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

Carcinoma, Hepatocellular Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02635347
• Other study ID #: Pro20150002276
• Status: Completed
• Phase: N/A
• Start date: November 2015
• Est. completion date: December 31, 2017

Study information

• Verified date: July 2019
• Source: Rutgers, The State University of New Jersey
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: December 31, 2017
• Est. primary completion date: October 31, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Brain Death
• Carcinoma, Hepatocellular
• Ischemia
• Liver Failure

Intervention

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.

Locations

Country	Name	City	State
United States	Rutgers University - University Hospital	Newark	New Jersey

Sponsors (1)

Lead Sponsor	Collaborator
Rutgers, The State University of New Jersey

Country where clinical trial is conducted

United States, 

References & Publications (25)

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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. — View Citation

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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. — View Citation

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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. — View Citation

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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. Review. — View Citation

Rehni AK, Shri R, Singh M. Remote ischaemic preconditioning and prevention of cerebral injury. Indian J Exp Biol. 2007 Mar;45(3):247-52. — View Citation

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Zarbock A, Schmidt C, Van Aken H, Wempe C, Martens S, Zahn PK, Wolf B, Goebel U, Schwer CI, Rosenberger P, Haeberle H, Görlich 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. — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Completing Entire Intervention Protocol	Proportion of enrolled liver recipients that complete all 6 remote ischemic conditioning (RIC) interventions.	Pre-op - Post-op day 4
Secondary	Intervention-related Pain Score	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
Secondary	Withdrawal of Consent Due to Pain	- Withdrawal of consent due to discomfort/pain in the lower extremity	Pre-op - Post-op day 7
Secondary	Percentage of Participants Who Developed Early Allograft Dysfunction (EAD)	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.	Post-op days 0-7
Secondary	Percentage of Participants Who Developed Prolonged Respiratory Insufficiency (PRI)	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.	Post-op days 0-7
Secondary	Percentage of Participants Who Developed Acute Kidney Injury (AKI) Stages 2 or 3	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.	Post-op days 0-7
Secondary	Time to Dialysis Discontinuation	In patients who are receiving dialysis pre-op, time to discontinuation of dialysis, if occurring within 90 days of transplantation.	Post-op days 0-90
Secondary	Presence of Clavien-Dindo Grade IIIb or Higher Complications	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
Secondary	Clavien-Dindo Grade IIIb or Higher - Number of Complications	In patients with Clavien-Dindo >/= IIIb complications, number of such complications per patient.	Post-op days 0-30
Secondary	Intensive Care Unit (ICU) Length of Stay (LOS)	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.	Post-op days 0 up to 90 days
Secondary	Hospital LOS	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.	Post-op days 0 up to 90 days
Secondary	Liver Allograft Survival	Percentage of patients with functioning allograft at 90 days post-transplant	Post-op day 90
Secondary	Patient Survival	Percentage of patients alive at 90 days post-transplant	Post-op day 90
Secondary	Number of Subjects Not Completing Intervention Protocol	Number of subjects that received fewer than 6 interventions,.	Pre-op - Post-op day 4