The effect of fresh red cell transfusions on clinical outcomes in premature infants: the ARIPI randomized trial
Dean Fergusson MHA, PhD 1,2
Paul Hébert MD, FRCPC, MHSc (Epid) 1,2,4
Debora L Hogan B.Sc.N., B.A, M.Sc.N. 1,3
Louise LeBel B.Sc.N.1
Nicole Rouvinez-Bouali MD FRCP(C) 2,3,4
John A Smyth LRCPSI 5,6
Koravangattu Sankaran,MBBS FRCP(C) FCCM 7,8
Alan Tinmouth MD, MSc (Clin Epi), FRCP(C), 1, 2, 4
Morris A Blajchman MD, FRCP(C) 9
Lajos Kovacs MD FRCP(C) 10,11
Christian Lachance MD FRCP(C) 12,13
Shoo Lee MBBS, FRCPC, FAAP, PhD 14, 15,16,17,18,19
C Robin Walker MB, ChB, FRCP(C), FAAP 20,21
Brian Hutton PhD, 1,22
Robin Ducharme H.B.Sc., 1,22
Katelyn Balchin M.Sc.1
Tim Ramsay PhD 1
Jason C Ford MD, FRCP(C) 23,24
Ashok Kakadekar MD, FRCP(C) 7,8
Kuppuchipalayam Ramesh MD, FRCP(C) 5,6
Stan Shapiro PhD 25
1 Ottawa Hospital Research Institute, Clinical Epidemiology Program
2 University of Ottawa, Department of Medicine
3 Children's Hospital of Eastern Ontario
4 The Ottawa Hospital
5 Children's & Women's Health Centre of British Columbia, Pediatrics
6 University of British Columbia, Pediatrics
7 Royal University Hospital, Neonatology
8 University of Saskatchewan
9 McMaster University, Department of Pathology and Medicine
10 Jewish General Hospital, Neonatology
11 McGill University, Department of Medicine
12 CHU Sainte-Justine, Neonatology
13 University of Montreal
14 Mt Sinai Hospital
15 MiCare Research Centre
16 Canadian Institutes of Health Research
17 Institute of Human Development; University of Toronto
18 Samuel Lunenfeld Research Institute
19 Hospital for Sick Children
20 St Joseph's Healthcare and London Health Sciences Center
21 Schulich School of Medicine & Dentistry, University of Western Ontario
22 University of Ottawa, Department of Epidemiology and Community Medicine
23 Children's & Women's Health Centre of British Columbia, Division of Hematopathology;
24 University of British Columbia, Department of Pathology & Laboratory Medicine
25 McGill University, Epidemiology, Biostatistics & Occupational Health
Revision date: August 3rd, 2012
Revised word count: 3119
Corresponding Author: Dean A. Fergusson, MHA, PhD
Senior Scientist & Director, Clinical Epidemiology Program, Ottawa Hospital Research Institute
Associate Professor, Departments of Medicine, Surgery, & of Epidemiology and Community Medicine, University of Ottawa
Centre for Practice-Changing Research,
501 Smyth Road, Box 201
Ottawa, Ontario, Canada K1H 8L6
We would like to thank the following team members for their contributions to the success of this trial.
Participating Centers: The Ottawa Hospital (General Campus)1, Children’s Hospital of Eastern Ontario2, The Jewish General Hospital in Montréal3, Royal University Hospital in Saskatoon4, Children's and Women's Health Centre of British Columbia5 and CHU Sainte-Justine in Montréal6.
Research Coordinators and Research Assistants (2006-2011): Jane Frank R.N.1, Louise LeBel B.Sc.N.2, Debora Hogan B.Sc.N., B.A., M.Sc.N.2, Danielle Cardiff B.SSc., B.A.2, Elizabeth Tse B.Sc.N., Marc Altres B.Sc.3, Chris Cadman R.N.4, Carla Watson B.Sc.N.5, Kristi Finlay R.N.5, Nadine Lusney B.Sc.N.5, Julie Lavoie R.N.6. The Research Coordinators and Research Assistants screened patients, obtained consent, randomized participants and collected data.
Senior Blood Bank Technologists: Shauna Love Charge MLT1, Doris Neurath, BScPharm, ART, MBA1 , Joan Grant MLT, ART2, Gale Stratton RT, MLT 3 , Lorrie Baryluk MLT4, Linda Friesen MLT4, Rose Gillett MLT5 and Anne-Marie Girouard MT6. The blood bank technologists implemented the study interventions.
Medical Directors, Blood Bank: Dr A Giulivi MD1, Dr N Lepage PhD2, Dr D Sheridan MD4, Dr S Caplan MD3 , Dr Jason Ford MD5 and Dr N Robitaille MD6.
Adjudicators: Dr R Sherlock MD, FRCP(C)7, Dr N Rouvinez Bouali MD, FRCP(C)1,2. Primary Outcomes were adjudicated for presence and severity.
DSMB: Dr D Cook M.Sc., MD FRCP(C)8, Dr R Platt, PhD9,10, Dr H Kirpalani B.M., M.Sc.8. The Data and Safety Monitoring Board reviewed two formal interim analyses and regular reports of our primary composite outcome as well as serious adverse events.
OHRI Statisticians: Catherine Bordeleau B.A.11, Steve Doucette M.Sc.11. The statisticians performed quality assurance checks on data and conducted the study analysis.
OHRI Data Entry: Jennie Cote11, Mohammed Kabir B.Sc.11, Sheryl Domingo11 and Lindsay Carson11. Data Entry personnel uploaded Case Report Forms, reconciled data queries and conducted quality assurance checks on the database.
1 The Ottawa Hospital
2 Children's Hospital of Eastern Ontario
3 Jewish General Hospital
4 Royal University Hospital
5 Children's & Women's Health Centre of British Columbia
6 CHU Sainte-Justine
7 Surrey Memorial Hospital, Clinical Assistant Professor at University of British Columbia
8 McMaster University Health Sciences Centre
9 McGill University
10 McGill University Health Centre Research Institute
11 Ottawa Hospital Research Institute
Data Access and Responsibility: The principal investigator, Dean Fergusson, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Potential conflicts of interest: None
Financial support: Funding for ARIPI was provided by Canadian Institutes for Health Research (MCT 75527). The Canadian Institutes for Health Research had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Context: Even though red cells are life saving in neonatal intensive care, transfusing older red cells may result in higher rates of organ dysfunction, nosocomial infection and lengths of hospital stay.
Objective: To determine if red cells stored 7 days or less as compared to usual standards decreased rates of major nosocomial infection and organ dysfunction in patients needing at least one red cell transfusion while admitted to neonatal intensive care units.
Design, Setting, Participants: We conducted a double-blind randomized controlled trial in 377 patients admitted to 6 Canadian tertiary neonatal intensive care units between May 2006 and June 2011.
Interventions: Transfusion of red cells stored 7 days or less versus standard issue red cells in patients requiring at least one red cell transfusion in accordance to standard blood bank practice.
Main Outcome Measure: The primary outcome was a composite measure of major neonatal morbidities including necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia, and intraventricular hemorrhage and death. The primary outcome was measured within the entire period of NICU stay up to 90 days post-randomization.
Results: A total of 1,752 neonates were screened and 377 were randomized. The average age of transfusion was 5 days in the fresh group and two weeks in the standard group. Among neonates in the fresh red cell group, 99 (52.7%) met our primary outcome compared to 100 (52.9%) in the standard red cell group (relative risk: 1.00, 95 % CI 0.82 to 1.20). The rate of clinically suspected infection in the fresh red cell group was 77.7% (n=146) compared to 77.2% (n=146) in the standard red cell group (relative risk: 1.01, 95% CI 0.90 to 1.12) and the rate of positive cultures was 67.5% (n=127) in the fresh red cell group compared to 64.0% (n=121) in the standard red cell group (relative risk: 1.06, 95% CIs 0.91 to 1.22).
Conclusion: The use of fresh red blood cells did not improve outcomes in neonates as compared to standard blood bank practice.
Abstract word count: 326
Trial Registration: The ARIPI trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT00326924 and Current Controlled Trials ISRCTN65939658.
Funding: Funding for ARIPI was provided by Canadian Institutes for Health Research (MCT 75527).
While red cell transfusions are changes such as decreased levels of 2,3 DPG, may be even more important than the generation of cytokines as they impair the ability of red cells to deliver oxygen to meet tissue needs.2-3 In vulnerable patients such as critically ill premature infants, transfusing older red cells may result in higher rates of organ dysfunction and morbidity because of the deleterious oxygen deficits, or the pro-inflammatory effects of bioactive materials which accumulate during red cell storage.
In recent years, several observational studies conducted primarily in adults have demonstrated that prolonged red cell storage is associated with increased rates of infection, organ failure and death, and increased lengths of stay.4-14 Unfortunately, it is extremely difficult to disentangle cause-effect relationships in observational studies when sicker patients often receive more red cell transfusions and frequently a greater number of older units.
Premature infants requiring multiple transfusions are routinely exposed to older red cells because of a ‘dedicated’ donor policy introduced in the 1980s to decrease the risk of viral transmission through transfusions of blood from multiple donors. The dedicated donor policy designates a specific unit of donated red cells for use by one infant exclusively over the course of their transfusion needs up to the expiry date of the unit. Despite the inherent significant decrease in risk of viral transmission with dedicated units, by design this approach increases rates of transfusion of older red cells. The policy remains a standard of practice in most neonatal intensive care units in Canada and the United States.15-16 In a previous study examining RBC characteristics and their impact on outcomes, we documented that transfusion of leukoreduced red cells was associated with a decrease in organ injury in premature infants17, therefore, the type of red cells transfused may in fact matter. It is possible that prolonged cell storage may have exacerbated the observed effect of non-leukoreduction given the possible interaction between length of storage and presence of white cells.18
In neonatal intensive care, the dedicated donor policy provided an ideal setting to evaluate the effects of prolonged red cell storage in vulnerable patients. Therefore, our objective in the Age of Red Blood Cells in Premature Infants (ARIPI) trial was to evaluate whether red cells stored 7 days or less decreased serious neonatal morbidity and mortality as compared to standard blood bank issue.
In 6 tertiary neonatal intensive care units, we randomized infants in a double-blind, randomized controlled trial comparing the clinical consequences of transfusing red blood cells stored 7 days or less versus standard practice between May 2006 and June 2011.19 The study was approved by the Research Ethics Boards both at the central coordinating centre and at each of the participating sites. The ARIPI trial was registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT00326924 and Current Controlled Trials ISRCTN65939658.
We assessed the eligibility of all infants admitted to each of the 6 participating neonatal intensive care units that had a birth weight of <1250 grams and required one or more red cell transfusions for the treatment of anemia. We excluded premature infants who had already received a red cell transfusion, were scheduled to undergo an exchange transfusion or to receive a directed donation, had rare blood types which would lead to difficulty with cross-matching, were moribund upon admission to the neonatal intensive care unit, were not expected to survive because of a severe congenital anomaly, or whose attending clinical team specifically requested fresh red cells. A representative in the infants circle of care approached families to ask if they would be willing to have a research coordinator speak to them about the study. If yes, the coordinator spoke with the family, described the study (risks / benefits, voluntary participation, procedures). Families were given adequate time to reflect on the information, had any questions answered and gave free and voluntary consent. Parents or legal guardians then provided written informed consent. We did not approach parents or guardians of infants when the healthcare team thought it was inappropriate (e.g. extreme family crisis, child protection issues, etc.). Ethnicity of the infants was not ascertained, however, research coordinators ascertained parental ethnicity through direct parent interview or by chart review as ethnicity has been associated with variation in neonatal intensive care outcomes.20
Premature infants were randomly assigned to receive either red cells stored 7 days or less – the fresh red cell group- or current standard issue red cells with storage time ranging from 2 to 42 days depending on site – the standard red cell group. For all neonatal red cell transfusions, standard issue red cell units were divided into aliquots to increase utilization and to decrease waste due to the smaller volume of red cells required for premature infants.
Adherence to the 7 days or less rule was monitored by local blood bank personnel in order to maintain blinding, and blood bank log statistics were collated by the blinded statistician at the coordinating centre and provided to the Data and Safety Monitoring Board. In the standard red cell group, each aliquot was designated for use in a single infant up to its expiry date.21 A summary of the standard blood bank practices is provided in eTable 1.
All blood products used in this trial were collected by Canadian Blood Services or Héma-Québec and prepared by the local hospital blood bank according to local institutional practice. Red cells and other blood products were administered in accordance with the standard clinical practice at each site. Transfusion triggers were not protocolized and there were no other controlled interventions in keeping with the trial’s pragmatic design.
Research coordinators at each centre randomly assigned eligible infants using an Interactive Voice Response (IVR) system. Following eligibility screening by the research coordinator, the system generated a unique number. The research coordinator then telephoned the hospital blood bank staff and reported the number. In turn, blood bank staff referred to a manual of unique numbers generated by an independent statistician prior to study activation to determine the study intervention allocated to the randomized patient. The randomization schedule was stratified by site in variable blocks of 4 and 6. Allocation only occurred once an order to transfuse was received and only if a supply of red cells stored 7 days or less was available at the time of allocation. Randomized patients received all transfusions during the study period according to the intervention they were allocated. Study investigators, research coordinators, attending care teams and the infants’ families were blinded to treatment allocation.
The primary outcome was a composite outcome comprised of mortality and major neonatal morbidities associated with acute organ dysfunction or failure. In addition to death, the four major morbidities comprising the composite outcome were, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and intraventricular hemorrhage. Red cell transfusions have been associated with the morbidities included in our composite outcome.22-24 Bronchopulmonary dysplasia was defined as oxygen dependency for at least 28 days at 36 weeks post-menstrual age.25 The presence of retinopathy of prematurity (presence of extraretinal fibro vascular tissue on ophthalmological examination) of stage 3 or greater was recorded as an outcome. A diagnosis of necrotizing enterocolitis was based upon a grading of stage 2 or greater, using Bell’s criteria26, and a diagnosis of intraventricular hemorrhage was based on grade III or greater (blood in ventricles with evidence of ventricular enlargement) using Papile’s criteria.27
All relevant major morbidities comprising the primary outcomes that were present on the day of randomization were recorded. We followed infants for up to 90 days of their stay in the neonatal intensive care unit to ascertain whether they met the threshold and definition for one of the complications included in the composite outcome. Individual complications had to occur after the point of randomization (the receipt of the initial transfusion) in order to be included as part of the primary outcome. We also assessed worsening of outcomes over the study duration. Individual elements of the composite outcome were adjudicated independently by two neonatologists blinded to the study group allocation.
As secondary outcomes, we recorded rates of individual complications comprising the composite outcome and rates of nosocomial infections. Nosocomial infections were categorized as clinically suspected and positive cultures. Clinically suspected infections implied that attending teams observed signs suggestive of infection. This information was derived from medical progress notes and included administration of antibiotics. We also recorded information on the site of infection and the organism identified by culture.
As tertiary outcomes, we examined length of mechanical ventilation and supplemental oxygen use, need for vasopressors, other blood products, and invasive vascular access as well as length of stay in the neonatal intensive care unit. Rates of minor and major interventions were also examined. Major interventions included all major surgical procedures such as laparatomies and thoracotomies. Minor interventions included laser therapy for the retinopathy of prematurity, tracheostomy, endoscopic procedures such as bronchoscopy, and all transcutaneous procedures such as nephrostomy and cardiac catheterizations.
Sample Size and Statistical Analysis
We estimated that a total of 450 infants would be needed to detect a difference between groups, with a two-tailed α of 0.05 and a (1-β) of 0.80, for a comparison of 2 independent proportions if there was an absolute decrease of 15 percent in the composite outcome measure. Our initial estimate of sample size included an assumption of blood bank non-compliance of 10 percent. The Data and Safety Monitoring Board, blinded to treatment group, reviewed two formal interim analyses and regular reports of our primary composite outcome as well as serious adverse events. With Data and Safety Monitoring Board approval, we re-adjusted our sample size calculation to 372 infants after the first interim analysis demonstrated an actual non-compliance rate of less than 4 percent.
Our primary analysis was conducted using an intent-to-treat approach, and therefore included all randomized infants. Baseline characteristics of patients in the two treatment groups were reported using frequency distributions and descriptive statistics including measures of central tendency and dispersion. The principal analysis of our composite measure of major neonatal morbidities and mortality was an unadjusted Chi-Square test comparing the proportion of events in each treatment group. Further logistic regression analyses examined the effect of adjustment for clinically relevant covariates which were known strong predictors of the outcome (gender, birth weight, gestational age) or that reflected imbalances at baseline. We measured the average storage using the age of each individual transfusion episode as well as weighting the average age by the volume of each transfusion episode. We conducted pre-specified subgroup analyses by birth weight, gestational age, and neonatal acuity. An “as per protocol” analysis of infants compliant with their allocated treatment was also conducted to examine the robustness of our primary estimates. All analyses were conducted using SAS (version 9.2).
A total of 1,752 neonates were screened for eligibility and 377 met eligibility criteria and were randomized between May 2006 and June 2011 (Figure 1). All randomized infants completed the trial. Fourteen patients randomized to the fresh red cell group (n=188) received at least one transfusion of RBCs stored for greater than 7 days. Specifically, 23 of the 151 red cell transfusions administered to the 14 infants were of red cells stored greater than 7 days (Figure 1). Baseline demographic and clinical characteristics were similar in both groups with the exception of more male infants allocated to the fresh red cell group (Table 1). The mean age of blood in the fresh red cell group was 5.1 days (median = 5 days) compared to 14.6 days (median= 13) in the standard red cell group (Figure 2). The mean and median volumes transfused were similar in both groups as were pre-transfusion hemoglobin values (Table 2). The mean number of donor exposures in the fresh red cell group was 3.7 compared to 2.1 in the standard red cell group (Table 2). Post-randomization co-interventions including modes of ventilation, insertion of lines and catheters, other blood products, and major surgical and diagnostic procedures, did not differ between the two groups. (Table 3)
Major complications and death
A total of 199 (53.0%) infants met our composite primary outcome of major complications or death. Among infants in the fresh red cell group, 99 (52.7%) met our primary outcome compared to 100 (52.9%) in the standard red cell group (relative risk: 1.00, 95 % CI 0.82 to 1.20) (Table 4). Ninety-seven infants representing 107 events of intraventricular hemorrhage (n=35 events), necrotizing enterocolitis (n=37 events) or retinopathy of prematurity (n=35) were adjudicated for presence and severity. Analysis of the individual components of our composite outcome did not identify any clinically significant difference between groups except for a statistically non-significant increase in rates of grade III-IV intraventricular hemorrhage in the fresh group (relative risk: 1.65, 95% CI 0.80 to 3.39). Analysis of a composite measure of patients experiencing any progression of intraventricular hemhorrage, necrotizing enterocolitis or retinopathy of prematurity yielded a relative risk of 1.04 (95% CI 0.89 to 1.22) and a relative risk of 1.01 (95% CI 0.90 to 1.13) with the addition of bronchopulmonary dysplasia or death.
Infection and Length of Stay
A total of 292 (77.4%) infants had at least one clinically suspected infection, while 248 infants had at least one confirmed infection. The rate of clinically suspected infection in the fresh red cell group was 77.7% (n=146) compared to 77.2% (n=146) in the standard red cell group (relative risk: 1.01, 95% CI 0.90 to 1.12). Rates of confirmed infections were 67.5% (n=127) in the fresh group compared to 64.0% (n= 121) in the standard red cell group (relative risk: 1.06, 95% CIs 0.91 to 1.22) (Table 5). Among confirmed cases, rates of bacterial, fungal, and viral infections were similar between the two groups. Major sequellae of infections including rates of pneumonia, meningitis, and osteomyelitis were also similar (Table 5). The median length of NICU stay was 77 years (IQR: 50 to 104) in the standard red cell group and 84 days (IQR: 50 to 104) in the fresh red cell group (Wilcoxon p-value: 0.55).
Subgroup and Sensitivity Analyses
Pre-specified subgroup analyses by birth weight, gestational age, and acuity (SNAP-II scores and CRIB scores) did not document any appreciable differences between fresh and standard red cell groups. A per protocol analysis did not alter the observed effect on our primary outcome (RR: 0.92, 95% CI 0.61 to 1.40).
Transfusion-Associated Adverse events
There were no transfusion reactions observed in either group. One serious adverse event potentially related to transfusion was a diagnosis of cytomegalovirus infection in an infant randomized to the standard red cell group.
Among critically ill premature infants, fresh red cell transfusions compared to standard red cell transfusion practice did not decrease or increase rates of complications or death in our composite measure. We did not find any clinically meaningful or statistically significant differences in individual complications, in secondary or tertiary outcomes, or in the pre-specified subgroup analyses.
Premature infants of birth weight less than 1250 grams enrolled in our study represent a population frequently exposed to transfusions and extremely susceptible to high complication and mortality rates. We considered these infants to be at high risk of complications from the adverse effects of older red cells. With an immature circulation, limited physiologic reserve, immature immune responses and enhanced susceptibility to oxygen damage, we would have expected to be able to find evidence of benefit if fresh red cells had favorable biological properties.
Infants who participated in the ARIPI trial were exposed to a significant volume and frequency of red cell transfusions. On average, infants were given 5 transfusions (median = 4.0), each of 14 mL. Given an estimated total blood volume of 100mL/kg28, this represents a significant transfusion exposure.
Only a few small studies have compared the consequences of red cell storage times29-31. None of these studies evaluate clinically important consequences and none were conducted in vulnerable premature infants. In an unblinded randomized trial, Gruenwald and colleagues compared the use of fresh reconstituted whole blood to standard blood products in 64 newborns undergoing cardiac surgery. They documented that transfusion of fresh reconstituted whole blood decreased chest tube blood loss, improved bleeding scores, and shortened periods of ventilation and hospital lengths of stay.32 However, the role of fresh red cells in this population remains unanswered.
We did not find any clinically meaningful or statistically significant differences and therefore the many laboratory changes that occur with prolonged red cell storage may not be as important as once thought. Alternatively, an average red cell storage time of 2 weeks in the standard red cell group may not have been sufficient to detect biological effects attributed to storage or clinically significant storage lesions occurring toward the end of the accepted red cell shelf-life. Our choice of a 7-day threshold for fresh red cells was based primarily on feasibility, as well as on limited laboratory evidence and precedence in other clinical studies rather than on a strong biological rationale. Similarly, our choice of standard issue red cells as a comparator was primarily based upon ethical considerations. Choosing a specific range with much older red cells would have more deliberately evaluated the clinical consequences of more extreme storage lesions but would have constituted a deviation from standard of practice and raise recruitment concerns given the lack of clinical benefit anticipated from transfusion of exclusively older red cells.
We tried to ensure that our choice of complications included in the composite primary outcome had a plausible biological relationship to outcomes. Three suggested mechanisms have been postulated to cause deleterious effects attributed to stored red cells. First, several alterations in cell membranes and in depletion of 2,3 DPG adversely affect oxygen transport, thereby impairing oxygen delivery to target organs.33-36 Second, older red cells may induce a greater inflammatory response than fresh cells because of the buildup of RBC supernatant volume.28,37,38 Finally, red cells elicit an immunosuppressive effect in transfusion recipients. This immunomodulatory effect in critically ill or compromised infants may result in increased rates of nosocomial infections, in turn leading to organ dysfunction and death. Previous studies have focused on physiological and laboratory effects of the dedicated donor policy rather than clinically important outcomes.39-42
In conclusion, the transfusion of fresh red blood cells did not improve clinical outcomes in very low birth weight infants. We thus do not recommend any changes to storage time practices for the provision of red cells for infants admitted to neonatal intensive care.
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Table 1: Baseline Characteristics
Number of Subjects (n)
Race or ethnic group
Other or unknown
Vaginal breech delivery
Born at study hospital
Gestational age (weeks)
Birth weight (grams)
5 minute APGAR
SNAP II (day1) Score**
SNAP II (day3) Score
Hemoglobin level at NICU admission (g/L)
* The CRIB score is a score that assesses the initial (first 12 hours of life) clinical severity in preterm infants based on birth weight, gestational age, congenital malformation, base excess and fraction of inspired oxygen. The higher the score, the higher the risk of mortality.
** The Score for Neonatal Acute Physiology, Version II (SNAP-II) is a neonatal illness severity score that evaluates six empirically weighted, physiology-based items during a 12-hour time frame, including lowest blood pressure, lowest temperature, PO2/FiO2 ratio, lowest serum pH, seizures, and urine output. SNAP-II has a score range of 0 (low severity) to 115 (high severity)
Table 2: Transfusion Data
Wilcoxon p-values for comparison of medians
Mean donor exposures (SD)
1.61 (1.16, 2.07)
Mean age of red cells (SD)
-9.48 (-10.02, -8.93)
Median age or red cells (IQR)
13.00 (8.00 to 19.00)
5.00 (4.00 to 6.00
Weighted average age of red cells (SD)*
-8.83 (-9.61, -8.05)
Weighted median age of red cells (IQR)
14.00 (10.50 to 17.04)
5.00 (4.42 to 5.53)
Mean pre-transfusion hemoglobin (g/L)
0.70 (-1.61, 3.01)
Mean volume per transfusion episode (mL)
-0.14 (-0.81, 0.53)
Mean total volume of transfusion episodes (SD)
0.56 (-7.86, 8.98)
Median total volume of transfusion episodes (IQR)
Mean number of transfusion episodes (SD)
0.06 (-0.73, 0.86)
Median number of transfusion episodes (IQR)
Number of transfusion episodes
Chi square p-value=0.53
* weighted by volume of transfusion received
Table 3: Post Randomization Co-interventions
1.02 (0.98, 1.07)
0.99 (0.89, 1.09)
0.99 (0.90, 1.10)
High Frequency ventilation
1.02 (0.79, 1.31)
0.95 (0.62, 1.46)
1.11 (0.85, 1.46)
1.01 (0.95, 1.08)
1.06 (0.82, 1.36)
1.01 (0.92, 1.10)
Peripheral arterial line
0.86 (0.60, 1.23)
Central venous line
0.92 (0.41, 2.03)
Peripherally inserted central catheter (PICC)
0.95 (0.83, 1.09)
Umbilical vein catheter
1.07 (0.84, 1.36)
Umbilical artery catheter
1.03 (0.81, 1.29)
1.19 (0.74, 1.93)
0.95 (0.53, 1.70)
1.05 (0.58, 1.91)
1.05 (0.71, 1.55)
1.12 (0.46, 2.69)
1.27 (0.87, 1.85)
0.95 (0.51, 1.79)
Laser eye surgery
1.36 (0.75, 2.46)
1.01 (0.06, 15.95)
Inguinal hernia repair
0.82 (0.30, 2.52)
Central line insertion
1.01 (0.14, 7.06)
Table 4: Primary Outcome
Necrotizing enterocolitis (≥ Stage 2 Bell’s)
1.00 (0.48 to 2.12)
Intraventricular hemorrhage (≥ Grade 3 Papile)
1.65 (0.80 to 3.39)
Retinopathy of prematurity (≥ Stage 3)
0.89 (0.53 to 1.50)
0.96 (0.72 to 1.28)
0.97 (0.61 to 1.54)
Composite Primary (any of above)
1.00 (0.82 to 1.21)
Table 5: Infection Outcomes
Risk Ratio (RR) or
Mean Difference (MD)
Clinically Suspected Infections
At least one infection (%)
RR: 1.01 (0.90, 1.12)
Mean number of infections (SD)
MD: 0.23 (-0.62, 1.08)
Median number of infections (IQR)
Wilcoxon p-value: 0.65
Culturally Confirmed Infections
At least one infection (%)
RR: 1.06 (0.91, 1.22)
# patients with at least one infection confirmed in:
RR: 1.05 (0.86, 1.29)
RR: 0.92 (0.42, 2.04)
RR: 1.24 (0.93, 1.65)
Mean number of infections (SD)
MD: 0.1 (-0.50, 0.70)
Median number of infections (IQR)
Wilcoxon p-value: 0.75
Any bacterial (%)
RR: 1.02 (0.88, 1.19)
# patients with at least one infection confirmed in:
RR: 1.03 (0.84, 1.26)
RR: 0.92 (0.42, 2.04)
RR: 1.22 (0.91, 1.63)
Mean number of bacterial (SD)
MD: 0.0 (-0.55, 0.55)
Median number of infections (IQR)
Wilcoxon p-value: 0.98
Any viral (%)
RR: 1.26 (0.34, 4.61)
Mean number of viral (SD)
MD: 0.01 (-0.03, 0.05)
Median number of infections (IQR)
Wilcoxon p-value: 0.73
Any fungal (%)
RR: 1.23 (0.68, 2.22)
Mean number of fungal (SD)
MD: 0.0 (-0.12, 0.12)
Median number of infections (IQR)
Wilcoxon p-value: 0.48
Pneumonia (n, %)
RR: 0.91 (0.51, 1.64)
Meningitis (n, %)
RR: 4.02 (0.45, 35.65)
Osteomyelitis (n, %)
RR: Not estimable