R. Keays

Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial.

OBJECTIVE--To see whether intravenous acetylcysteine would improve outcome in patients with fulminant hepatic failure after paracetamol overdose. DESIGN--A prospective randomised controlled study. SETTING--The Institute of Liver Studies, Kings College Hospital, London. PATIENTS--50 consecutive patients (21 male) aged 16-60 with fulminant hepatic failure after paracetamol overdose who had not previously received acetylcysteine. INTERVENTIONS--Conventional intensive liver care plus either acetylcysteine (25 patients) in the same dose regimen as used early after a paracetamol overdose, except that the infusion was continued until recovery from encephalopathy or death, or an equivalent volume of 5% dextrose (25 patients). MAIN OUTCOME MEASURES--Survival; incidence of cerebral oedema, renal failure, and hypotension requiring inotropic support; liver function as assessed by prolongation of the prothrombin time; and degree of encephalopathy. RESULTS--The rate of survival was significantly higher in the acetylcysteine treated group than in the controls (48% (12/25 patients) v 20% (5/25); p = 0.037, 95% confidence interval for difference in proportions surviving 3% to 53%). Acetylcysteine treated patients had a lower incidence of cerebral oedema (40% (10/25) v 68% (17/25); p = 0.047, 95% confidence interval for difference in incidence 2% to 54%), and fewer developed hypotension requiring inotropic support (48% (12/25) v 80% (20/25); p = 0.018, 95% confidence interval 7% to 57%). Rates of deterioration and recovery of liver function, however, were similar in the two groups. No adverse reactions to acetylcysteine were seen. CONCLUSIONS--Acetylcysteine is safe and effective in fulminant hepatic failure after paracetamol overdose.

Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine

The influence of acetylcysteine, administered at presentation to hospital, on the subsequent clinical course of 100 patients who developed paracetamol-induced fulminant hepatic failure was analysed retrospectively. Mortality was 37% in patients who received acetylcysteine 10-36 h after the overdose, compared with 58% in patients not given the antidote. In patients given acetylcysteine, progression to grade III/IV coma was significantly less common than in those who did not receive the antidote (51% vs 75%), although the median peak prothrombin time was similar for both groups. Whether the beneficial effect is related to replenishment of glutathione stores or a consequence of another hepatic protective mechanism of acetylcysteine requires further study.

Serial prothrombin time as prognostic indicator in paracetamol induced fulminant hepatic failure.

OBJECTIVE--To find out whether changes in the daily prothrombin time are of prognostic importance in patients with paracetamol induced fulminant hepatic failure. DESIGN--Retrospective study. SETTING--The Liver Unit, Kings College Hospital, London. PATIENTS--150 Consecutive patients with paracetamol induced fulminant hepatic failure admitted between October 1986 and February 1989. MAIN OUTCOME MEASURE--Death. RESULTS--Of the 150 patients, 72 (48%) died. In all, 34 of the 37 (92%) patients with a peak prothrombin time of greater than or equal to 180 seconds died as did 20 of the 41 (49%) with a time of 130-179 seconds, nine of the 25 (36%) with a time of 90-129 seconds, and nine of the 47 (19%) with a time of less than 90 seconds. Of the 42 patients with a continuing rise in prothrombin time between days 3 and 4 after overdose, 39 died (93%) compared with 21 of the 96 (22%) in whom the prothrombin time fell. CONCLUSIONS--These data indicate that a continued increase in prothrombin time on day 4 after overdose and a peak prothrombin time of greater than or equal to 180 seconds identify at an early stage those patients with a less than 8% chance of survival. Liver transplantation should be considered in patients meeting either of these criteria.

The safety and value of extradural intracranial pressure monitors in fulminant hepatic failure

Thirty-six of 68 consecutive patients with fulminant hepatic failure (FHF) progressing to grade 4 encephalopathy who had extradural ICP monitors inserted were reviewed to determine the safety and the value of ICP monitoring. Only minor complications were encountered. These included local wound bleeding at the burrhole site in four patients and a small cerebral hemorrhage in relation to the monitor in one other patient. No significant long-term sequelae were related to the operative procedure. ICP monitoring identified rises in ICP unaccompanied by clinical signs and as a consequence treatment was given to the monitored patients more often than the non-monitored group (median 6 vs. 2 treatments, P < 0.01). The duration of survival from the onset of grade 4 encephalopathy was significantly greater in the ICP monitored group (median 60 vs. 10 h, P < 0.01) although overall survival was unchanged. Monitoring also provided important prognostic information since the peak ICP was higher in non-survivors than in survivors (median 45 vs. 35 mmHg, P = 0.051). The pattern of clinical signs accompanying episodes of intracranial hypertension differed between survivors and non-survivors. Pupillary abnormalities were detected more often in non-survivors while systolic hypertension occurred more frequently amongst survivors with the peak systolic blood pressure being significantly higher. ICP monitoring proved safe and effective, provided valuable information regarding subclinical intracranial hypertension and prognosis and should be regarded as part of the routine management of intracranial hypertension complicating FHF.

Controlled trial of antithrombin III supplementation in fulminant hepatic failure

Patients with fulminant hepatic failure have severe circulatory disturbances which may be due to fibrin and cellular plugs in micro-vessels which are a consequence of intravascular coagulation and which can lead to multiorgan failure. Since antithrombin III supplementation has been shown to be beneficial in animal models of septic shock with disseminated intravascular coagulation, a controlled study was performed to investigate the effect of antithrombin III supplementation in fulminant hepatic failure. Twenty-five patients in grade III or IV coma were selected on the basis of evidence of sepsis, intravascular coagulation and a high risk of developing multiorgan failure. Thirteen patients received 3000 units of antithrombin III (Kybernin P; Behringwerke), followed by a further 1000 units every 6 h. Antithrombin III activity increased from 0.26 +/- 0.04 SE U/ml to 0.82 +/- 0.07 U/ml at 3 h post infusion (normal range 0.80-1.20 U/ml) and remained greater than 0.80 U/ml throughout the study without any apparent increase in the frequency of bleeding. However, survival was not improved and markers of intravascular coagulation remained similar between the two groups. Thus, although the antithrombin III deficiency in fulminant hepatic failure can be corrected by supplementation with antithrombin III concentrate, its use in the prevention of intravascular coagulation and to avoid microvessel plugging needs to be studied at an earlier stage in the disease.

Arterial-venous pH differences and tissue hypoxia in patients with fulminant hepatic failure

ObjectiveA recent report suggested that, for hypotensive patients, tissue acidemia is best monitored by simultaneous estimates of arterial pH, mixed venous pH, and bicarbonate. This method of detecting tissue acidemia may therefore apply to fulminant hepatic failure patients, who are known to have a high frequency of covert tissue hypoxia. In the present study, both arterial pH and mixed venous pH and bicarbonate were compared in 22 patients with fulminant hepatic failure. Blood samples were drawn from the pulmonary artery and radial artery and this blood was analyzed to determine oxygen delivery and consumption. The arterial pH, mixed venous pH, and bicarbonate were compared using an oxygen flux test to determine the optimal method of demonstrating tissue hypoxia in this group of patients. DesignA prospective study. SettingThe Liver Unit of our institution. PatientsPatients (n = 22) with fulminant hepatic failure admitted between January 1989 and January 1990. InterventionsPatients were studied before and after an infusion of prostacyclin. Measurements and ResultsThe findings of this study suggest that pH and bicarbonate differences in arterial and mixed venous blood samples were not indicative of tissue hypoxia in patients with fulminant hepatic failure. By contrast, measurement of oxygen consumption after the infusion of prostacyclin, with the demonstrated increase in oxygen uptake, provided a more accurate indication of covert tissue hypoxia. ConclusionsIn critically ill patients with a hyperdynamic circulation, such as those patients with fulminant hepatic failure, an oxygen flux test remains the best method of determining the presence of covert tissue hypoxia.

The diagnosis of acute renal failure in intensive care: mongrel or pedigree?

Acute renal failure is common in the intensive care unit; it is well recognised that patients who develop acute renal failure have a high mortality rate. While there have been improvements in the management of acute renal failure, the mortality remains high. Acute renal failure is easily diagnosed biochemically and clinically but it is not a single disease entity. It is a syndrome that affects a very heterogeneous population. Studies of acute renal failure and of the impact of renal replacement therapy in intensive care are usually inconclusive, which may be the natural consequence of studying a syndrome. This article focuses on the more uncertain features of acute renal failure, the problems of investigating acute renal failure as a disease and the difficulties of applying the results of a study of a heterogeneous population to the management of individuals.

Cerebral oedema in acute liver failure

One of the most hazardous complications of acute liver failure (ALF) is raised intracranial pressure and the development of cerebral oedema. Until very recently it had been cited as the commonest mode of death, with an incidence of between 50 and 80% amongst those patients who progress to the deepest grades of coma, although that situation may now be changing. The purpose of this article is to discuss why failure of the liver leads to cerebral oedema and what treatment options are available.