Efficacy of Intravenous 'L-ornithine L-aspartate' in Reversal of Overt Acute Hepatic Encephalopathy in Patients With Liver Cirrhosis: a Prospective, Randomized, Double-blind, Placebo Controlled Trial
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 200
- 试验地点
- 2
- 主要终点
- Mental state grade
研究概览
简要总结
Hepatic encephalopathy (HE) is a potentially reversible functional disorder of the brain with neurological and psychiatric symptoms. HE occurs in up to 70% of patients with cirrhosis at some time during the course of disease. The chief neurotoxin implicated in the development of HE is ammonia. An important aim of treatment of HE is the reduction of the ammonia in the body by lowering the amount of ammonia produced and increasing its detoxification. Enteric production of ammonia can be decreased by non-absorbable disaccharides such as lactulose and antibiotics such as rifaximin. L-ornithine- L-aspartate (LOLA), the salt of the natural amino acids ornithine and aspartate acts through the mechanism of substrate activation to detoxify ammonia. In clinical trials, LOLA has shown a statistically significant effect with respect to reduction in HE grade, reduction of blood ammonia concentration and positive effects on psychomotor function in patients of cirrhosis with minimal HE and overt chronic Grade I HE, as compared to placebo. However, there is lack of data on the efficacy of LOLA in patients with overt acute hepatic encephalopathy which is one of the major causes of hospital admissions and resource utilization in decompensated cirrhotics. Each admission for HE causes a major financial loss to the family and financial burden on the society. Any drug which decreases the hospital stay by rapidly improving HE, will clearly lead to decreased hospital costs to the individual and the society as a whole. Hence, such a trial is a national priority. The investigators hypothesize that LOLA, if added to the standard treatment of overt acute HE (i.e lactulose), may lead to a faster recovery and decrease in hospital stay of these patients. In this prospective, randomized, placebo controlled trial, the investigators aim to evaluate the efficacy of intravenous L-ornithine, L-aspartate in reversal of overt acute hepatic encephalopathy in patients with liver cirrhosis.
详细描述
A. Introduction and Review of literature
Hepatic encephalopathy (HE) is broadly defined as an alteration in mental status and cognitive function occurring in presence of liver failure. The clinical picture of HE arises as a complication of chronic and, more rarely, acute liver disease. HE occurs in up to 70% of patients with cirrhosis at some time during the course of their disease (1,2). It is characterized by personality changes, intellectual impairment and a depressed level of consciousness. HE may be clinical unapparent (minimal HE) detected by abnormal neuropsychometric or neurophysiological tests (3). The common presentation is overt HE which occurs in patients with advanced cirrhosis with portal-systemic collateral circulation. Episodes of HE in patients with cirrhosis are induced by precipitating factors, like dehydration, hypokalemia, large protein intake, gastrointestinal bleeding, constipation, infections, use of psychotropic drugs, alcohol intake or acute liver injury (hepatitis).
Pathogenesis of hepatic encephalopathy In patients with liver cirrhosis, increasing structural replacement of hepatocytes with connective tissue leads to the loss of functioning hepatic parenchymal tissue and a reduction in the detoxification capacity of the liver. In addition, developing portal hypertension leads to the formation of a collateral circulation through which non-detoxified blood can by-pass the liver to reach the systemic circulation. Both these mechanisms contribute to the neurotoxins present in portal vein blood reaching the brain via the systemic circulation. A number of neurotoxins have been implicated in the pathogenesis of HE with ammonia being the most important (4,5). Fundamental conceptual advances in our understanding of hepatic encephalopathy have confirmed the central role of ammonia in the pathogenesis of portosystemic encephalopathy. Ammonia disrupts the function of neurones and astrocytes, giving rise to the symptoms of hepatic encephalopathy.
Classification/Grading of HE can be classified as type A (in Acute Liver Failure), B (in Portosystemic shunts without intrinsic liver disease) and C (patients of cirrhosis with portal hypertension/or portosystemic shunts) (5,6). In cirrhotics, the type C HE is further classified into Episodic, Persistent and Minimal HE. Chronic persistent overt HE patients are those who can be relatively stable with little day to day fluctuation in their mental status. Episodic (Unstable) HE patients are defined as those who were previously stable, but who over hours and possibly days develop clinically discernible features of HE, requiring medical attention and hospitalization. Minimal HE is clinically inapparent and detected by abnormal neuropsychometric or neurophysiological tests (3).
A precise gradation of HE is essential to prognosticate and plan an appropriate approach to treatment. According to the severity, HE has been traditionally divided into four stages based on alterations in the state of consciousness, intellectual function, behaviour, and neuromuscular signs (West Haven scale) (5).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Hepatic cirrhosis based on clinical, biochemical, radiological and/or histological data
- •Patients with overt acute grade 2, 3 and 4 HE, according to the West Haven criteria, with or without precipitating factors.
- •Age of patient 18-70 years
排除标准
- •Patients who are terminally ill
- •Acute on chronic liver failure
- •Hepatocellular carcinoma
- •Wilson's disease as the etiological factor of liver disease
- •Advanced cardiac or pulmonary disease
- •Presence of underlying chronic renal failure
- •Neuro-degenerative disease or major psychiatric illness
- •Patients on sedatives or antidepressants
- •Pregnancy or breastfeeding
研究组 & 干预措施
L-ornithine L-aspartate
L-ornithine L-aspartate (6 ampules, each ampule containing 5 grams of the drug in 10 ml solution) to be diluted in 440 ml of Dextrose 5% (to make a total of 500 ml of solution), as intravenous infusion at the rate of 21 ml/hour, over 24 hours, for 5 days
干预措施: L-ornithine L-aspartate (Drug)
Placebo (sterile water)
Placebo (sterile water, 6 ampuoles of 10 ml each) diluted in 440 ml of Dextrose 5%, as intravenous infusion at the rate of 21 ml/hour, over 24 hours, for 5 days
干预措施: Placebo (Drug)
结局指标
主要结局
Mental state grade
时间窗: 5 days
Mental state grade according to West Haven criteria for Hepatic encephalopathy
次要结局
- Blood Ammonia levels(5 days)
- Serum Cytokine levels(5 days)
- Length of Hospital stay(4 weeks)
- Mortality(4 weeks)
研究者
Prof. Sandeep S Sidhu
Professor
Dayanand Medical College and Hospital