Hepatic Encephalopathy Clinical Trial
Official title:
Therapeutic Efficacy of Oral PEG3350 Plus Lactulose Versus Lactulose Alone in Patients of Acute on Chronic Liver Failure With Overt Hepatic Encephalopathy: A Single Blind Prospective Randomized Controlled Study
it is a single blind randomised control study which aims to study the effect of PEG3350 in resolution of overt hepatic encephalopathy in patients of acute on chronic liver failure. this will be compared with the standard of care in the management of hepatic encephalopathy.
Therapeutic Efficacy of oral PEG3350 plus Lactulose Versus Lactulose alone in Patients of
Acute on Chronic Liver Failure with Overt Hepatic Encephalopathy: A Single Blind Prospective
Randomized Controlled Study
INTRODUCTION:
Hepatic encephalopathy (HE) refers to syndrome observed in patients with cirrhosis exhibiting
clinical manifestations of mild to severe cognitive dysfunction (neuropsychiatric
abnormalities) characterised by alterations in sleep pattern, sudden behavioural changes &
personality changes along with altered cognition, or coma. The basic pathophysiology involved
in development of potentially reversible neuropsychiatric abnormalities associated with HE
are not clearly understood but ammonia generation by gut microbiota is considered as
significant contributing factor. HE is categorized into overt hepatic encephalopathy (OHE)
and minimal hepatic encephalopathy (MHE). Previous studies have reported the incidence of OHE
and MHE to be 30-45% and 60-80% respectively in patients suffering from cirrhosis .
In the present study, we propose to assess the efficacy of an ammonia reducing therapy
utilisisng PEG 3350 in patients with Acute on Chronic Liver Failure (ACLF).
Hepatic encephalopathy in Acute on Chronic Liver Failure (ACLF) The syndrome of acute on
chronic liver failure is a recently described clinical entity. The defining criterion for
acute-on-chronic liver failure (ACLF) takes into consideration the existence of hepatic
encephalopathy (HE) within 4 weeks. In Asia, the following definition has been suggested:
"acute hepatic insult manifesting as jaundice (serum bilirubin level ≥5 mg/dl) and
coagulopathy (international normalized ratio ≥1.5), complicated within 4 weeks by ascites
and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver
disease" . In the West, experts proposed to define ACLF as "an acute deterioration of liver
function in patients with cirrhosis which is usually associated with a precipitating event
and results in the failure of one or more organs and high short-term mortality". This
definition is on the basis of the European Association for the Study of the Liver
(EASL)-Chronic Liver Failure (CLIF) Consortium Acute-on-Chronic Liver Failure in Cirrhosis
(CANONIC)" study which established diagnostic criteria for ACLF in hospitalized patients who
had an acute decompensation (AD) of cirrhosis . In ACLF, hyperammonemia, systemic
inflammatory state mediated by various cytokines which includes sepsis/SIRS, bacterial
translocation, insulin resistance resulting in hyperglycemia and oxidant induced injury, in
addition modulation by glutaminase gene alteration along with alterations in cerebral
hemodynamics appear to be crucial factors in the pathogenesis of encephalopathy.Various
studies have explored the potential of bacterial infections, hyponatremia, alcohol intake and
factors responsible for systemic inflammation in HE. HE is diagnosed after excluding other
causes of altered cognition such as metabolic, neurological and psychiatric conditions.
Clinical features of HE in ACLF patients are very much similar to those with HE in acute
liver failure (ALF). The clear correlation of serum ammonia levels, systemic inflammation and
outcome of HE in ACLF patients is not well understood .
Factors precipitating, HE, such as constipation, hyponatremia, infections etc. must be
promptly identified and addressed appropriately. Currently Evidence-based medicine approach
for the management of HE is restricted to early bowel evacuation and administration of
non-absorbable antibiotics such as rifaximin. Antibiotics, prebiotics, treatment of diabetes
and other supportive management reduces the systemic inflammation .
Most of the therapy regimens in treatment of hepatic encephalopathy are directed towards
reduction of the generation of nitrogenous products, for which gut is the major site of
generation and the organ of accumulation of nitrogenous toxins especially Ammonia in patients
with liver failure and portosystemic shunting Treatment of Hepatic Encephalopathy Lactulose
(beta-1,4-galactosido-fructose) has been used in practice for the management of HE because of
its ammonia lowering effects . The mechanism by which lactulose act still remains
controversial and is hypothesized to be by following methods, first is metabolism of
lactulose by gut bacteria release organic acids which play vital role in trapping ammonium
ions, second is by elimination of ammonia generating organisms and third is by replacing
amminogenic organisms with urease lacking acidophilic bacteria . The role of inhibition of
glutamine followed by decreased ammonia genesis has also been considered. Management and
treatment of patients with OHE is mainly focused on elimination of underlying precipitating
factors, nutritional supports, and lowering ammonemia . Lactulose and rifaximin are the most
widely used medications to lower ammonia generation; however, their exact mechanism of action
is still not well understood .
REVIEW OF LITERATURE:
Proposed Role of PEG 3350 in HE Before the routine use of non-absorbable disaccharides,
simple laxatives were used in the management of hepatic encephalopathy assuming the
beneficial effects of bowel evacuation in resolution of neurocognitive disturbances in liver
diseases. With this principle, there were trials done assessing the clinical benefits of PEG
solution, which is a commonly used laxative is used routinely in bowel preparation for
colonoscopy. Currently there is a significant data showing the beneficial effects of PEG 3350
in overt HE due to underlying cirrhosis, however its efficacy in ACLF remains to be looked
into. Similar to lactulose, polyethylene glycol is unabsorbed from the gut but in addition it
also lacks the unabsorbed carbohydrate load which aids in lowering of stool pH and enhancing
the amount of water lost from the stools. Furthermore, the rate of ammonia excretion via
feces is enhanced with PEG as compared to lactulose. In this study, we propose to evaluate
the efficacy & safety profile of PEG3350 plus lactulose vs. lactulose alone for treatment of
ACLF. An essential understanding required with PEG usage is to consider that it exerts a
significant cathartic effect and thus may progress to dehydration, hypovolemia,
dyselectrolemia, and even blood gas abnormalities. It's also the most prominently used
preparative agent in patients undergoing colonoscopy, and is thus widely used in human
population worldwide. PEG preparations are easily available and are cost effective. Another
potential benefit of utilizing PEG for OHE is that it may result in decrease in the duration
of hospitalization, depending on the causes of the HE. By accelerating the treatment of
hepatic encephalopathy, PEG can help patients to return to normal life more rapidly and
decrease the direct and indirect cost of illness caused by hepatic encephalopathy. PEG, which
resolves decreased level of consciousness more effectively and more rapidly in the first 24
hours, can also help physicians to identify the other causes of altered mental status more
quickly and more accurately.
Some of the trials which have compared the efficacy of PEG in management of HE are:
Author Trial Conclusion. Rahimi et al., (n=50) "Lactulose vs Polyethylene Glycol
3350-Electrolyte Solution for Treatment of Overt Hepatic Encephalopathy The HELP Randomized
Clinical Trial" "PEG led to more rapid HE resolution than standard therapy".
Naderian et al., (n=40) "Polyethylene Glycol and Lactulose versus Lactulose Alone in the
Treatment of Hepatic Encephalopathy in Patients with Cirrhosis: A Non-Inferiority Randomized
Controlled Trial" "The use of PEG along with lactulose in comparison with lactulose alone is
more effective in the treatment of hepatic encephalopathy in patients with cir¬rhosis".
Patients and methods:
Study Design: A prospective interventional cohort study using the drug PEG3350 + lactulose
versus lactulose alone.
Allocation: randomized Intervention model: parallel assignment Masking: none, open label
Primary purpose: treatment. Setting: Academic hospital - PGI (Chandigarh, India). Patients
fulfilling eligibility criteria will be approached for informed written consent.
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