Sustained Low Efficiency Dialysis Versus Continuous Renal Replacement Therapy for Acute Kidney Injury in Critically Ill Cirrhotics

Study Overview
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Brief Summary
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The current prospective pliot randomized controlled trial has been designed to demonstrate non-inferiority of sustained low efficiency dialysis (SLED) when compared to continuous renal replacement therapy in managing AKI in context of cirrhotics with septic shock who are hemodynamically unstable. The patients would be randomized 1:1 to either SLED or CRRT after screening for the inclusion and exclusion criteria.

Detailed Description
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Aim & Objectives Primary objective To study the efficacy of sustained low efficiency dialysis versus continuous renal replacement therapy in cirrhotics with septic shock and severe AKI Secondary Objectives Effects on renal recovery rates in the two groups To assess the effects on 7-day and 28-day mortality Efficacy on Lactate Clearance Duration of mechanical ventilation and ICU stay Effect on systemic hemodynamics and reversal of shock Clearance of endotoxin and pro-inflammatory cytokines Effect on coagulation and endothelial function Improvement in SOFA scores at 48 hours and day 5 Methodology All included patients would be randomised to receive either continuous renal replacement therapy or sustained low efficiency dialysis (SLED) Patients with septic shock would be screened. Following this, patients meeting the inclusion and exclusion criteria will be screened and randomized to the two treatment groups. Standard criteria will be considered to define refractoriness to fluids and initiation of dialysis. Fluid management would be performed using the dynamic indices in patients on mechanical ventilation or using IVC diameter and passive-leg rasing in non-intubated patients. In all patients, baseline endotoxin activity assay and blood and urine sample will be stored for looking at the effect of therapy on cytokine profile (TNF alpha, IL-IB, IL6, IFN-gamma, MCP-1, IL-10 and ADAMTS and vWillebrand factor). Septic shock would be defined as a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain MAP>=65 mm of Hg and having a serum lactate >2 mmol/L despite adequate volume resuscitation. The blood flow rate, dialysis flow rate and need of ultrafiltration would be recorded for all enrolled patients. Subsequent sessions of therapy would be done as per requirement and recorded. The dose of vasopressor in norepinephrine equivalent would be recorded for all patients at enrolment as under Study Population: Patients with cirrhosis with septic shock and AKI requiring dialysis Indications for initiation of dialysis Metabolic acidosis with ph<7.2 or serum bicarbonate <15 mEq/lt Hyperkalemia with serum potassium >5.5 Meq/L non-responsive to standard treatment Oliguria with or without fluid overload (non-responsive to diuretics) with urine output of less than 0.5ml/kg/hr despite fluid resuscitation Uremic complications (encephalopathy, pericarditis etc.) Study Design: A randomized controlled study- Non-inferiority trial The study will be conducted on patients admitted to Department of Hepatology from June 2020 to December 2020 at ILBS, New Delhi Study group will comprise critically ill patients with cirrhosis with septic shock and AKI requiring dialysis Study Period: The study will be conducted on patients admitted to Department of Hepatology from May 2020 to December 2020 at ILBS, New Delhi Sample Size Calculation: The study will be designed as a pilot RCT with an aim to enrol 25 patients in each group. At completion a decision for termination versus continuation of the study would be taken. Intervention: CRRT versus SLED until renal recovery Renal recovery would be defined as increase in urine output to more than 400ml/day in patients with anuria, resolution of metabolic complications or spontaneous decline in urea and creatinine necessitating stopping dialytic support Monitoring and Assessment: Hourly till the patient is in the intensive care then every 7 days until day 28 Statistical analysis All variables shall be expressed in mean (sd) or median (range) Variables will be compared by Mann- Whitney U test For Categorical variables we will use Chi-Square or Fisher's test Survival analysis will be done using Cox-proportional regression analysis Actuarial probability of survival shall be calculated by Kaplan- Meier graph and compared by log- rank test. Adverse Effects: Worsening of hypotension, bleeding any cardiac side-effects, worsening lactate, hypothermia, bradycardia Stopping Rule: clinically relevant bleeding (i.e., transfusion requirements of at least 2 units of packed red cells), arrythmias (brady or tachyarryhthmias), poorly tolerated supraventricular arrhythmia related blood stream infections, development of electrolyte abnormalities hypokalemia, hypophosphatemia or hypomagnesemia refractory to medical management, renal recovery

Official Title
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Sustained Low Efficiency Dialysis Versus Continuous Renal Replacement Therapy for Acute Kidney Injury in Critically Ill Cirrhotics-A Pilot Randomized Controlled Trial.

Conditions
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Liver Cirrhosis

Intervention / Treatment
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* Procedure: Sustained Low Efficiency Dialysis (SLED)
* Procedure: Continuous Renal Replacement Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Critically ill cirrhotics with septic shock defined as need of vasopressors to maintain MAP> 65 mm Hg and lacate >2 mmol/L despite adequate fluid resuscitation with severe AKI meeting criteria for dialysis Exclusion Criteria: Patients with age less than 18 years or more than 65 years Severe known cardiopulmonary disease (structural or valvular heart disease, coronary artery disease, COPD, CKD) Patients with ACLF Patients with cerebral edema Patients with refractory shock i.e. requiring norepinephrine or equivalent >0.5ug/kg/min Severe coagulopathy platelets <20,000 and INR >4 Active Bleed (Mucosal or variceal) Pregnancy Patients with moderate-severe ARDS i.e. Pa02/Fio2 ratio <200 Extremely moribund patients with an expected life expectancy of less than 24 hours Failure to give informed consent from family members. Patient enrolled in other clinical trials Patients with Hepatorenal Syndrome, post renal obstructive AKI, AKI suspected due to glomerulonephritis, interstitial nephritis or vasculitis based on clinical history and urine analysis Patients who have already been on hemodialysis before their arrival in the intensive care unit Patients with severe vasodilatation SVR <400 dyn·s/cm5 and/or lactate > 5 mmol/L

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sustained Low Efficiency Dialysis<br>Sustained Low Efficiency Dialysis | Procedure: Sustained Low Efficiency Dialysis (SLED)<br>* sustained low efficiency dialysis (SLED)<br>|
| Active Comparator: Continuous Renal Replacement Therapy<br>continuous renal replacement therapy | Procedure: Continuous Renal Replacement Therapy<br>* Continuous Renal Replacement Therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Development of intradialytic hypotension i.e. decrease in defined as a decrease in systolic blood pressure by ≥20 mm Hg or a decrease in MAP by 10 mm Hg after initiation of dialysis |  | at 6 hours after dialysis initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality in both groups |  | Day 28 | 
| Duration of mechanical ventilation and ICU stay |  | Day 28 | 
| AKI recovery at day 14 |  | Day 14 | 
| Renal failure related death at day 7 |  | Day 7 | 
| Lactate clearance at 12 in both groups |  | 12 hours | 
| Lactate clearance at 24 hours in both groups |  | 24 hours | 
| Reversal of shock at 48 hours |  | 48 hours |