Clinical Trial: Therapeutic Efficacy of L-Ornithine L-Aspartate Infusion in Patients With Acute Liver Failure

Study Status: Completed
Recruit Status: Unknown status
Study Type: Interventional

Official Title: Therapeutic Efficacy of L-Ornithine L-Aspartate Infusion in Patients With Acute Liver Failure: A Double- Blind, Randomized, Placebo- Controlled Study

Brief Summary: The purpose of the study is to determine whether L-Ornithine L-Aspartate infusion improves the survival of patients with acute liver failure.

Detailed Summary:

Acute liver failure (ALF) has a high mortality. However, those who survive recover completely without any sequel. Liver transplantation is logistically and financially difficult in most countries with the highest disease burden. It also entails a lifelong commitment to immunosuppression. We therefore need new treatment options to improve the survival of medically managed patients with ALF.

Ammonia is believed to be the major neurotoxin in ALF. There is experimental evidence of direct and indirect ammonia neurotoxicity in ALF. The brain does not have a urea cycle, and relies on glutamine synthesis in the astrocytes for removal of excess ammonia. Increased intracellular glutamine in the astrocytes leads to cellular swelling. Increased brain ammonia concentrations also result in altered expression of key astrocyte proteins including glial fibrillary acidic protein, glutamate and glycine transporters and "peripheral-type" (mitochondrial) BZD receptors. Accumulation of ammonia in brain results in a redistribution of cerebral blood flow from cortical to sub-cortical structures, and also has direct effects on neurotransmission. Increased ammonia concentration upregulates the peripheral-type benzodiazepine (PTBR) receptors in the outer membrane of astroglial mitochondria, and enhance the synthesis and release of neurosteroids, some of which are known GABA (A) receptor agonists.

There is now evidence of high blood ammonia levels in ALF , with a substantial blood-to-brain ammonia transfer.Brain-blood ammonia concentration ratios (normally of the order of 2) are increased up to 4 fold in liver failure. Higher ammonia levels have been co-related with higher mortality and complications in human clinical trials. Clemmesen et al found that ALF patients who died of cerebral herniation had higher ammonia levels as compared to the
Sponsor: All India Institute of Medical Sciences, New Delhi

Current Primary Outcome: Improvement in survival. [ Time Frame: Within 30 days of disease onset ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Reduction in ammonia levels during and at the end of 72 hour LOLA infusion. [ Time Frame: 72 hours ]
  • Improvement of encephalopathy by one or more grades. [ Time Frame: 72 hours ]
  • Reduction of consciousness recovery time (CRT) among survivors. [ Time Frame: Within 30 days of disease onset ]
  • Prolongation of time to death among non-survivors. [ Time Frame: Within 30 days of disease onset ]
  • Prevention / reduction of cerebral edema. [ Time Frame: 72 hours ]
  • Reduction of seizures frequency. [ Time Frame: Within 30 days of disease onset ]


Original Secondary Outcome: Same as current

Information By: All India Institute of Medical Sciences, New Delhi

Dates:
Date Received: May 4, 2007
Date Started: January 2005
Date Completion: May 2007
Last Updated: January 4, 2008
Last Verified: April 2007