The Age of Red Blood Cells in Premature Infants (ARIPI) Randomized Controlled Trial: Study Design

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Despite recent trends in decreasing transfusion thresholds and the development of technologies designed to avoid allogeneic exposure, allogeneic red blood cell (RBC) transfusions remain an important supportive and life-saving measure for neonatal intensive care patients experiencing illness and anemia. Reluctantly, a number of laboratory and observational studies have indicated that the amount of time RBCs are stored can affect oxygen delivery to tissues. Consequently, older RBCs may result in higher rates of organ dysfunction, nosocomial infection, and lengths of stay. Because of such harmful effects, an evaluation of the association between age of blood and nosocomial infection and organ dysfunction is warranted. The aim of the study was to determine if RBCs stored for 7 days or less (fresh RBCs) compared to current standard transfusion practice decreases major nosocomial infection and organ dysfunction in neonates admitted to the neonatal intensive care unit and requiring at least one RBC transfusion. This study is a double-blind, multicenter, randomized controlled trial design. The trial will be an effectiveness study evaluating the effectiveness of stored vs fresh RBCs in neonates requiring transfusion. Neonatal patients requiring at least one unit of RBCs will be randomized to receive either (1) RBCs stored no longer than 7 days or (2) standard practice. The study was conducted in Canadian university-affiliated level III (tertiary) neonatal intensive care units. The primary outcome for this study will be a composite measure of major neonatal morbidities (necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia, intraventricular hemorrhage, and mortality). Secondary outcomes include individual items of the composite measure and nosocomial infection (bacteremia, septic shock, and pneumonia). The sample size calculations have been estimated based on the formula for 2 independent proportions using an α of .05, a (1-β) of .80, and a 10% noncompliance factor. The baseline rate for our composite measure is estimated to be 65% as indicated by the literature. Assuming a 15% absolute risk reduction with the use of RBCs stored 7 days or less, our estimated total sample size required will be 450 (225 patients per treatment arm). The Age of Red Blood Cells in Premature Infants (ARIPI) trial is registered at the US National Institutes of Health (ClinicalTrials.gov) no. NCT00326924 and current controlled trials ISRCTN65939658.

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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.

    1

    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.

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