Remote Ischemic Preconditioning in Neurological Death Organ Donors

Study Overview
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Brief Summary
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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
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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.

Official Title
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Remote Ischemic Preconditioning in Neurological Death Organ Donors

Conditions
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Organ Transplantation

Intervention / Treatment
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* Other: RIPC (Remote Ischemic Preconditioning)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Neurological death donors in whom brain death determination is imminent First person consent or next of kin consent for research Donors >=6 years of age Organ recovery not expected within 6 hours of consent. Both sexes and ethnicities. Exclusion Criteria: Donation after cardiac death donors (DCD) Live organ donors No first person consent and next of kin decline research consent Donor Age < 6 years Lower extremity trauma or recent amputation Tissue only donors

Ages Eligible for Study
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Minimum Age: 6 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No Remote Ischemic Preconditioning<br>The donors assigned to this group will receive standard of care of management of brain death donors in each organ procurement organization. | |
| Experimental: Remote Ischemic Preconditioning<br>The donors assigned to this group would receive two RIPC interventions. The first one would occur immediately after brain death declaration and consent for organ donation. The second one would occur immediately before commencement of organ recovery. At each occasion RIPC would be induced by 4 cycles of mid-thigh inflation of tourniquet for 5 min followed by deflation for 5 minutes. | Other: RIPC (Remote Ischemic Preconditioning)<br>* Remote Ischemic Preconditioning (RIPC) by Inflation of Pneumatic Tourniquet. The intervention will consist of tourniquet inflation on the mid-thigh for 5 minutes, followed by a deflation period of 5 minutes for a total of 4 cycles. The intervention will take place at two time points: First, after determination of brain death and consent for organ donation and again upon incision for organ recovery. The second intervention will occur in a manner identical to the first intervention but in the opposite limb.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Organs Recovered Per Donor | Number of organs recovered per organ donor | At time of organ recovery, up to 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Organs Transplanted Per Donor | Number of organs transplanted from each organ donor | Within 24 hours of organ recovery | 
| Change in Vasopressor Score | Changes in the following: Vasopressor usage, serum Lactate, Creatinine clearance, arterial oxygen pressure:fraction of inspired oxygen (P:F) ratios, Lung Compliance, Cardiac biomarkers, ejection fraction (EF) from 2-dimensional Echocardiogram. Here we will present data for the change in vasopressor use evaluated using a vasopressor score. A numerical score calculated for number and dose of Vasopressors in use. The score is calculated using the following formula (from Zuppa AF et. al.CRIT CARE MED 2004 Vol. 32 p 2318-2322): Vasopressor Score= (dopamine dose[y=ug/kg/min x 1]) + (dobutamine dose [ug/kg/min] x 1) + (epinephrine dose [ug/kg/min] x100) + (norepinephrine dose [ug/kg/min] x 100) + (phenylephrine dose [ug/kg/min] x 100). The range for our study was 0-4900 with higher doses indicating higher vasopressor use in the donor. | Vasopressor score was determined before aortic cross clamp minus the value prior to the first intervention, an average of 19 hours | 
| Change in Serum Lactate | Change in serum lactate levels (mg/dL) from before intervention to the final value | Subjects will be followed from admission to explantation, an average of 4.5 days | 
| Change in Creatinine Clearance | Change in creatinine clearance (mL/min by Cockcroft-Gault method) from before intervention to terminal value | Subjects will be followed from admission to explantation, an average of 4.5 days | 
| Change in P:F Ratio | Change in ratio of arterial oxygen pressure:fraction inspired oxygen ratio from before intervention to terminal value | Subjects will be followed from admission to explantation, an average of 4.5 days | 
| Change in Dynamic Compliance | Change in dynamic compliance of the lung from before intervention to terminal value Cdyn = Dynamic compliance; Vt = tidal volume; PIP = Peak inspiratory pressure (the maximum pressure during inspiration); PEEP = Positive End Expiratory Pressure: Cdyn= Vt/PIP - PEEP | Subjects will be followed from admission to explantation, an average of 4.5 days | 
| Change in Troponins | Change in serum troponin I (ng/mL) from before intervention to terminal value | Subjects will be followed from admission to explantation, an average of 4.5 days | 
| Pulsatile Perfusion Flow | Perfusate flow (mL/min) in machine perfused kidneys. | Up to 24 hours of machine perfusion | 
| Six Month Hospital Free Survival of All Organ Recipients | Six month hospital-free survival was defined as the number of days recipients survived following the initial discharge after the transplant. | 6 months post-transplant | 
| Delayed Graft Function (DGF) of Kidney Recipients. | DGF is defined as the need for dialysis within the first week post transplantation. | 7 days post-transplant | 
| Pulsatile Perfusion Parameters | Perfusate resistance (mm Hg/mL/min) in machine perfused kidneys. | Up to 24 hours of machine perfusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Remote Ischemic Preconditioning, Brain death organ donors, Delayed graft function, Donor management, Pulsatile perfusion