PEG3350 in ACLF With Hepatic Encephalopathy
PEG3350 in ACLF With Hepatic Encephalopathy
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.
Inclusion Criteria:

 -  Age 18-75 years.

 -  Patients with ACLF with presence of hepatic encephalopathy > grade 2 as per WHC

 Exclusion Criteria:

 -  Pregnant women or those who are suspected to be having acute fatty liver of pregnancy

 -  Malarial hepatopathy, enteric hepatitis, or ischemic hepatitis.

 -  Serum Na <125 mEq/litre

 -  Gastrointestinal (GI) obstruction, ileus, or gastric retention

 -  Bowel perforation

 -  Toxic colitis or toxic megacolon

 -  Structural brain lesions (as indicated by computed tomography imaging if available and
 confirmed by neurological exam)

 -  Other causes of altered mental status (i.e. not meeting the definition of hepatic
 encephalopathy

 -  Uncontrolled infection with hemodynamic instability requiring vasopressors.