B. G. Gazzard

CHARCOAL HÆMOPERFUSION IN THE TREATMENT OF FULMINANT HEPATIC FAILURE

Abstract Twenty-two patients with fulminant hepatic failure who deteriorated to grade-IV coma despite full supportive therapy were treated by repeated periods of haemoperfusion through columns containing activated charcoal. The procedure was well tolerated clinically. Eleven of the patients regained consciousness and ten left hospital. Follow-up liver biopsies in the first three patients at around six months after discharge from hospital showed restitution of the normal lobular architecture. Of the eleven treatment failures, haemorrhage was responsible for death in three, and in six brain herniation secondary to cerebral œdema was an important contributory factor. The column extracted most aminoacids from plasma, and during perfusion arterial concentrations of phenylalanine, tyrosine, and methionine-aminoacids known to be involved in the pathogenesis of the encephalopathy—fell significantly. The charcoal was coated with a biocompatible polymer, and there was no evidence for removal of coagulation factors. The extraction of platelets was below 30% in most instances, and in only two patients was there evidence that bleeding may have been precipitated by the haemoperfusion. These survival figures are to be compared with a previous survival figure of 10% in a series of ninety-two cases with fulminant hepatic failure and grade III or IV encephalopathy treated by full supportive measures.

RELATION OF RENAL IMPAIRMENT AND HAEMORRHAGIC DIATHESIS TO ENDOTOXAEMIA IN FULMINANT HEPATIC FAILURE

Abstract Endotoxaemia, as detected by the Summary Limulus lysate assay, was found in 14 of 22 consecutive patients with fulminant hepatic failure. In most cases there was no other evidence of gram-negative infection and the endotoxaemia may have been due to impaired hepatic clearance of toxins normally absorbed from the gastrointestinal tract. There were statistically significant correlations between the occurrence of endotoxaemia and the development of renal failure and intravascular coagulation, which may be explained by the known properties of endotoxin as a renal vasoconstrictor and an activator of Hageman factor.

Effects of haemoperfusion through charcoal or XAD-2 resin on an animal model of fulminant liver failure

In a group of dogs in whom fulminant liver failure had been induced, perfusion of blood through activated charcoal resulted in a significantly longer survival than that of a similar group of dogs whose blood was not so treated. An otherwise progressive rise in blood ammonia concentration was halted in the treatment group. In another group of dogs with fulminant liver failure perfusion of blood through the resin Amberlite XAD-2 was associated with a fall in the serum bilirubin concentration and complete clearance from the blood of 14C-labelled sodium glycocholate. Survival in this group of animals was not significantly prolonged. This was due at least in part to the occurrence of haemorrhage due to thrombocytopenia. Platelets adhere to the resin but do not adhere to the same degree to charcoal coated with a thin layer of polymer.

A controlled trial of heparin therapy in the coagulation defect of paracetamol-induced hepatic necrosis

Treatment of the coagulation disturbances developing with hepatic damage following a paracetamol overdose was assessed in a controlled trial of 22 patients, one half being given heparin and fresh frozen plasma and the other fresh frozen plasma alone. No significant difference was observed either in the speed of correction of the coagulation defect or in the clinical outcome. Two-thirds of the patients had evidence of disseminated intravascular coagulation, but despite the presence of a severe coagulation defect, significant bleeding occurred in only five patients. This may be because with paracetamol-induced hepatic necrosis both the coagulation defect (and possibly other features attributable to severe hepatic insufficiency) are of shorter duration than in hepatic necrosis due to causes such as viral hepatitis in which the liver damage may be a continuing process.

Prognostic value of serum alpha-fetoprotein in fulminant hepatic failure including patients treated by charcoal haemoperfusion.

Serum alpha-fetoprotein (AFP) levels have been measured sequentially by a radio-immunoassay method in 64 patients with fulminant hepatic failure. In 15 of the 64 patients (23%) AFP levels were raised but in only two did they exceed 500 ng/ml. Of the 23 survivors 11 (48%) had raised AFP levels compared with four of the 41 (9-8%) fatal cases (P less than 0-005). This rise in AFP levels was found early after the development of grade IV coma and constitutes an encouraging prognostic sign at a time when the liver function tests and EEG are unhelpful. A radioimmunoassay must be used if these small but significant rises in plasma concentration are to be detected. Twelve patients survived without showing a rise in plasma AFP at anytime during the illness. The four fatal cases who had raised AFP levels all had serious complications of fulminant hepatic failure. Charcoal haemoperfusion did not seem to increase the survival of AFP negative patients.

Coagulation factor concentrate in the treatment of the haemorrhagic diathesis of fulminant hepatic failure

To assess the value of clotting factor concentrate infusions in fulminant hepatic failure, a controlled trial was performed in which nine patients were randomly allocated to treatment with either concentrate alone or concentrate plus heparin. The five patients receiving concentrate alone all died, with major bleeding as the direct cause of death in three, whereas in the four receiving heparin as well there was only one instance of bleeding and one patient survived. Clinical evidence of intravascular coagulation appeared in two patients treated with concentrate alone and the laboratory evidence of this progressed during the period of infusions in all patients in both treatment groups, although to a lesser extent in those receiving heparin. Additional evidence for intravascular coagulation came from the changes observed in factor VIII levels which, although initially high in all patients, fell subsequently, particularly in those given concentrate alone. There was some improvement in the prothrombin ratio in both groups of patients but not complete correction, and serial assays of clotting factors showed that although factor II rose to high levels during treatment, factors IX and X showed little response. Thus, the use of concentrate of factor IX in this trial, as well as potentiating intravascular coagulation, was inadequate as replacement for the clotting factor deficiencies.

Fibrinogen metabolism in acute hepatitis and active chronic hepatitis.

Summary. Coagulation studies, including those of radioactive fibrinogen metabolism, were performed in seven patients with acute viral hepatitis and 12 patients with active chronic hepatitis. An increased fractional catabolic rate for fibrinogen was observed in four patients from the first group, and seven from the second. The catabolic rate was increased in those patients with the greatest degree of hepatic necrosis as demonstrated by the raised serum aminotransferase levels. There was no correlation between the rate of fibrinogen catabolism and the standard clotting tests, but the SDPS test (indicating the presence of fibrin monomers in the circulation) was consistently positive in those cases where the catabolic rate was increased.

The use of cysteamine and dimercaprol.

Introduction It has been suggested that hepatic damage following a paracetamol* overdose might be prevented by the administration of compounds containing sulphydryl groups (Mitchell et al 1973) which would either increase the amount of glutathione available in the liver or substitute for the action of this compound. One such substance, cysteamine is effective in preventing hepatic necrosis in laboratory animals (Mitchell et a/ 1974, Gazzard et a/ 1974). A preliminary uncontrolled study suggested that it was effective in man (Prescott et al 1974) but recently it was found in a controlled clinical trial not to give significant protection against hepatic damage (Douglas, Hamlyn & James 1976). This study was undertaken in patients following paracetamol overdose to compare the protective effect ofcysteamine with that of dimercaprol, another sulphydryl group donor, found to be of some protective effect in laboratory animals (Mitchell et al 1974) and which had the advantage of being commercially available for human use. We present here the results of the thirty-five patients treated in the trial to date.