Safety and Efficacy of CRRT (Medical therapy)in Patients With Acute Liver Failure (Liver Disease).

Recruiting

Conditions: Hepatic failure, unspecified,

Registration Number: CTRI/2021/07/034577

Lead Sponsor: Institute of Liver and Biliary Sciences

Brief Summary: In this prospective randomizedcontrolled trial we aim to evaluate the impact of early initiation of CRRT onoutcomes in patients with acute liver failure with cerebral edema andhyperammonemia in improving cerebral edema and clinical outcomes. We also aimto evaluate the effects of early initiation of CRRT on systemic hemodynamics(cardiac output and systemic vascular resistive index, extravascular lung waterand lung permeability index), endothelial function and coagulation,microcirculation (as assessed by lactate clearance and central venous oxygensaturation), mitochondrial function. Patients with ALF who meet the inclusionand exclusion criteria.

Group 1: CRRT initiation withinthe first 12 hours Group 2: CRRT would be initiated i) In patients with worseninghyperammonemia despite two sessions of plasma-exchange ii) Patients meetingrenal indications (hyperkalemia, volume overload, oliguria or metabolicacidosis etc)

Hypothesis: We hypothesize thatpreemptive administration of continuous renal replacement therapy would besynergistic to plasma-exchange in ameliorating the cytokine storm, cerebraledema and improve outcomes in patients with non-acetaminophen ALF with cerebraledema compared to late initiation.

Aim and Objective -

AIM:

Primary

1) 21-day transplant freesurvival with Prometheus Secondary

To compare the improvement effectin cerebral edema and hepatic encephalopathy in both groups

To study the safety of therapy(incidence of intradialytic hypotension, impairment of coagulation,hypothermia)

Duration of mechanicalventilation and ICU stay in both groups

Impact on arterial lactate

Improvement in SIRS

Effect on systemic hemodynamicsand pulmonary function

Effect on endotoxin, DAMPS,pro-inflammatory cytokines, endothelial functions and coagulation

Methodology Study Protocol

All patients will be evaluated asfollows:

Clinical history and examination

Etiology of acute event

Severity assessment indices

Complications if anyInvestigations Arterial blood gas analysis

Hematology

CBC, Prothrombin time and INR

Peripheral smear, Retics

Thromboelastogram(ROTEM)

S.Fibrinogen level

Biochemistry

Liver function testing

Kidney function test

Arterial ammonia levels

Serum lactate

CRP and procalcitonin

S.Ferritin and LDH

Etiology of acute event:

Infectious etiology: IgM antiHAV, IgM anti HEV, IgM anti HBc ( If HBsAg +ve), IgM anti HDV ( If HBsAg +ve) ,total antiHBc, anti HCV

Non Infectious etiology: Alcoholbinging in last 4 weeks, hepatotoxic drugs, ANA (>1: 80), IgG

Non infectious etiology:Autoimmune markers, copper studies, iron studies, HOMA IR, FBS Imaging USGabdomen with Doppler for spleno-portal axis NCCT abdomen and brain Assessmentof cerebral edema

Optic nerve sheath diameter

Transcranial doppler

Electroechocardiogram

Study Population: 60 patientswith ALF will be randomized to two groups in 1:1 ratio.

Study Design:

A randomized controlled study.

The study will be conducted onpatients admitted to Department of Hepatology from May 2021 to March 2023 atILBS, New Delhi

Study group will comprise ofpatients with acute liver failure (ALF) with documented cerebral edema onCT-scan and arterial ammonia >150 ug/dl Study Period: May 2021 to March 2023Sample Size calculation: Currently there are lack of studies investigating thetiming of CRRT in patients with ALF therefore a minimum of 60 patients 30 ineach group would be included in the current study.

The detailed cytokine profile,endotoxin assay, markers of endothelial dysfunction and bioenergetics would beperformed in a subset of 10 patients in each group.

Intervention: Continuous renalreplacement therapy

Monitoring and Assessment: Hourlytill the patient is in the intensive care unit then every 7 days for 1 month

Statistical analysis

All variables shall be expressedin median (range). Variables will be compared by Mann- Whitney U test. ForCategorical variables we will use Chi-Square or Fisherâ€™s test. Survivalanalysis will be done using cox-proportional regression analysis. Actuarialprobability of survival shall be calculated by Kaplan- Meier graph and comparedby log- rank test.

Standard medical treatment: Allpatients will undergo plain CT-scan of the brain to screen for the presence andseverity of cerebral edema in the emergency before being shifted to the L-ICU.In the L- ICU, patients will be managed by a multidisciplinary team. Intubationand ventilation will be undertaken for standard indications in addition to thedevelopment of grade 3 encephalopathy or evidence of cerebral edema on CT-scan.Ventilation will be managed by fentanyl and propofol along with the use ofatracurium for paralysis wherever required. All patients will be monitoredconstantly for macro-hemodynamics, global tissue perfusion, andmicrocirculation. The macro-hemodynamic parameters included continuousmonitoring of mean arterial pressure (MAP), heart rate and urine output perhour. The real-time monitoring of systemic vascular resistance (SVR), strokevolume variation (SVV), cardiac index (CI) and cardiac output (CO) will be doneby a hemodynamic monitor (FloTracâ„¢ system 4.0, Edwards Lifesciences,California, US) wherever feasible. Global tissue perfusion adequacy andindirect assessment of microcirculation will be done by measurement of arteriallactate. Fluid management will be done with crystalloids, with the use ofcolloids (5% albumin) in patients with severe hypoalbuminemia (serum albuminless than 2.5gm/dl). Norepinephrine will be the primary vasopressor used totarget a mean arterial pressure of 65-70 mm of Hg. with adjunctive use ofintravenous low dose hydrocortisone and vasopressin in patients not responsiveto initial therapy.

Cerebral edema: The monitoring ofcerebral edema will be performed measuring the optic nerve sheath diameter(ONSD) in both the eyes using a 7.5 MHz probe every 6-8 hours. Apart from this,routine monitoring of pupillary size and reactions, extensor posturing andplantar reflexes will be performed every 6-8 hrs. Transcranial doppler would bedone every 6-8 hours. Patients will receive 3% hypertonic saline as acontinuous infusion, initially started at 25ml /hr and titrated 6 hourly tobetween 5 and 20 mL per hour (maximum 100 ml/hour) to achieve serum sodiumlevels between 145-150 mmol/L. Intravenous 20% mannitol (1 g/kg IV bolus) over20 to 30 minutes will be administered to those without renal failure. Allpatients will in addition receive intravenous N-acetylcysteine for 5day.Routine electroencephalogram (EEG) will be done for all patients daily toscreen for non-convulsive seizures which will be managed by intravenouslevetiracetam. Assessment of coagulation will be performed by ROTEM at baselineand subsequently as required.

Protocol for standard-volumeplasma-exchange

Standard-Volume Plasma Exchange:SVPE procedures will be performed using either Spectra Optia (SPO, Terumo BCT,Lakewood, CO, USA) continuous-flow centrifugal apheresis system or HaemoneticsMCS+ (Braintree, MA, USA) intermittent flow centrifugal apheresis system via adouble-lumen central venous dialysis catheter. All patients will receive plasma-exchangewithin first 6 hours of admission to the L-ICU along with a target volume of1.5 to 2.0 plasma volumes per session. The replacement fluid used will be 90%FFP and 10% normal saline.PE will be performed on consecutive days until thedesired response is achieved. [using our previously published protocol].

The number of sessions of SVPE ineach patient will be decided based on the clinical response to SVPE. Dynamicassessment of the clinical parameters (signs of CE as assessed by pupillarysize, reaction, and optic nerve-sheath diameter), INR, lactate and arterialammonia will be performed at after each TPE. In patients with an improvement inINR, and signs of CE along with a reduction in ammonia at 6 hours which wassustained at 12 and 24 hours post-SVPE, subsequent sessions will bediscontinued. PE will also be discontinued in patients who would show worseningin either clinical and/ or biochemical parameters. In patients who will developadverse events, the PE procedure will be resumed or discontinued depending onthe severity of adverse event and its resolution.

Randomization will be done bytaking 1:1 ratio by computer-generated sealed envelopes by the clinical trialco-ordinator Group 1-Preemptive CRRT: In patients randomized to early CRRT,CRRT would be initiated within 12 hours of randomization.

Group 2: SMT - In patientsrandomized to SMT group, CRRT would be initiated as per the existing standardprotocol.

in patients with worseninghyperammonemia despite two sessions of plasma-exchange patients meeting renalindications (hyperkalemia, volume overload, oliguria or metabolic acidosisetc).

The time to initiation of CRRTwould be recorded in both groups after randomization.

Continuous renal replacementtherapy will be administered as continuous venovenous hemodiafiltration(CVVHDF) using Prisma and Prismaflex (Gambro) devices, with blood flows rangingfrom 150-180 mL/hr and target effluent rates of 20 - 25 mL/kg/hr.Anticoagulation was not used during dialysis. CRRT would be continued untilresolution of cerebral edema and in decrease in ammonia levels below 150 ug/dlor in those who develop adverse effects of therapy.

Detailed Description: Not available

Recruitment & Eligibility

Status: Open to Recruitment

Sex: All

Target Recruitment: 60

Inclusion Criteria

Patients with acute liver failure defined patients with jaundice which is complicated by encephalopathy and coagulopathy within 4 weeks of the onset of jaundice and without underlying chronic liver disease with documented cerebral edema on CT-scan and arterial ammonia >150 ug/dL.

Exclusion Criteria

1.Age <18 or > 70 years 2.Hepatocellular Carcinoma 3.Active untreated Sepsis/DIC 4.Hemodynamic instability requiring high dose of vasopressors 5.Post-resection and malignancy related liver failure 6.Coma of non-hepatic origin 7.Patients with post renal obstructive AKI, AKI suspected due to glomerulonephritis, interstitial nephritis or vasculitis based on clinical history and urine analysis 8.Patients already meeting emergency criteria for immediate initiation of dialysis at the time of randomization (serum potassium>6 meq/lt, metabolic acidosis ph<7.12, acute pulmonary edema, severe volume overload with hypoxemia non-responsive to diuretic treatment) 9.Patients transferred from other hospitals who have already been on hemodialysis before their arrival in the intensive care unit 10.Extremely moribund patients with an expected life expectancy of less than 24 hours 11.Pregnancy related liver failure 12.Patients with significant renal dysfunction meeting absolute criteria for initiation of dialysis 13.Comorbidities associated with poor outcome (Extrahepatic neoplasia, severe cardiopulmonary disease defined by a New York Heart Association score >3, or oxygen/steroid-dependent chronic obstructive pulmonary disease) 14.Patients being taken up for liver transplant 15.Refusal to participate in the study.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Transplant free survival	Day 21

Secondary Outcome Measures

Name	Time	Method
Improvement in cerebral edema and hepatic encephalopathy.	Day 5 and day 14
Impact on arterial lactate	6 hours,12 hours, 24 hours,Day 5 and day 14
Improvement in SIRS	Day 5
Effect on systemic hemodynamics and pulmonary function.	24 hours,Day 5 and Day 14
Duration of mechanical ventilation and ICU stay	2 years
Effect on endotoxin, DAMPS, pro-inflammatory cytokines, endothelial functions and coagulation	2 years
To study the safety of therapy (incidence of intradialytic hypotension, impairment of coagulation, hypothermia).	2 years

Trial Locations

Locations (1): Institute of Liver and Biliary Sciences
🇮🇳
South, DELHI, India
Institute of Liver and Biliary Sciences
🇮🇳South, DELHI, India
Dr Rakhi Maiwall
Principal investigator
01146300000
rakhi_2011@yahoo.co.in