Clinical trial NCT01515072: Remote Ischemic Preconditioning in Neurological Death Organ Donors
Official title: Remote Ischemic Preconditioning in Neurological Death Organ Donors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Organ Transplantation
Keywords: Remote Ischemic Preconditioning
Brain death organ donors
Delayed graft function
Donor management
Pulsatile perfusion
Lead sponsor: Rutgers, The State University of New Jersey
Sponsor class: OTHER
Collaborators: name: Health Resources and Services Administration (HRSA)
name: The University of Texas Health Science Center at San Antonio
First posted: 2012-01-23
Enrollment: 321
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether application of lower limb remote ischemic preconditioning (RIPC) after determination of brain death improves donor stability, organ quality, organ yield, and early post transplant clinical outcomes.

Neurological death donors will be stratified into standard and extended criteria donors (SCD/ECD) and randomized in a 1:1 fashion to RIPC or No intervention. The primary outcome is the number of organs recovered per donor. Secondary outcomes include donor hemodynamic state, donor organ-specific function parameters, pulsatile perfusion parameters, number of organs transplanted per donor, recipient hospital free survival and delayed graft function of kidneys. The sample size is powered to detect a difference of 0.44 organs recovered.

Detailed description: Study Design and Participants The RIPNOD trial was conducted from July 2011 to July 2014 as a prospective randomized trial in two OPOs (in New Jersey and in Texas) in the U.S. The funding organization, institutional review boards and the physician committees of the two organ procurement organizations (OPOs) approved the study. Exemptions for consent from potential recipients and for a data and safety monitoring board were granted. Consent for research was obtained from the donor's next of kin by OPO staff unless a 'first-person' consent existed. The study population consisted of neurological death organ donors. Eligible donors were age \> 6 years, in whom death declaration was either imminent or completed, and organ recovery was not expected within 6 hours of enrollment. Donors with severe trauma to lower extremity or on sulfonylurea agents were excluded (Trial Protocol in Supplement).

Procedures Randomization (1:1) to No RIPC or RIPC groups in standard and extended criteria donors (SCD and ECD) strata occurred based on a computer-generated random table of numbers. In Texas, field coordinators performed the randomization through a website and administered the intervention. In New Jersey, research staff performed all trial activities and randomized using opaque, sealed envelopes. Organ recovery teams were informed of the study and sometimes knew of the group assignment. The recipient care teams and recipients were not aware of the group assignment.

The intervention consisted of four cycles of inflation of a tourniquet around mid-thigh to 250 mm Hg for 5 minutes followed by 5 minutes of deflation. The initial intervention occurred in the right thigh as early as possible after declaration of death. The second intervention occurred in the left thigh 24 hours after the initial intervention, or immediately before recovery, if this was earlier. Videoconferences between the two sites helped standardize the intervention before the trial commenced. All decisions regarding donor management, organ recovery, machine perfusion of kidneys, transplantation of organs and care after transplantation were independent of the research teams.

Outcomes and Data Collection The primary outcome was the total number of organs recovered per donor. Secondary outcomes were number of organs transplanted per donor, and changes from baseline to terminal (before aortic cross clamp) in vasopressor support, serum lactate, creatinine clearance, left ventricular ejection fraction, serum troponins, partial pressure of arterial oxygen: fraction inspired oxygen (P:F) ratio, dynamic and static lung compliance, and perfusate flow and resistance in machine perfused kidneys, delayed graft function (DGF) in transplanted kidneys and six-month hospital free survival in all recipients. A score quantified vasopressor support.14 All laboratory tests were performed at donor hospitals. Cockcroft-Gault equation was used to calculate creatinine clearance.15 Donor hospital cardiologists estimated the ventricular ejection fraction in transthoracic echocardiograms. OPO policies dictated machine perfusion of kidneys; perfusion, occurred at a central location in each OPO. Delayed graft function was defined as dialysis in the first week after transplant. Six month hospital-free survival was defined as the number of days recipients survived following the initial discharge after the transplant. All donor data were obtained prospectively from OPO records. Data after transplantation were obtained from the Scientific Registry of Transplant Recipients (SRTR). The SRTR data system includes data on all donors, waitlist candidates, and transplant recipients in the United States, submitted by members of the Organ Procurement and Transplantation Network (OPTN). The Health Resources and Services Administration (HRSA), U.S. Department of Health and Human Services provides oversight to the activities of the OPTN and SRTR contractors.

Sample Size A sample size of 150 donors in each arm was estimated to provide 80% power to detect a difference of 0.44 of an organ recovered and 0.48 of an organ transplanted per donor. The difference criterion was chosen based on published results achieved with hormonal resuscitation in organ donors. 6 Pooled standard deviations (organs recovered: 1.35; organs transplanted: 1.5) from data of two OPOs were used.

Statistical Analyses Intention to treat principle was used in all analyses. Discrete descriptive data are reported as counts and percent and continuous data as means (sd) or medians (interquartile range). Continuous variables were compared using either t, or equivalent non-parametric tests. Categorical variables were compared using chi square tests. Multivariate modeling with backward elimination - linear ones to model RIPC on recovery and transplantation of all (0-8) and abdominal organs (0-5) per donor, and logistic ones to model recovery/transplantation of \> 1 thoracic organ per donor and DGF - was performed. Because only seven fewer thoracic organs were transplanted than recovered the model for organs transplanted was used to analyze both outcomes. Donor characteristics of age, sex, race, cause of death, BMI, comorbidities (hypertension, diabetes, alcohol use, and hepatitis C), treatments (insulin, diuretics and steroids) and laboratory parameters (serum creatinine and P:F ratio) and OPO site were predictor variables in organ yield models. Donor age or stratum, cold ischemia, number of human leukocyte antigen mismatches and recipients' characteristics of age, sex, race, BMI, diabetes, hypertension, etiology of renal failure, panel reactive antibody and OPO site were predictor variables in models of DGF. For linear regression models, adjusted R2 was computed and residuals were assessed for normality; the C statistic was used to assess goodness of the fit for logistic regression. Statistical significance was set at p\<0.05.

Post Hoc Analyses Rates of acute rejection of kidney during the first six months were compared between the two groups using chi square tests. Kaplan-Meier estimates and log rank tests were used to compare unadjusted outcomes of graft and patient survival at 6, 12 and 24 months. In heart, lung and liver recipients, retransplantation or death was defined as graft loss. In all other organs graft loss was death-censored. Cox proportional hazards models were used to estimate the effect of RIPC on the adjusted hazard ratio for six-month graft loss after controlling for OPO site, donor age or stratum and sex, cold ischemia time, number of antigen mismatches, organ transplanted, and recipient age, sex, race, BMI, diabetes and hypertension.

Eligibility criteria: Inclusion Criteria:

1. Neurological death donors in whom brain death determination is imminent
2. First person consent or next of kin consent for research
3. Donors \>=6 years of age
4. Organ recovery not expected within 6 hours of consent.
5. Both sexes and ethnicities.

Exclusion Criteria:

1. Donation after cardiac death donors (DCD)
2. Live organ donors
3. No first person consent and next of kin decline research consent
4. Donor Age \< 6 years
5. Lower extremity trauma or recent amputation
6. Tissue only donors

Primary outcomes:
measure: Number of Organs Recovered Per Donor
timeFrame: At time of organ recovery, up to 1 day
Secondary outcomes:
measure: Number of Organs Transplanted Per Donor
timeFrame: Within 24 hours of organ recovery
measure: Change in Vasopressor Score
timeFrame: Vasopressor score was determined before aortic cross clamp minus the value prior to the first intervention, an average of 19 hours
measure: Change in Serum Lactate
timeFrame: Subjects will be followed from admission to explantation, an average of 4.5 days
measure: Change in Creatinine Clearance
timeFrame: Subjects will be followed from admission to explantation, an average of 4.5 days
measure: Change in P:F Ratio
timeFrame: Subjects will be followed from admission to explantation, an average of 4.5 days
measure: Change in Dynamic Compliance
timeFrame: Subjects will be followed from admission to explantation, an average of 4.5 days
measure: Change in Troponins
timeFrame: Subjects will be followed from admission to explantation, an average of 4.5 days
measure: Pulsatile Perfusion Flow
timeFrame: Up to 24 hours of machine perfusion
measure: Six Month Hospital Free Survival of All Organ Recipients
timeFrame: 6 months post-transplant
measure: Delayed Graft Function (DGF) of Kidney Recipients.
timeFrame: 7 days post-transplant
measure: Pulsatile Perfusion Parameters
timeFrame: Up to 24 hours of machine perfusion
Other outcomes:
Locations:
city: Newark
country: United States
facility: Rutgers, The State University of New Jersey
state: New Jersey
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
Study officials:
affiliation: University of Medicine and Dentistry New Jersey-Newark
name: Baburao Koneru, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas Health Sciences at San Antonio
name: William K Washburn, MD
role: PRINCIPAL_INVESTIGATOR
References: