home-based intervention on unplanned readmissions and mortality among patients with congestive heart failure

BACKGROUND: A single home-based intervention (HBI) applied immediately after hospital discharge in a cohort of "high-risk" patients with congestive heart failure has been shown to decrease numbers of unplanned readmissions plus out-of-hospital deaths during a period of 6 months. The duration of this beneficial effect remains uncertain. METHODS: Hospitalized patients with congestive heart failure who had been randomly assigned to receive either usual care (n=48) or HBI 1 week after discharge (n=49) were subject to an extended follow-up of 18 months. The primary end point of the study was frequency of unplanned readmissions plus out-of-hospital deaths. Secondary end points included total hospital stay, frequency of multiple readmissions, cost of hospital-based care, and total mortality. RESULTS: During 18-month follow-up, HBI patients had fewer unplanned readmissions (64 vs 125; P=.02) and out-of-hospital deaths (2 vs 9; P=.02), representing 1.4+/-1.3 vs 2.7+/-2.8 events per HBI and usual-care patient, respectively (P=.03). The HBI patients also had fewer days of hospitalization (2.5+/-2.7 vs 4.5+/-4.8 per patient; P=.004) and, once readmitted, were less likely to experience 4 or more readmissions (3/31 vs 12/38; P=.03). Hospital-based costs were significantly lower among HBI patients (Aust $5100 vs Aust $10600 per patient; P=.02). Unplanned readmission was positively correlated with 14 days or more of unplanned readmission in the 6 months before study entry (odds ratio [OR], 5.4; P=.006). Positive correlates of death were (1) non-English speaking (OR, 4.9; P=.008), (2) 14 days or more of unplanned readmission in the 6 months before study entry (OR, 4.9; P=.008), and (3) left ventricular ejection fraction of 40% or less (OR, 3.0; P=.03); conversely, assignment to HBI was a negative correlate (OR, 0.3; P=.02). CONCLUSIONS: In this controlled study, among a cohort of high-risk patients with congestive heart failure, beneficial effects of a postdischarge HBI were sustained for at least 18 months, with a significant reduction in unplanned readmissions, total hospital stay, hospital-based costs, and mortality.     

The effects of various diphosphonates on a rat model of cardiac calciphylaxis

Compartmental analysis of the disappearance curve of serum cholesterol specific activity after an intravenous administration of a tracer does of cholesterol-4-14C was carried out in five patients with resection of the distal small intestine, cecum, and proximal colon. The data fit best a two compartment model in all five cases with the rapidly exchangeable pool of 16.6+/-3.2 g (mean +/- SD, 60% of the mean of 15 normal subjects) and the slowly exchangeable pool of 31.5 +/- 10.9 g (65%). The reduction of the pool sizes was associated with a shorter mean transit time of cholesterol, 22.15 +/- 8.07 days (40%) and increased turnover rate, 2.42 +/- 0.72g/ day (172%). Direct fecal analysis for the neutral sterols and bile acids derived from the exchangeable pool confirmed the turnover rate obtained from the compartmental analysis. The increased fecal excretion was mainly in the bile acid fraction. The study suggests that the ileal and proximal colon resection results in bile acid malabsorption which, in turn, increases hepatic cholesterol and bile acid synthesis. The synthetic rates, however, could not compensate totally for the excretory rate. Therefore, the pool size decreased to a new low steady state of equilibrium.     

Use of transjugular intrahepatic portosystemic shunt as a bridge to transplantation in fulminant hepatic failure due to Budd-Chiari syndrome

We report a case of fulminant hepatic failure in a 55-yr-old man due to Budd-Chiari syndrome in the setting of polycythemia rubra vera. The patient presented with acute hepatic failure, which rapidly progressed to grade IV hepatic encephalopathy. Placement of a transjugular intrahepatic portosystemic shunt resulted in marked improvement of the encephalopathy and stabilized the liver failure. Subsequently, he underwent successful nonemergent orthotopic liver transplantation. Transjugular intrahepatic portosystemic shunt placement is a safe, effective, therapeutic option to bridge patients with fulminant Budd-Chiari to liver transplantation.     

Age-dependence of hepatic dimethylnitrosamine-demethylase activity in the rat

The mixed-function oxidase which activates the carcinogen dimethylnitrosamine (DMN) was determined in the rat liver as a function of animal age. DMN-demethylase activity increased considerably at first to reach a maximum on day 29, and then substantially decreased to day 59; thereafter, enzyme activity remained essentially stable up to at least day 110. Pretreatment with 3-methylcholanthrene, which caused a pronounced decrease in this enzyme activity, did not affect the general shape of the age-dependence curve. The results suggest that rats between weaning and sexual maturity are more susceptible to the carcinogenic effects of pulse doses of DMN than are neonates or adult animals.     

Effect of lead on hepatic delta-aminolaevulinic acid synthetase activity in the rat: a model for drug sensitivity in intermittent acute porphyria

The hereditary hepatic porphyrias are disorders of porphyrin and haem synthesis characterized by a marked idiosyncrasy towards a variety of lipid soluble drugs. Most of these agents are inducers of the haemoprotein cytochrome P450, the terminal oxidase in drug metabolism. The primary genetic defect in intermittent acute porphyria is a partial deficiency of uroporphyrinogen I synthetase, which may result in a secondary derepression of delta-aminoaevulinic acid synthetase, the rate-limiting enzyme in the haem pathway. Analogous defects at more distant sites may explain the other hereditary hepatic porphyrias. As drug sensitivity may be related to the defect in haem synthesis, we investigated the effects of experimental partial blocks in haem synthesis produced by lead in rats. Drug effects on delta-aminolaevulinic acid synthetase, cytochrome P450, And drug metabolism were studied. Our findings indicate: a) While partial impairment of haem biosynthesis has only minor effects on delta-aminolaevulinic acid synthetase activity, it greatly enhances the sensitivity of delta-aminolaevulinic acid synthetase to induction by drugs and steroids, which when given alone, have little or no inducing effect on the enzyme. b) The experimental partial block in haem synthesis delays and impairs drug-mediated induction cytochrome P450 and drug metabolism in vitro. The findings may explain why a large number of structurally unrelated compounds with little effect on normal liver can precipitate "aucte porphyria".     

Effects of clonidine in a primed rat model of acute hepatic porphyria

The hypothesis that local release of prostanoids may contribute to the pharmacologic effect of nitroglycerin (NTG) has long been debated. Results of prostanoid blockade by indomethacin on NTG-induced effects, to date, have been inconclusive. To quantitate the effects of intravenous indomethacin on NTG-induced myocardial blood flow by using positron-emission tomography, we conducted a prospective, controlled, parallel-design study comparing patients with coronary artery disease with healthy volunteers. Eight subjects, four Canadian Class II-III coronary artery disease (CAD) with luminal narrowing of > 80% in a minimum of two vessels, and four healthy volunteers were evaluated. Baseline global myocardial blood flow was equivalent between the groups. NTG produced a 49.3 +/- 4.7% increase in myocardial blood flow in healthy volunteers (p = 0.006) and an -0.5 +/- 19.8% decrease in the group with CAD (p = 0.62 between groups). After indomethacin, both groups had a 24% decline in myocardial blood flow (CAD, p = 0.25; healthy, p = 0.03). One patient with CAD had acute ischemia after indomethacin. The study demonstrated that short-term intravenous indomethacin decreases NTG-induced myocardial blood flow to the same degree in both subjects with CAD and healthy individuals. Impairment of myocardial blood flow from this pharmacologic combination may be most important in patients with severe fixed lesions.     

A comparison between the Fick method and indirect calorimetry for determining oxygen consumption in patients with fulminant hepatic failure

OBJECTIVE: To compare the Fick method of determining oxygen consumption (VO2) with a gas exchange method in a group of patients in whom the cardiac output and mixed venous oxygen saturation values were consistently high. DESIGN: A prospective, observational study. SETTING: A ten-bed intensive therapy unit at a university teaching hospital. PATIENTS: Seventeen patients suffering from fulminant hepatic failure who required ventilatory support and invasive hemodynamic monitoring. All patients were sedated and paralyzed throughout the study period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: VO2 was determined simultaneously by indirect calorimetry and by the Fick method five or six times in each patient over a 5-hr period after resuscitation with fluids and, if clinically indicated, norepinephrine infusion. The agreement between the methods was poor (limits of agreement +19 to -101 mL/min/m2) and the Fick method consistently underestimated gas exchange measurements (mean bias 41 mL/min/m2). The bias varied widely, both between and within individual patients. The reproducibility of the Fick-derived VO2 was worse than the indirect calorimetry measurements, indicating that the dispersion of data attributable to measurement error was greater with the Fick method. CONCLUSIONS: Under clinical conditions, the agreement between Fick calculations and indirect calorimetry measurements of VO2 in hyperdynamic patients with fulminant hepatic failure was extremely poor. The reproducibility of Fick calculations was less than the reproducibility derived by gas exchange measurements because of the large measurement errors that may occur with the Fick method when the cardiac output is large and the arterial-venous oxygen content difference is small. Fick calculations systematically underestimate gas exchange measurements. The Fick method is inaccurate and unreliable when an estimation of VO2 is required in patients with this hemodynamic pattern.