The Age of Red Blood Cells in Premature Infants (ARIPI) Randomized Controlled Trial: Study Design
Section snippets
Methods and Trial Designs
The ARIPI study is a multicenter, double-blind, parallel group, randomized controlled trial evaluating RBCs stored 7 days or less vs the current standard of practice of using dedicated single units of donated RBCs (Fig 1). All blood products are provided for each patient by the hospital blood bank. The donor blood is collected by either Canadian Blood Services or Héma-Québec and is provided as leukoreduced units of blood product. Six Canadian university-affiliated level III (tertiary) neonatal
Study Population
All neonates requiring one or more allogeneic RBC transfusions for the treatment of anemia and meeting the following criteria are eligible: 1250 g or less birth weight, admitted to a participating NICU, and whose parents or guardian have signed (proxy) informed consent. The following exclusion criteria apply to the infants enrolled: have already received an RBC transfusion, are scheduled to undergo an exchange transfusion, will be receiving directed donations, have rare blood types or there is
Interventions
Patients meeting eligibility criteria are randomized to receive 1 of 2 RBC products as follows: (1) RBCs stored for 7 days or less or (2) RBCs based on the current standard of practice in Canada. For neonatal blood transfusion, it is standard blood bank practice in Canada that a standard unit of RBCs (approximately 300 mL) is divided into satellite units of 4 aliquots (quad-packs) or up to 8 aliquots (pedi-packs) to increase use and decrease wastage due to the smaller volume of RBCs required by
Randomization and Treatment Allocation
Once the neonatology team orders an RBC transfusion and the hospital blood bank staff ensures that RBCs stored 7 days or less are available, the patient is randomized to receive either of the 2 treatments. All transfusion decisions will be at the discretion of the neonatology team, and no additional directives are imposed by this trial. Because the administration of the correct intervention is crucial to this trial, compliance protocols have been drafted and implemented based on consultation
Blinding
The study investigators, the NICU teams, and the study subjects are blinded to the treatment allocation. As part of standard blood bank procedures, a label affixed to each RBC unit contains a unique identifier that tracks all RBC units from donor to patient. This label cannot be altered or changed in any manner before and during transfusion, and therefore, allocation concealment is not guaranteed as the label indicates dates of expiry from which the age of the RBC unit can be determined. Once
Primary Outcome
The primary outcome for this study is a composite one composed of mortality and major neonatal morbidities associated with acute organ dysfunction or failure. In addition to death, the 4 major morbidities comprising the composite outcome are necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia, and intraventricular hemorrhage. As mentioned, RBC transfusions have been associated with increased injury to each of the organs comprising our composite outcome.11,45, 46, 47
Secondary Outcomes
Nosocomial infections and the individual morbidities comprising the composite outcome will be identified as secondary outcomes. Length of mechanical ventilation, length of stay in the NICU, and both minor and major interventions received while in the intensive care unit will be recorded as tertiary outcomes. Major interventions will include all major surgical procedures such as laparotomies and thoracotomies. Minor interventions will include cryogenic or laser therapy for the retinopathy of
Sample Size
Sample size for this study was estimated based on the formula for comparison of 2 independent proportions using a 2-tailed α of .05 and a power (1-β) of .80. The baseline rate of any major neonatal morbidity was estimated to be 65%, as indicated by results of our leukoreduction study.11 We hypothesize that “fresh” RBCs would decrease the rate of the composite outcome measure by an absolute risk reduction of 15%. A survey of neonatologists was conducted and supported our hypothesized difference
Patient Consent Issues
Given that this study will involve the enrollment of infants, informed consent will be sought from the legal guardians of each neonate meeting the eligibility criteria of the ARIPI study. When possible, parents shall be informed of the study's protocol before the birth of their premature infant to provide the greatest possible amount of time to contemplate their decision for participation, should their child be eligible. In the remaining cases, a research nurse and/or attending neonatologist,
Statistical Analysis
Baseline characteristics of patients in the 2 treatment groups will be analyzed with frequency distributions and descriptive statistics including measures of central tendency and dispersion. An intent-to-treat approach will be used to analyze all primary and secondary outcomes, and therefore, all analyses will be conducted using the entire cohort of patients. The principal analysis of our composite measure of major neonatal morbidities and mortality will be done using an unadjusted χ2 test
Trial Management
The Coordinating Center is located at the Center for Transfusion Research at the University of Ottawa, Ottawa, Ontario, Canada. Personnel at the Coordinating Center include the study chair, research nurse coordinator, biostatistician, data analysts, and data entry staff. The Coordinating Center is responsible for the day-to-day management of the trial. Each site will have a principal site investigator and at least one research nurse dedicated to this project. The site research nurse has the
Enrollment to Date
To date, 5 enrolling sites have screened 500 and randomized 105 infants. The major reasons for nonrandomization include desire for directed donation (n = 101), declining to participate (n = 86), and is given emergency transfusion before randomization (n = 51). Other potential sites have been approached to increase enrollment.
Summary
Despite concerns regarding transfusion transmitted viruses, RBC transfusions clearly save lives in the neonatal critical care setting.37 Patients in NICU are also among the most frequently transfused patients in tertiary care hospitals and consume a significant amount of health care resources, both in the short-term and long-term. If RBCs stored for 7 days or less decrease harmful sequalae, then this will undoubtedly translate into long-term clinically beneficial consequences. It has also been
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Cited by (0)
This study has been funded by the Canadian Institutes of Health Research, Ottawa, Ontario, Canada.
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Authors DF, BH, DH, MB, PH, LK, SL, KS, SS, AT and RW all provided significant contributions to the development of the study protocol in its development phase, and all are involved in this ongoing study in the role of either site investigator, site coordinator or steering committee member.