Mild Hypothermia and Acute Kidney Injury in Liver Transplantation

Study Overview
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Brief Summary
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Acute kidney injury (AKI), or worsening kidney function, is a common complication after liver transplantation (20-90% in published studies). Patients who experience AKI after liver transplantation have higher mortality, increased graft loss, longer hospital and intensive care unit stays, and more progression to chronic kidney disease compared with those who do not. In this study, half of the participants will have their body temperature cooled to slightly lower than normal (mild hypothermia) for a portion of the liver transplant operation, while the other half will have their body temperature maintained at normal. The study will evaluate if mild hypothermia protects from AKI during liver transplantation.

Detailed Description
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This study is a single-blinded, randomized controlled trial of mild hypothermia during liver transplantation to provide protection from AKI. Participants will be randomized to normothermia (36.5-37.5 °C) versus mild hypothermia (34-35 °C) during a portion of the liver transplant operation. The protocol is based on preliminary data from rodent models showing that hypothermia protects the kidneys from ischemia-reperfusion injury, as well as studies in deceased organ donors showing that cooling improves post-transplant organ function. Temperature will be maintained with standard techniques plus a minimally-invasive esophageal cooling device that is approved by the U.S. Food and Drug Administration. The investigators hypothesize that mild hypothermia will reduce the incidence and severity of AKI after LTx. Standard surrogates (e.g., change in serum creatinine, need for initiation of dialysis) and biomarkers will be used to assess the severity of kidney injury.

Official Title
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Mild Hypothermia and Acute Kidney Injury in Liver Transplantation (MHALT) Trial

Conditions
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Cirrhosis, End Stage Liver Disease, Acute Kidney Injury, Liver Transplant; Complications, Chronic Kidney Diseases, Hepatitis c, Hepatitis B, NASH - Nonalcoholic Steatohepatitis, Alcoholic Cirrhosis, Hepatocellular Carcinoma

Intervention / Treatment
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* Device: Esophageal cooling/warming device
* Other: Mild hypothermia
* Other: Normothermia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Liver transplantation from a donor after neurologic determination of death Exclusion Criteria: Liver transplantation from a donor after cardiac death Acute liver failure Living-donor liver transplantation Simultaneous liver-kidney transplantation Preoperative renal replacement therapy Preoperative intubation Portopulmonary hypertension Machine perfusion of liver graft

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mild hypothermia & Esophageal cooling/warming device<br>The target core temperature is 34-35 °C. | Device: Esophageal cooling/warming device<br>* The EnsoETM (formerly known as Esophageal Cooling Device) is a non-sterile multilumen silicone tube placed in the esophagus for the purpose of cooling or warming a patient while allowing gastric decompression and drainage. It is placed in a manner identical to a standard orogastric tube, which is standard equipment for liver transplant surgery. It is removed at the end of surgery. Control of the patient's temperature is achieved by connecting the EnsoETM to an external heat exchanger (Gaymar Medi-Therm III or similar system). The Medi-Therm III is a standard device used in operating rooms for warming patients with a conductive table warming pad. The Medi-Therm III circulates temperature-controlled water through a closed-loop system via the two outer lumens of the EnsoETM. Water temperature ranges from 4°C - 42°C.<br>* Other names: ECD - Esophageal Cooling Device;Other: Mild hypothermia<br>* Cooling will be initiated after induction of anesthesia and maintained throughout the anhepatic phase of liver transplantation. In all feasible cases the surgeon will cover the peritoneal surface over the right kidney, which is exposed during the operation, with ice-cold sponges to enhance cooling of the renal parenchyma. After blood flow is completely restored to the liver, the esophageal cooling device and other standard measures (forced-air, fluid, and table warmers, plus a heated anesthesia circuit) will be used to actively re-warm the patient (expected warming rate ≥ 1 deg C/hour). The goal is to achieve normothermia by case end.<br>|
| Active Comparator: Normothermia & Esophageal cooling/warming device<br>The target core temperature is 36.5-37.5 °C. | Device: Esophageal cooling/warming device<br>* The EnsoETM (formerly known as Esophageal Cooling Device) is a non-sterile multilumen silicone tube placed in the esophagus for the purpose of cooling or warming a patient while allowing gastric decompression and drainage. It is placed in a manner identical to a standard orogastric tube, which is standard equipment for liver transplant surgery. It is removed at the end of surgery. Control of the patient's temperature is achieved by connecting the EnsoETM to an external heat exchanger (Gaymar Medi-Therm III or similar system). The Medi-Therm III is a standard device used in operating rooms for warming patients with a conductive table warming pad. The Medi-Therm III circulates temperature-controlled water through a closed-loop system via the two outer lumens of the EnsoETM. Water temperature ranges from 4°C - 42°C.<br>* Other names: ECD - Esophageal Cooling Device;Other: Normothermia<br>* After induction of anesthesia, the esophageal cooling/warming device and standard warming measures will be used to maintain normothermia throughout the operation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Acute Kidney Injury (AKI) | The International Club for Ascites (ICA) 2015 criteria, a revision of the Kidney Disease Improving Global Outcome (KDIGO) criteria for patients with cirrhosis, will be used to define AKI. A predefined subgroup analysis of this primary outcome will be performed in patients undergoing liver transplantation for hepatocellular carcinoma (HCC) with Model for End-stage Liver Disease exception points. | 72 hours from the end of surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distribution of the Stages of Acute Kidney Injury (AKI) | The International Club for Ascites (ICA) 2015 criteria, a revision of the Kidney Disease Improving Global Outcome (KDIGO) criteria for patients with cirrhosis, will be used to define the stage of AKI (Stage 1, 2, or 3). A predefined subgroup analysis of this secondary outcome will be performed in patients undergoing liver transplantation for hepatocellular carcinoma (HCC) with Model for End-stage Liver Disease exception points. | 72 hours from the end of surgery | 
| Duration of intensive care unit (ICU) stay | Time after liver transplantation until patient is discharged from the ICU to a regular hospital bed. | up to 1 year | 
| Duration of hospital stay | From the date of liver transplantation until the date patient is discharged from the hospital. | up to 1 year | 
| Patient survival | From the date of liver transplantation until the date of death from any cause. | up to 1 year | 
| Need for renal replacement therapy | Patient is receiving continuous renal replacement therapy or dialysis at the time of follow-up. | 7 days, 30 days, and 1 year | 
| Persistent renal dysfunction | Presence of a reduction in GFR by ≥ 25 mL/min or ≥ 50% from baseline at the time of follow-up. | 90 days and 1 year | 
| Serum neutrophil gelatinase-associated lipocalin (NGAL) | Change in serum NGAL levels from baseline to 2 hours after reperfusion of the portal vein. | Baseline (start of surgery) and 2 hours after reperfusion of the portal vein | 
| Urine neutrophil gelatinase-associated lipocalin (NGAL) | Change in urine NGAL levels from baseline to 2 hours after reperfusion of the portal vein. | Baseline (start of surgery) and 2 hours after reperfusion of the portal vein | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypothermia, NGAL - Neutrophil Gelatinase-associated Lipocalin