Remote Ischemic Conditioning (RIC) in Recipients of Brain Death Donor Livers – A Feasibility and Safety Study

Overview

This study will assess the feasibility of lower limb-ischemia induced Remote Ischemic Conditioning (RIC) in the perioperative period before, during, and after Orthotopic Liver Transplantation (OLT). Remote ischemic conditioning will consist of 3 cycles of 5 minutes of lower limb ischemia induced via a mid-thigh pneumatic tourniquet, followed by 5 minutes of reperfusion. Interventions will take place after anesthesia induction but before surgery, at the completion of the procedure, and on the mornings of post-operative days 1-4.

Full Title of Study: “Remote Ischemic Conditioning (RIC) in Recipients of Brain Death Donor Livers – A Feasibility and Safety Study”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: October 31, 2017

Detailed Description

Orthotopic liver transplantation (OLT) is associated with a very high risk of complications. In a recent multi-center study of 450 patients, 79% had at least one complication and 63% had severe (Clavien-Dindo grade III or higher) complications. The number and severity of complications are associated with death within 30 days, hospital length of stay, graft and patient survival. Infections are the most common group of complications, followed by pulmonary, renal and liver graft dysfunction. Interventions that decrease these complications after OLT are likely to improve clinical outcomes.

Remote ischemic conditioning is an innate biological phenomenon wherein a brief single or repetitive ischemic stimulus in an organ or tissue such as skeletal muscle induce protection in remote/distant organs against ischemia and other noxious stimuli. This effect can be induced by inflating a pneumatic tourniquet on a leg or arm for a few minutes (usually 5-10) and subsequently deflating to allow reperfusion. This process is usually repeated 3-4 times to ensure an adequate dose of the conditioning stimulus. The conditioning stimulus could be applied before (Preconditioning), concurrent with (Perconditioning), or soon after the index noxious/ischemic insult (Postconditioning).

The goal of this study is to assess the feasibility, patient acceptance, and safety of RIC in liver recipients. In addition, the investigators will obtain data on posttransplant complications. Information obtained from this study will help guide the design of a future randomized, controlled trial to test the benefit of RIC in liver recipients.

Interventions

  • Procedure: Remote Ischemic Conditioning (RIC)
    • Each RIC intervention will comprise three cycles of 5 minutes of inflation followed by 5 minutes of deflation of a pneumatic tourniquet placed in mid-thigh.
  • Device: Pneumatic tourniquet
    • Portable Tourniquet System(PTSii, Delfi Medical Innovations, Inc.) used to perform RIC interventions.

Arms, Groups and Cohorts

  • Experimental: Remote Ischemic Conditioning (RIC) group
    • Participants will receive RIC during transplant and the initial four post-transplant days. During transplant: first intervention after induction of anesthesia but before commencing surgery and the second at the conclusion of the procedure. After transplant: RIC applied daily during the first four consecutive postoperative days. Pneumatic tourniquet will be used to induce RIC

Clinical Trial Outcome Measures

Primary Measures

  • Percentage of Participants Completing Entire Intervention Protocol
    • Time Frame: Pre-op – Post-op day 4
    • Proportion of enrolled liver recipients that complete all 6 remote ischemic conditioning (RIC) interventions.

Secondary Measures

  • Intervention-related Pain Score
    • Time Frame: Post-op days 1-4
    • Median intervention-related pain score during each of the post-operative interventions, in extubated patients who are able to communicate. Using the Numerical Rating Scale (NRS, Ferrieira-Valente MA PAIN Volume 152, 2011), patients were asked to rate their pain following the intervention on a scale of 0-10 with 0 being no pain experienced to 10 as the maximum pain felt.
  • Withdrawal of Consent Due to Pain
    • Time Frame: Pre-op – Post-op day 7
    • - Withdrawal of consent due to discomfort/pain in the lower extremity
  • Percentage of Participants Who Developed Early Allograft Dysfunction (EAD)
    • Time Frame: Post-op days 0-7
    • Percentage of participants who developed Early Allograft Dysfunction (EAD) which is defined as: Aspartate Transaminase (AST) or Alanine Transaminase (ALT)> 2,000 U/L at any point within the first seven post-transplant days, or Total Bilirubin (TB) > 10 mg/dL on postoperative day 7,or International Normalized Ratio (INR)> 1.6 on postoperative day 7.
  • Percentage of Participants Who Developed Prolonged Respiratory Insufficiency (PRI)
    • Time Frame: Post-op days 0-7
    • Percentage of Participants who developed Prolonged Respiratory Insufficiency (PRI) defined as: Ventilator support for >2 postoperative days after transplant, or Reintubation after extubation, within 7 days of transplant. Patients who require brief re-intubation for an endoscopic, radiologic, or surgical procedure would not be considered to have PRI if they are extubated within 2 days of the end of the procedure.
  • Percentage of Participants Who Developed Acute Kidney Injury (AKI) Stages 2 or 3
    • Time Frame: Post-op days 0-7
    • Percentage of participants who developed Acute Kidney Injury (AKI) Based on Kidney Disease – Improving Global Outcomes (KDIGO) criteria, AKI criteria are: Stage 2: - 2.0-2.9 fold rise in serum creatinine from baseline Stage 3: > 3.0 fold rise in serum creatinine from baseline, or Serum creatinine of > 4.0 mg/dL, with an acute (<48 hours) increase of 0.3 mg/dL in serum creatinine or subacute (< 7 days) increase in serum creatinine of 0.5 mg/dL, or Initiation of renal replacement therapy.
  • Time to Dialysis Discontinuation
    • Time Frame: Post-op days 0-90
    • In patients who are receiving dialysis pre-op, time to discontinuation of dialysis, if occurring within 90 days of transplantation.
  • Presence of Clavien-Dindo Grade IIIb or Higher Complications
    • Time Frame: Post-op days 0-30
    • Percentage of patients with Clavien-Dindo >/= grade III b complications (Dindo D, Demartines N, Clavien P, Annals of Surgery 2004). The Clavien-Dindo Complications grade ranges from Grade I (Any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic and radiological interventions Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, analgetics, diuretics and electrolytes and physiotherapy. This grade also includes wound infections opened at the bedside) to Grade V (Death). Grade IIIb would be any intervention requiring general anesthesia.
  • Clavien-Dindo Grade IIIb or Higher – Number of Complications
    • Time Frame: Post-op days 0-30
    • In patients with Clavien-Dindo >/= IIIb complications, number of such complications per patient.
  • Intensive Care Unit (ICU) Length of Stay (LOS)
    • Time Frame: Post-op days 0 up to 90 days
    • Number of days in ICU post-transplant. Starting at post-op day 0 and ending on the calendar date that the patient is transferred out of ICU, dies, or post-op day 90, whichever is soonest.
  • Hospital LOS
    • Time Frame: Post-op days 0 up to 90 days
    • Number of days in hospital post-transplant. Starting at post-op day 0 and ending on the calendar date that the patient is leaves the hospital, dies, or post-op day 90, whichever is soonest.
  • Liver Allograft Survival
    • Time Frame: Post-op day 90
    • Percentage of patients with functioning allograft at 90 days post-transplant
  • Patient Survival
    • Time Frame: Post-op day 90
    • Percentage of patients alive at 90 days post-transplant
  • Number of Subjects Not Completing Intervention Protocol
    • Time Frame: Pre-op – Post-op day 4
    • Number of subjects that received fewer than 6 interventions,.

Participating in This Clinical Trial

Inclusion Criteria

  • Adults (> 18 years of age) with acute and chronic liver failure requiring liver transplants or patients undergoing transplantation for hepatocellular carcinoma.
  • Both sexes
  • Written consent to participate in the study

Exclusion Criteria

  • < 18 years of age
  • Recipients of split livers
  • Retransplantation
  • Recipients of livers combined with other organs
  • Recipients of livers from cardiac death donors
  • Lower extremity amputees
  • History of peripheral vascular disease
  • Patients taking sulfonylurea anti-diabetic agents at the time of transplant
  • Patients taking nitrates at the time of transplant
  • Body mass index > 45
  • Pregnant patients
  • Patients in whom complete lower extremity ischemia is not achieved despite maximum tourniquet inflation to 250 mmHg during the first intervention
  • Patients with lower extremity paralysis

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Rutgers, The State University of New Jersey
  • Provider of Information About this Clinical Study
    • Principal Investigator: Baburao Koneru, MD, MPH, Professor, Department of Surgery – Rutgers, The State University of New Jersey
  • Overall Official(s)
    • Baburao Koneru, MD, MPH, Principal Investigator, Rutgers New Jersey Medical School

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