Levodopa in the treatment of hepatic coma due to fulminant hepatic failureJM Mehta1, SG Karamarkar1, BD Pimparkar2, UK Sheth3
1 Department of Medicine, K.E.M Hospital, Bombay 40012, India
2 Department of Gastroenterology, K.E.M Hospital, Bombay 400012, India
3 Department of Pharmacology and Clinical Pharmacology Unit, Seth G. S. Medical College and K.E.M. Hospital, Bombay-400012, India
Fifteen cases of -advancing stupor or coma due to viral hepatitis, received levodopa intragastrically in the dose of 4 Gm. per day, in addition to the routine treatment of i.v. glucose, bowel wash -neomycin, parenteral corticosteroids and antibiotics. Liver Biopsy in all cases showed a massive liver cell necrosis. 4 patients regained consciousness. 2 of these cases recovered and two others died on 15th day after starting the treatment. The rest of the patients died at different time intervals between 4th and 5th days. Although mortality in this series was high, levodopa had a definite and impressive awakening effect.
Parkes et al (1970) reported marked improvement in conscious level with oral. levodopa given to patients with hepatic coma. Fischer and Baldessarini (1971), confirmed the beneficial effects of levodopa on the mental status of patients with hepatic coma and also noted an improvement in cardiovascular function. On the basis of these and certain experimental findings, they put forward the hypothesis that the effects observed are due to the replenishment by levodopa of the catecholamine stores in the nervous system, which have become depleted as a result of the accumulation of amine products acting as false neuro-transmitters. Possible precursors of the latterphenylalanine, tyrosine and their amines -which are produced in the gut by the action of bacterial amino acid decarboxylases are normally catabolized in the liver. Thus, with severe impairment of liver function these substances could flood the nervous system and after undergoing 13-hydroxylation locally, could replace the normal central and peripheral neurotransmitters.
In this study we present the effects of the addition of levodopa to the routine management of fulminant hepatic failure.
Fifteen cases, who on epidemiological and other considerations appeared to be cases of viral hepatitis and who had an acute onset of progressive and severe mental changes starting with confusion and rapidly advancing to stupor or coma, were selected for this study. The criteria laid down by Trey and Davidson (1970), for the stages in the development of hepatic coma were used as a clinical index of the degree of liver cell failure and of the likely prognosis.
The cases consisted of 6 males and 9 females between 20 and 45 years of age. Of the nine females, 2 cases had a full term normal delivery just one week prior to the onset of symptoms. Five females were from 2 to 7 months pregnant and 2 females were not pregnant. All patients were admitted in Stage III to Stage IV coma as judged by criteria laid down by Trey and Davidson (1970). The test for Australia antigen was negative in all the cases. Liver biopsy or autopsy studies showed presence of massive liver cell necrosis in all the cases. All the patients were managed with the standard conservative treatment of intravenous 25% glucose, neomycin, bowel washes twice a day, protein deprivation, parenteral corti , costeroids, antibiotics and vitamin K. Fresh blood transfusions were given to those who showed a haemorrhagic diathesis. Electrolyte and acid base studies were carried out and any abnormality corrected. Central venous pressure was monitored and a pressure of 6 to 8 cms of blood was maintained by adequate fluids. Adequate urinary output was maintained by intravenous mannitol or frusemide when required. Vasopressor drugs were used terminally to maintain the blood pressure.
In addition to the above measures all patients were given crushed levodopa tablets through a Ryle's tube. The first 2 patients received 2 gm. per day, and the remaining 13 patients 4 gm. per day in 4 divided doses. At the end of the 10th day, levodopa therapy was withdrawn if the patient was alive. Only those patients who were alive 24 hours after the beginning of the treatment were included in this report.
[Table 1] shows the overall results. Four patients regained consciousness (Gr. I)-three patients on 4th day and the remaining 4th patient on 7th day. Thirteen of 15 patients died-two after recovering from coma and 11 without regaining consciousness. Case 1 was dead on 2nd day, Case 11 died at the end of 48 hours, Case 4 was dead at the end of 72 hours and Cases 2, 6, 8, 9, 14, 15 died after 4 days of treatment. Cases 10 and 12 were alive for 5 days. Out of the 4 remaining cases who were alive at the end of 10 days of treatment (Cases 3, 5, 7 and 13), 2 cases (5 and 13) went home fully recovered. The remaining 2 cases (3 and 7) as slated above died on the 15th and 16th day respectively, one due to septicaemia and the other after slipping back into coma.
Out of the 15 cases, 7 cases were in Gr. IV coma when treatment was started. Of these all remained in Gr. IV coma and died except 1 case (Case 7) who had a complete neurological recovery but died of septicaemia on the 15th day.
Of the remaining 8 cases who were in Gr. III coma 3 cases were alive at the end of 10 days, but one of them slipped back into coma on the 15th day and died. The remaining 2 cases (Cases 5 and 13) recovered completely and went home. All the 5 cases who died showed progressive increase of the grade of coma to Gr. IV before death.
Thirteen of 15 cases developed haemorrhagic diathesis and had evidence of internal or external bleeding [Table 1], An autopsy study carried out in 4 fatal cases, showed evidence of internal bleeding, including bleeding in the brain, in 3 cases. Of these 13 cases with bleeding only two cases (Cases 3 and 7) recovered from hepatic coma to die later due to relapse of coma and septicaemia. The other 2 cases who did not bleed recovered from hepatic coma.
None of the 15 cases studied showed any impairment of renal function although one of the autopsied fatal cases showed evidence of congested glomeruli and tubular necrosis.
Fulminant hepatic failure, whatever its etiology, causes a high mortality rate, survival rate being only 17.4% in those with Grade IV coma (Trey & Davidson, 1970). There are a number of possible causes for the fatal outcome such as renal failure, bleeding diathesis, electrolyte and acid base disturbances, other metabolic disturbances like hypoglycaemia, susceptibility to infections and a depression of brain stem function leading to the failure of the respiratory and vasomotor centres.
The liver, however, has an immense power of regeneration and the aim of therapy has always been to buy time and keep the patient alive till the liver regenerates and the liver function recovers. The prognosis of fulminant hepatic failure is closely connected with the mental status of the patient and varies with the grade of coma. Patients in Grade II coma for instance have a much higher survival rat than patients in grade III or IV coma. Any measure, therefore, that lessens the grade of unconsciousness may have a favourable effect in the overall mortality.
Although in the present study the overall mortality remained as high as that reported with the usual conservative management, it was noted that levodopa has a definite and impressive awakening effect. The patients who came out of coma, did so rapidly and were capable of coherent talk and clear thinking within a very short period as compared to those cases, one has come across, which come out of coma without levodopa therapy. Most of our fatal cases were already in Grade IV coma when treatment was started, whereas those that regained consciousness were mostly in Grade III coma. It is possible that if levodopa is started early, before the patient becomes deeply comatose, the results of treatment will be more impressive. Another interesting observation of our study is that all the cases who died had a haemorrhagic diathesis and 3 out of the 4 cases at autopsy showed evidence of haemorrhage in the nervous system. It is possible that in some of our cases the failure of levodopa to lessen the degree of unconsciousness, may have been due to destruction by haemorrhage of centres in the brain, concerned with wakefulness.
It is also remarkable that none of our cases died of renal failure although the incidence of this complication of fulminant hepatic failure is high in the medical literature.
It may be said that a fatal outcome of fulminant hepatic failure is due to many factors and each factor has to be tackled as and when it occurs. Levodopa may be useful for one of the facets of this multifaceted clinical syndrome.
We thank the Dean of the K.E.M. Hospital, Bombay-12 for his permission to carry out this trial. We are also thankful to Roche Laboratories for their liberal supply of levodopa tablets.