- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02635347
Remote Ischemic Conditioning (RIC) in Recipients of Brain Death Donor Livers - A Feasibility and Safety Study
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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New Jersey
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Newark, New Jersey, United States, 07101-0820
- Rutgers University - University Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
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
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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.
Portable Tourniquet System(PTSii, Delfi Medical Innovations, Inc.) used to perform RIC interventions.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
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Pre-op - Post-op day 4
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
Post-op days 1-4
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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
|
Pre-op - Post-op day 7
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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:
|
Post-op days 0-7
|
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:
|
Post-op days 0-7
|
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:
|
Post-op days 0-7
|
Time to Dialysis Discontinuation
Time Frame: Post-op days 0-90
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In patients who are receiving dialysis pre-op, time to discontinuation of dialysis, if occurring within 90 days of transplantation.
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Post-op days 0-90
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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. |
Post-op days 0-30
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Clavien-Dindo Grade IIIb or Higher - Number of Complications
Time Frame: Post-op days 0-30
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In patients with Clavien-Dindo >/= IIIb complications, number of such complications per patient.
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Post-op days 0-30
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Intensive Care Unit (ICU) Length of Stay (LOS)
Time Frame: Post-op days 0 up to 90 days
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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.
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Post-op days 0 up to 90 days
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Hospital LOS
Time Frame: Post-op days 0 up to 90 days
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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.
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Post-op days 0 up to 90 days
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Liver Allograft Survival
Time Frame: Post-op day 90
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Percentage of patients with functioning allograft at 90 days post-transplant
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Post-op day 90
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Patient Survival
Time Frame: Post-op day 90
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Percentage of patients alive at 90 days post-transplant
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Post-op day 90
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Number of Subjects Not Completing Intervention Protocol
Time Frame: Pre-op - Post-op day 4
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Number of subjects that received fewer than 6 interventions,.
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Pre-op - Post-op day 4
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Collaborators and Investigators
Investigators
- Principal Investigator: Baburao Koneru, MD, MPH, Rutgers University
Publications and helpful links
General Publications
- Olthoff KM, Kulik L, Samstein B, Kaminski M, Abecassis M, Emond J, Shaked A, Christie JD. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl. 2010 Aug;16(8):943-9. doi: 10.1002/lt.22091.
- Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-13. doi: 10.1097/01.sla.0000133083.54934.ae.
- Ali ZA, Callaghan CJ, Lim E, Ali AA, Nouraei SA, Akthar AM, Boyle JR, Varty K, Kharbanda RK, Dutka DP, Gaunt ME. Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial. Circulation. 2007 Sep 11;116(11 Suppl):I98-105. doi: 10.1161/circulationaha.106.679167.
- Section 2: AKI Definition. Kidney Int Suppl (2011). 2012 Mar;2(1):19-36. doi: 10.1038/kisup.2011.32. No abstract available.
- Feng S, Goodrich NP, Bragg-Gresham JL, Dykstra DM, Punch JD, DebRoy MA, Greenstein SM, Merion RM. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant. 2006 Apr;6(4):783-90. doi: 10.1111/j.1600-6143.2006.01242.x. Erratum In: Am J Transplant. 2018 Dec;18(12):3085.
- Hilmi IA, Damian D, Al-Khafaji A, Planinsic R, Boucek C, Sakai T, Chang CC, Kellum JA. Acute kidney injury following orthotopic liver transplantation: incidence, risk factors, and effects on patient and graft outcomes. Br J Anaesth. 2015 Jun;114(6):919-26. doi: 10.1093/bja/aeu556. Epub 2015 Feb 10.
- Zarbock A, Schmidt C, Van Aken H, Wempe C, Martens S, Zahn PK, Wolf B, Goebel U, Schwer CI, Rosenberger P, Haeberle H, Gorlich D, Kellum JA, Meersch M; RenalRIPC Investigators. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA. 2015 Jun 2;313(21):2133-41. doi: 10.1001/jama.2015.4189.
- Tapuria N, Kumar Y, Habib MM, Abu Amara M, Seifalian AM, Davidson BR. Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury--a review. J Surg Res. 2008 Dec;150(2):304-30. doi: 10.1016/j.jss.2007.12.747. Epub 2008 Jan 22.
- Koch S, Katsnelson M, Dong C, Perez-Pinzon M. Remote ischemic limb preconditioning after subarachnoid hemorrhage: a phase Ib study of safety and feasibility. Stroke. 2011 May;42(5):1387-91. doi: 10.1161/STROKEAHA.110.605840. Epub 2011 Mar 17.
- Parikh A, Washburn KW, Matsuoka L, Pandit U, Kim JE, Almeda J, Mora-Esteves C, Halff G, Genyk Y, Holland B, Wilson DJ, Sher L, Koneru B. A multicenter study of 30 days complications after deceased donor liver transplantation in the model for end-stage liver disease score era. Liver Transpl. 2015 Sep;21(9):1160-8. doi: 10.1002/lt.24181.
- Huang CT, Lin HC, Chang SC, Lee WC. Pre-operative risk factors predict post-operative respiratory failure after liver transplantation. PLoS One. 2011;6(8):e22689. doi: 10.1371/journal.pone.0022689. Epub 2011 Aug 1.
- Levesque E, Hoti E, Azoulay D, Honore I, Guignard B, Vibert E, Ichai P, Antoun F, Saliba F, Samuel D. Pulmonary complications after elective liver transplantation-incidence, risk factors, and outcome. Transplantation. 2012 Sep 15;94(5):532-8. doi: 10.1097/TP.0b013e31825c1d41.
- Gracey DR, Divertie MB, Didier EP. Preoperative pulmonary preparation of patients with chronic obstructive pulmonary disease: a prospective study. Chest. 1979 Aug;76(2):123-9. doi: 10.1378/chest.76.2.123.
- Svensson LG, Hess KR, Coselli JS, Safi HJ, Crawford ES. A prospective study of respiratory failure after high-risk surgery on the thoracoabdominal aorta. J Vasc Surg. 1991 Sep;14(3):271-82.
- Arozullah AM, Daley J, Henderson WG, Khuri SF. Multifactorial risk index for predicting postoperative respiratory failure in men after major noncardiac surgery. The National Veterans Administration Surgical Quality Improvement Program. Ann Surg. 2000 Aug;232(2):242-53. doi: 10.1097/00000658-200008000-00015.
- Salvalaggio PR, Felga GE, Afonso RC, Ferraz-Neto BH. Early allograft dysfunction and liver transplant outcomes: a single center retrospective study. Transplant Proc. 2012 Oct;44(8):2449-51. doi: 10.1016/j.transproceed.2012.08.002.
- Przyklenk K, Whittaker P. Genesis of remote conditioning: action at a distance--'hypotheses non fingo'? J Cardiovasc Med (Hagerstown). 2013 Mar;14(3):180-6. doi: 10.2459/JCM.0b013e328358c8eb.
- McCafferty K, Forbes S, Thiemermann C, Yaqoob MM. The challenge of translating ischemic conditioning from animal models to humans: the role of comorbidities. Dis Model Mech. 2014 Dec;7(12):1321-33. doi: 10.1242/dmm.016741.
- Kottenberg E, Thielmann M, Bergmann L, Heine T, Jakob H, Heusch G, Peters J. Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol - a clinical trial. Acta Anaesthesiol Scand. 2012 Jan;56(1):30-8. doi: 10.1111/j.1399-6576.2011.02585.x. Epub 2011 Nov 21.
- MacAllister R, Clayton T, Knight R, Robertson S, Nicholas J, Motwani M, Veighey K. REmote preconditioning for Protection Against Ischaemia-Reperfusion in renal transplantation (REPAIR): a multicentre, multinational, double-blind, factorial designed randomised controlled trial. Southampton (UK): NIHR Journals Library; 2015 May. Available from http://www.ncbi.nlm.nih.gov/books/NBK294375/
- Gonzalez NR, Hamilton R, Bilgin-Freiert A, Dusick J, Vespa P, Hu X, Asgari S. Cerebral hemodynamic and metabolic effects of remote ischemic preconditioning in patients with subarachnoid hemorrhage. Acta Neurochir Suppl. 2013;115:193-8. doi: 10.1007/978-3-7091-1192-5_36.
- Li S, Ma C, Shao G, Esmail F, Hua Y, Jia L, Qin J, Ren C, Luo Y, Ding Y, Borlongan CV, Ji X. Safety and Feasibility of Remote Limb Ischemic Preconditioning in Patients With Unilateral Middle Cerebral Artery Stenosis and Healthy Volunteers. Cell Transplant. 2015;24(9):1901-11. doi: 10.3727/096368914X683520. Epub 2014 Jul 30.
- Rehni AK, Shri R, Singh M. Remote ischaemic preconditioning and prevention of cerebral injury. Indian J Exp Biol. 2007 Mar;45(3):247-52.
- Meng R, Asmaro K, Meng L, Liu Y, Ma C, Xi C, Li G, Ren C, Luo Y, Ling F, Jia J, Hua Y, Wang X, Ding Y, Lo EH, Ji X. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology. 2012 Oct 30;79(18):1853-61. doi: 10.1212/WNL.0b013e318271f76a. Epub 2012 Oct 3.
- Bilgin-Freiert A, Dusick JR, Stein NR, Etchepare M, Vespa P, Gonzalez NR. Muscle microdialysis to confirm sublethal ischemia in the induction of remote ischemic preconditioning. Transl Stroke Res. 2012 Jun;3(2):266-72. doi: 10.1007/s12975-012-0153-1. Epub 2012 Apr 10.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Digestive System Diseases
- Hepatic Insufficiency
- Pathologic Processes
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Adenocarcinoma
- Carcinoma
- Neoplasms, Glandular and Epithelial
- Neurologic Manifestations
- Neurobehavioral Manifestations
- Digestive System Neoplasms
- Liver Diseases
- Liver Neoplasms
- Death
- Unconsciousness
- Consciousness Disorders
- Coma
- Liver Failure
- Carcinoma, Hepatocellular
- Brain Death
Other Study ID Numbers
- Pro20150002276
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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