Phase I Clinical Trial with the AMC-Bioartificial Liver

Recently a bio-artificial liver (BAL) system has been developed at the Academic Medical Center (AMC) of Amsterdam to bridge patients with acute liver failure (ALF) to orthotopic liver transplantation (OLT). After successful testing of the AMC-BAL in rodents and pigs with ALF, a phase I study in ALF patients waiting for (OLT) was started in Italy. We present the safety outcome of the first 7 patients aged 21–56 years with coma grade III or IV. The total AMC-BAL treatment time ranged from 8 to 35 hours. Three patients received 2 treatments with two different BAL's within three days. Six of the 7 patients were successfully bridged to OLT. One patient showed improved liver function after two treatments and did not need OLT. No severe adverse events of the BAL treatment were noted. Conclusion Treatment of ALF patients with the AMC-BAL is a safe and feasible technique to bridge the waiting time for an adequate liver-graft.

Long-Term Anticonvulsant Therapy Worsens Outcome in Paracetamol-Induced Fulminant Hepatic Failure

1 Paracetamol hepatotoxicity has been found to be potentiated by anticonvulsant drugs in animal experiments; isolated case reports in humans sugest that long-term anticonvulsant therapy may also adversely influence outcome following overdose. 2 We compared the clinical course, after paracetamol overdose, of 18 patients on long-term anticonvulsant therapy with corresponding features in two published series of paracetamol-induced fulminant hepatic failure from this unit: 297 patients seen between 1973 and 1985 and a further 99 between October 1986 and April 1988. 3 Mortality in those patients who were taking anticonvulsants, but who did not receive N-acetylcysteine, was higher than in either of these series (93.3% vs 64.6% and vs 57.9%, P< 0.025). Although not statistically significant, there were also trends towards more severe coma (grade 3 or 4: 93.3% vs 75.4%, 1986-88), acidosis (pH less than 7.30: 40% vs 22.6%, 1973-85) and coagulopathy (prothrombin time greater than 100 s: 53.3% vs 33.7%, 1973-85). In the small number of patients given N-acetylcysteine, mortality was similar to that in the 1986-88 series (1/3 vs 15/42). 4 We conclude that chronic use of anticonvulsants enhances clinical features of paracetamol toxicity and discuss possible mechanisms by which this could be mediated.

Plasmapheresis in Acute Liver Failure

A series of 9 patients with acute hepatic failure and Grade IV hepatic coma received daily plasmapheresis until they recovered or death ensued. Of the nine, seven (77%) showed an improvement in coma grade and five (55%) survived to leave hospital. Plasmapheresis significantly decreased serum bilirubin, asparate aminotransferase and plasma ammonia concentrations. Survival following plasmapheresis appeared substantially better than in a non randomized group of similar patients not plasmapheresed. The simplicity of the procedure, biochemical improvements observed and apparent efficacy, suggest that further evaluation of the technique as a means of providing temporary hepatic support is indicated.

Predicting outcome from closed head injury by early assessment of trauma severity

✓ The relationship between severity of head injury and outcome was studied in 96 patients. Severity was assessed based on the level of coma and presence of mass lesion, hemiparesis, skull fracture, and pupil abnormality. Outcome was assessed using the Wechsler Adult Intelligence Scale, the Halstead-Reitan neuropsychological battery, and the Glasgow Outcome Scale. The relationship between assessment of severity of trauma and the outcome measurements was calculated by multiple regression analysis. Results indicate that coma grade and estimates of premorbid intelligence quotient (IQ) served best to predict IQ as assessed after the injury. The combination of coma grade, mass lesion, and skull fracture were important predictors of the Halstead Impairment Index. Coma grade and pupil abnormality predicted the Glasgow Outcome Scale. Low to moderate relationships were found between the predictor variables and the measurement of IQ and the Glasgow Outcome Scale; multiple regression coefficients were 0.63 and 0.61, respectively. The relationship between measurement of trauma severity and the Halstead Impairment Index was also low (R = 0.37).

Antithrombin III Treatment In Acute Liver Failure

In acute liver failure (alf) there is a defect in synthesis of coagulation factors in addition there is a disseminated intravascular coagulation which is followed by an impairment of the microcirculation. With an early substitution of Antithrombin III (AT III) we tried to stop this situation. In 22 patients (10 female, 12 male, age 10-68) with alf presenting with hepatic coma (grade I-IV) we studied the time course of AT III plasma activity (the study started in December 1978 and is continued until now). AT III was measured with the chromogenic substrate method. When AT III activity fell below the level of 80% of normal, we started to substitute AT III and to give low dose heparin (125-500 U/hrs). In addition in case of bleeding or a decrease of coagulation factors or fibrinogen under the hemostatic active concentration, complexes of prothrombin and fibrinogen were administered. Besides the usual conservative treatment for alf, patients in coma (grade IV) were undergoing baboon liver perfusion. The rapid fall of the hepatic coagulation factors stopped. In patients, who still were able to synthesize coagulation factors a reincrease of these factors after administration of AT III was seen and there was a further fall in fibrinogen. The dosage of AT III in alf required to bring AT III to normal values depended on the degree of intravascular coagulation. The average dose in our study was 250 U/3 hrs. The clinical course of alf was prolonged in all patients and 7 patients with the prognostic deleterious colombindex (sum of factors II + V + VIII) < 75% eventually survived the alf. The coagulation disorders in alf can be treated with an early substitution of AT III; thus, there is more time for liver regeneration. Our results suggest an improved prognosis of the acute liver failure.

Concentration of 3′,5′ cyclic adenosine monophosphate in ventricular CSF of patients following severe head trauma

✓ Previous studies have demonstrated that cerebrospinal fluid (CSF) from the lateral ventricle of patients without disturbance of sensorium or intracranial pressure, contains 15 to 30 nM 3′,5′ cyclic adenosine monophosphate (cAMP). The concentration of this cyclic nucleotide was measured by radioimmunoassay in 133 samples of CSF from the lateral ventricle of 26 patients who were comatose following acute head trauma for periods up to 40 days. Concentration of CSF cAMP in diminishing coma Grades V, IV, III, II, and I was 1.5 ± 0.1 nM; 1.24 ± 0.34 nM; 3.14 ± 0.7 nM; 10.06 ± 3.47 nM; and 13.36 ± 1.38 nM, respectively. After the sensorium cleared (coma Grade 0), cAMP was 22.0 ± 1.7 nM. The correlation between the grade of coma and cAMP concentration was −0.80 (p > 0.01). These results imply that alteration in the level of consciousness following head trauma is associated with a disturbance of cAMP metabolism within the central nervous system. Possible mechanisms explaining this observation as well as therapeutic implications are discussed.