Transfusion Evidence Alert and Round-Up

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The Transfusion Evidence Alert is a monthly overview of the top ten evidence-based publications in the field of transfusion medicine. The articles are selected for quality and relevance by clinical experts, supported by members of the Systematic Review Initiative.

The Transfusion Evidence Round-Up is a quarterly overview of the top 10 high quality studies about an internationally relevant subject in the field of transfusion medicine. The articles are selected by members from the International Society of Blood Transfusion and drawn from the Transfusion Evidence Library and, where relevant, Stem Cell Evidence.

Register here to receive the free monthly Transfusion Evidence Alert and the quarterly Round-Up direct to your email account each month.

June 2024

Transfusion Evidence Round-Up: International Children’s Day - 1 June 2024
Editor's Choice
  • Ree IMC
  • de Haas M
  • van Geloven N
  • Juul SE
  • de Winter D
  • et al.
Lancet Haematol. 2023 Dec;10(12):e976-e984 doi: 10.1016/S2352-3026(23)00285-5.
POPULATION:

Infants with haemolytic disease of the foetus and newborn (n= 44).

INTERVENTION:

Darbepoetin alfa once a week subcutaneously for 8 weeks (n= 20).

COMPARISON:

Standard care (n= 24).

OUTCOME:

Follow-up lasted 3 months and one infant in the darbepoetin alfa group dropped out of the trial before commencement of treatment. The primary outcome was the number of erythrocyte transfusion episodes per infant from birth up to 3 months of life in the modified intention-to-treat population. A significant reduction in erythrocyte transfusion episodes was identified with darbepoetin alfa treatment compared with standard care (median 1.0 [IQR= 1.0, 2.0] transfusion episodes vs. 2.0 [1.3, 3.0] transfusion episodes). No adverse events were reported and no infants died during the study.

BACKGROUND:

Up to 88% of infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions require erythrocyte transfusions after birth. We aimed to investigate the effect of darbepoetin alfa on the prevention of postnatal anaemia in infants with haemolytic disease of the fetus and newborn.

METHODS:

We conducted an open-label, single-centre, phase 2 randomised controlled trial to evaluate the effect of darbepoetin alfa on the number of erythrocyte transfusions in infants with haemolytic disease of the fetus and newborn. All infants who were treated with intrauterine transfusion and born at 35 weeks of gestation or later at the Leiden University Medical Center, Leiden, Netherlands, were eligible for inclusion. Included infants were randomised by computer at birth to treatment with 10 μg/kg darbepoetin alfa subcutaneously once a week for 8 weeks or standard care (1:1 allocation, in varying blocks of four and six, with no stratification). Treating physicians and parents were not masked to treatment allocation, but the research team, data manager, and statistician were masked to treatment allocation during the process of data collection. The primary outcome was the number of erythrocyte transfusion episodes per infant from birth up to 3 months of life in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03104426) and has been completed.

FINDINGS:

Between Oct 31, 2017, and April 31, 2022, we recruited 76 infants, of whom 44 (58%) were randomly assigned to a treatment group (20 [45%] were allocated to receive darbepoetin alfa and 24 [55%] were allocated to receive standard care). Follow-up lasted 3 months and one infant dropped out of the trial before commencement of treatment. A significant reduction in erythrocyte transfusion episodes was identified with darbepoetin alfa treatment compared with standard care (median 1·0 [IQR 1·0-2·0] transfusion episodes vs 2·0 [1·3-3·0] transfusion episodes; p=0·0082). No adverse events were reported and no infants died during the study.

INTERPRETATION:

Darbepoetin alfa reduced the transfusion episodes after intrauterine transfusion treatment for haemolytic disease of the fetus and newborn. Treatment with darbepoetin alfa or other types of erythropoietin should be considered as part of the postnatal treatment of severe haemolytic disease of the fetus and newborn.

FUNDING:

Sanquin Blood Supply.

TRANSLATION:

For the Dutch translation of the abstract see Supplementary Materials section.

Editor's Choice
  • Prescott B
  • Jackson DE
Hematol Transfus Cell Ther. 2023 Oct 14; doi: 10.1016/j.htct.2023.07.013.
POPULATION:

Rh(D) alloimmunised pregnant women (15 studies).

INTERVENTION:

Systematic review and meta-analysis to determine the effectiveness and safety of intrauterine transfusions (IUTs).

COMPARISON:

OUTCOME:

The forest plots all showed statistically significant outcomes with heterogeneity of data. Results indicated a greater foetal survival rate with IUT to treat anaemic foetuses, a low foetal mortality rate, and low risk of procedure-related complications associated with foetal loss but a higher risk of foetal mortality when hydrops is present.

BACKGROUND:

Foetal anaemia is caused by a severe pregnancy complication, haemolytic disease of the foetus and newborn. Intrauterine transfusions (IUTs) are performed to treat foetal anaemia in alloimmunised pregnant women. If left untreated hydrops can develop thereby reducing the chance of survival. Survival rates have improved but the procedure is not without complications. Procedure-related complications can be associated with early gestational age, hence delaying IUT could improve outcomes. This review aims to determine the effectiveness and safety of IUTs by examining survival and mortality rates, procedure-related complications with associated foetal mortality and the influence of hydrops.

STUDY DESIGN AND METHOD:

A systematic review was conducted by searching keywords in four scientific databases from January 2000 to April 2022. A meta-analysis was performed with the OpenMeta-Analyst software using an arcsine transformed proportion with the binary random-effects model and maximum likelihood method.

RESULTS:

Fifteen studies were identified as eligible and used in the meta-analysis. The forest plots all showed statistically significant outcomes with heterogeneity of data. Results indicated a greater foetal survival rate with IUT to treat anaemic foetuses, a low foetal mortality rate, and low risk of procedure-related complications associated with foetal loss but a higher risk of foetal mortality when hydrops is present.

CONCLUSION:

The findings of this systematic review and meta-analysis provide evidence that IUT is a safe and effective treatment for foetal anaemia in the absence of hydrops when experienced personnel perform the procedure to minimise the risk of procedure-related complications.

Editor's Choice
  • Chock VY
  • Kirpalani H
  • Bell EF
  • Tan S
  • Hintz SR
  • et al.
JAMA Netw Open. 2023 Sep 5;6(9):e2334889 doi: 10.1001/jamanetworkopen.2023.34889.
POPULATION:

Preterm infants enrolled in the Transfusion of Prematures (TOP) trial at 16 neonatal intensive care units (n= 101).

INTERVENTION:

Higher haemoglobin threshold for red blood cell (RBC) transfusion (n= 65).

COMPARISON:

Lower haemoglobin threshold for RBC transfusion (n= 36).

OUTCOME:

This was a prospective observational secondary study conducted among a subset of infants enrolled in the TOP trial. Valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean cerebral saturation (Csat) of 4.8%, 95% CI [2.7%, 6.9%] in the lower-haemoglobin threshold group compared to 2.7%, 95% CI [1.2%, 4.2%] in the higher-haemoglobin threshold group, while mean mesenteric saturation (Msat) increased 6.7%, 95% CI [2.4%, 11.0%] vs. 5.6%, 95% CI [2.7%, 8.5%]. Mean cerebral fractional tissue oxygen extraction and mesenteric fractional tissue oxygen extraction decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation in either group (0.2% vs. -0.2%). Neurodevelopmental impairment (NDI) or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio 2.41; 95% CI [1.08, 5.41]).

IMPORTANCE:

Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes.

OBJECTIVE:

To determine whether RBC transfusion in preterm infants is associated with increases in cerebral and mesenteric tissue saturation (Csat and Msat, respectively) or decreases in cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) and whether associations vary based on degree of anemia, and to investigate the association of Csat with death or neurodevelopmental impairment (NDI) at 22 to 26 months corrected age.

DESIGN, SETTING, AND PARTICIPANTS:

This was a prospective observational secondary study conducted among a subset of infants between August 2015 and April 2017 in the Transfusion of Prematures (TOP) multicenter randomized clinical trial at 16 neonatal intensive care units of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Preterm neonates with gestational age 22 to 28 weeks and birth weight 1000 g or less were randomized to higher or lower hemoglobin thresholds for transfusion. Data were analyzed between October 2020 and May 2022.

INTERVENTIONS:

Near-infrared spectroscopy monitoring of Csat and Msat.

MAIN OUTCOMES AND MEASURES:

Primary outcomes were changes in Csat, Msat, cFTOE, and mFTOE after transfusion between hemoglobin threshold groups, adjusting for age at transfusion, gestational age, birth weight stratum, and center. Secondary outcome at 22 to 26 months was death or NDI defined as cognitive delay (Bayley Scales of Infant and Toddler Development-III score <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment.

RESULTS:

A total of 179 infants (45 [44.6%] male) with mean (SD) gestational age 25.9 (1.5) weeks were enrolled, and valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean Csat of 4.8% (95% CI, 2.7%-6.9%) in the lower-hemoglobin threshold group compared to 2.7% (95% CI, 1.2%-4.2%) in the higher-hemoglobin threshold group, while mean Msat increased 6.7% (95% CI, 2.4%-11.0%) vs 5.6% (95% CI, 2.7%-8.5%). Mean cFTOE and mFTOE decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation (SpO2) in either group (0.2% vs -0.2%). NDI or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio, 2.41; 95% CI, 1.08-5.41; P = .03).

CONCLUSIONS AND RELEVANCE:

In this secondary study of the TOP randomized clinical trial, Csat and Msat were increased after transfusion despite no change in SpO2. Lower pretransfusion Csat may be associated with adverse outcomes, supporting further investigation of targeted tissue saturation monitoring in preterm infants with anemia.

TRIAL REGISTRATION:

ClinicalTrials.gov Identifier: NCT01702805.

Editor's Choice
  • Moore CM
  • D'Amore A
  • Fustolo-Gunnink S
  • Hudson C
  • Newton A
  • et al.
Arch Dis Child Fetal Neonatal Ed. 2023 Sep;108(5):452-457 doi: 10.1136/archdischild-2022-324915.
POPULATION:

Preterm infants enrolled in the PlaNeT-2/MATISSE trial, at 43 neonatal intensive care units across UK, Netherlands and Ireland (n= 660).

INTERVENTION:

Higher platelet transfusion threshold (n= 296).

COMPARISON:

Lower platelet transfusion threshold (n= 305).

OUTCOME:

The prespecified long-term follow-up outcome was a composite of death or neurodevelopmental impairment (developmental delay, cerebral palsy, seizure disorder, profound hearing or vision loss) at 2 years of corrected age. Follow-up data were available for 601 of 653 (92%) eligible participants. Of the 296 infants assigned to the higher threshold group, 147 (50%) died or survived with neurodevelopmental impairment, as compared with 120 (39%) of 305 infants assigned to the lower threshold group (OR 1.54; 95% CI [1.09, 2.17]).

OBJECTIVE:

Assess mortality and neurodevelopmental outcomes at 2 years of corrected age in children who participated in the PlaNeT-2/MATISSE (Platelets for Neonatal Transfusion - 2/Management of Thrombocytopenia in Special Subgroup) study, which reported that a higher platelet transfusion threshold was associated with significantly increased mortality or major bleeding compared to a lower one.

DESIGN:

Randomised clinical trial, enrolling from June 2011 to August 2017. Follow-up was complete by January 2020. Caregivers were not blinded; however, outcome assessors were blinded to treatment group.

SETTING:

43 level II/III/IV neonatal intensive care units (NICUs) across UK, Netherlands and Ireland.

PATIENTS:

660 infants born at less than 34 weeks' gestation with platelet counts less than 50×109/L.

INTERVENTIONS:

Infants were randomised to undergo a platelet transfusion at platelet count thresholds of 50×109/L (higher threshold group) or 25×109/L (lower threshold group).

MAIN OUTCOMES MEASURES:

Our prespecified long-term follow-up outcome was a composite of death or neurodevelopmental impairment (developmental delay, cerebral palsy, seizure disorder, profound hearing or vision loss) at 2 years of corrected age.

RESULTS:

Follow-up data were available for 601 of 653 (92%) eligible participants. Of the 296 infants assigned to the higher threshold group, 147 (50%) died or survived with neurodevelopmental impairment, as compared with 120 (39%) of 305 infants assigned to the lower threshold group (OR 1.54, 95% CI 1.09 to 2.17, p=0.017).

CONCLUSIONS:

Infants randomised to a higher platelet transfusion threshold of 50×109/L compared with 25×109/L had a higher rate of death or significant neurodevelopmental impairment at a corrected age of 2 years. This further supports evidence of harm caused by high prophylactic platelet transfusion thresholds in preterm infants.

TRIAL REGISTRATION NUMBER:

ISRCTN87736839.

Editor's Choice
  • Chaudhary P
  • Priyadarshi M
  • Singh P
  • Chaurasia S
  • Chaturvedi J
  • et al.
Eur J Pediatr. 2023 Aug;182(8):3701-3711 doi: 10.1007/s00431-023-05053-6.
POPULATION:

Late preterm and term neonates (n= 204).

INTERVENTION:

Delayed cord clamping (DCC) at 30 seconds (n= 65).

COMPARISON:

DCC at 60 seconds (n= 70); DCC at 120 seconds (n= 69).

OUTCOME:

The primary outcome was venous haematocrit at 24 ± 2 hours of life. DCC at 120 was associated with a significant increase in the mean haematocrit by 2%, incidence of polycythemia, and duration of phototherapy, compared to DCC at 30 and DCC at 60; though the incidence of neonatal hyperbilirubinemia and need for phototherapy was similar. No other serious neonatal or maternal adverse events including postpartum haemorrhage were observed. No significant difference was documented in serum ferritin, incidences of iron deficiency, and growth parameters at 3 months even in the presence of a high exclusive breastfeeding rate.

Delayed cord clamping (DCC) at delivery has well-recognized benefits; however, current scientific guidelines lack uniformity in its definition. This parallel-group, three-arm assessor-blinded randomized controlled trial compared the effects of three different timings of DCC at 30, 60, and 120 s on venous hematocrit and serum ferritin levels in late preterm and term neonates not requiring resuscitation. Eligible newborns (n = 204) were randomized to DCC 30 (n = 65), DCC 60 (n = 70), and DCC 120 (n = 69) groups immediately after delivery. The primary outcome variable was venous hematocrit at 24 ± 2 h. Secondary outcome variables were respiratory support, axillary temperature, vital parameters, incidences of polycythemia, neonatal hyperbilirubinemia (NNH), need and duration of phototherapy, and postpartum hemorrhage (PPH). Additionally, serum ferritin levels, the incidence of iron deficiency, exclusive breastfeeding (EBF) rate, and anthropometric parameters were assessed during post-discharge follow-up at 12 ± 2 weeks. Over one-third of the included mothers were anemic. DCC 120 was associated with a significant increase in the mean hematocrit by 2%, incidence of polycythemia, and duration of phototherapy, compared to DCC30 and DCC60; though the incidence of NNH and need for phototherapy was similar. No other serious neonatal or maternal adverse events including PPH were observed. No significant difference was documented in serum ferritin, incidences of iron deficiency, and growth parameters at 3 months even in the presence of a high EBF rate.   Conclusion: The standard recommendation of DCC at 30-60 s may be considered a safe and effective intervention in the busy settings of low-middle-income countries with a high prevalence of maternal anemia.   Trial registration: Clinical trial registry of India (CTRI/2021/10/037070). What is Known: • The benefits of delayed cord clamping (DCC) makes it an increasingly well-accepted practice in the delivery room. • However, uncertainty continues regarding the optimal timing of clamping; this may be of concern both in the neonate and the mother. What is New: • DCC at 120 s led to higher hematocrit, polycythemia and longer duration of phototherapy, without any difference in serum ferritin, and incidence of iron deficiency. • DCC at 30-60 s may be considered a safe and effective intervention in LMICs.

Editor's Choice
  • Ribeiro HS
  • Assunção A
  • Vieira RJ
  • Soares P
  • Guimarães H
  • et al.
Eur J Pediatr. 2023 Aug;182(8):3433-3443 doi: 10.1007/s00431-023-05031-y.
POPULATION:

Preterm infants with thrombocytopenia (13 studies).

INTERVENTION:

Platelet transfusion (PTx).

COMPARISON:

No platelet transfusion; different transfusion thresholds; multiple PTx.

OUTCOME:

The qualitative analysis of the included studies revealed controversial results as several studies showed an association between PTx in preterm infants and a higher risk of mortality, major bleeding, sepsis, and necrotizing enterocolitis (NEC), while others did not present a significant relationship. The meta-analysis included only studies comparing PTx vs. non-transfusion. The meta-analysis results suggest a significant association between PTx and mortality (RR 2.4; 95% CI [1.8, 3.4]), as well as sepsis (RR 4.5; 95% CI [3.7, 5.6]), after a leave-one-out sensitivity analysis. There was a significant correlation between PTx and NEC (RR 5.2; 95% CI [3.3, 8.3]).

Platelet transfusions (PTx) are the principal approach for treating neonatal thrombocytopenia, a common hematological abnormality affecting neonates, particularly preterm infants. However, evidence about the outcomes associated with PTx and whether they provide clinical benefit or harm is lacking. The aim of this systematic review and meta-analysis is to assess the association between PTx in preterm infants and mortality, major bleeding, sepsis, and necrotizing enterocolitis (NEC) in comparison to not transfusing or using different platelet count thresholds for transfusion. A broad electronic search in three databases was performed in December 2022. We included randomized controlled trials, and cohort and case control studies of preterm infants with thrombocytopenia that (i) compared treatment with platelet transfusion vs. no platelet transfusion, (ii) assessed the platelet count threshold for PTx, or (iii) compared single to multiple PTx. We conducted a meta-analysis to assess the association between PTx and mortality, intraventricular hemorrhage (IVH), sepsis, and NEC and, in the presence of substantial heterogeneity, leave-one-out sensitivity analysis was performed. We screened 625 abstracts and 50 full texts and identified 18 reports of 13 eligible studies. The qualitative analysis of the included studies revealed controversial results as several studies showed an association between PTx in preterm infants and a higher risk of mortality, major bleeding, sepsis, and NEC, while others did not present a significant relationship. The meta-analysis results suggest a significant association between PTx and mortality (RR 2.4, 95% CI 1.8-3.4; p < 0.0001), as well as sepsis (RR 4.5, 95% CI 3.7-5.6; p < 0.0001), after a leave-one-out sensitivity analysis. There was also found a significant correlation between PTx and NEC (RR 5.2, 95% CI 3.3-8.3; p < 0.0001). As we were not able to reduce heterogeneity in the assessment of the relationship between PTx and IVH, no conclusion could be taken.    Conclusion: Platelet transfusions in preterm infants are associated to a higher risk of death, sepsis, and NEC and, possibly, to a higher incidence of IVH. Further studies are needed to confirm these associations, namely between PTx and IVH, and to define the threshold from which PTx should be given with less harm effect. What is Known: • Platelet transfusions are given to preterm infants with thrombocytopenia either to treat bleeding or to prevent hemorrhage. • Lack of consensual criteria for transfusion. What is New: • A significant association between platelet transfusions and mortality, sepsis, and NEC.

Editor's Choice
  • Fu X
  • Zhao X
  • Weng A
  • Zhang Q
Ann Hematol. 2023 Feb;102(2):283-297 doi: 10.1007/s00277-022-05072-7.
POPULATION:

Anaemic preterm infants (12 randomised controlled trials, n= 4,380).

INTERVENTION:

Restrictive transfusion threshold.

COMPARISON:

Liberal transfusion threshold.

OUTCOME:

Liberal transfusion threshold significantly increased the level of haemoglobin after transfusion (mean difference (MD) -10.03; 95% confidence interval (CI) [-15.98, -4.08]; I2= 94%) and haematocrit (MD -3.62; 95% CI [-6.78, -0.46] I2= 80%) compared with restrictive transfusion. Infants' age at first transfusion in restrictive transfusion group was higher than that of infants in liberal transfusion group (MD 5.08; 95% CI [2.27, 7.89] I2= 54%); however, restrictive transfusion was associated with more time on supplemental oxygen (MD 3.56; 95% CI [1.93, 5.18] I2= 62%) and ventilator or continuous positive airway pressure (MD 3.31; 95% CI [1.42, 5.20] I2= 75%).

The comparative efficacy and safety of restrictive with liberal transfusion thresholds remain controversial in anemic preterm infants. This meta-analysis aimed to compare the efficacy and safety of these two transfusion thresholds for anemic preterm infants. We searched PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure (CNKI) for relevant randomized controlled trials (RCTs) comparing restrictive with liberal transfusion thresholds in anemic preterm infants through April 30, 2022. Two independent investigators screened literature, extracted data, and appraised the methodological quality of eligible studies. Meta-analysis was conducted using RevMan version 5.3.5. Twelve RCTs with 4380 preterm infants were included. Liberal transfusion threshold significantly increased the level of hemoglobin after transfusion (mean difference (MD): -10.03; 95% confidence interval (CI): -15.98 to -4.08; p=0.001; I2=94%) and hematocrit (MD: -3.62; 95%CI: -6.78 to -0.46; p=0.02; I2=80%) compared with restrictive transfusion. Infants' age at first transfusion in restrictive transfusion group was higher than that of infants in liberal transfusion group (MD: 5.08; 95%CI: 2.27 to7.89; p=0.004; I2=54%); however, restrictive transfusion was associated with more time on supplemental oxygen (MD: 3.56; 95%CI: 1.93 to 5.18; p<0.001; I2=62%) and ventilator or CPAP (MD: 3.31; 95%CI: 1.42 to 5.20; p=0.006; I2=75%). For the remaining outcomes, two transfusion strategies were comparable. Furthermore, a series of sensitivity analyses confirmed the robustness of the level of hemoglobin after transfusion, age at first transfusion, time on ventilator or CPAP, and safety outcomes. Evidence with substantial heterogeneity indicates that liberal and restrictive transfusion thresholds are effective and safe blood cell transfusion strategies in anemic preterm infants, but the liberal strategy may be more effective in shortening the length of necessary respiratory support.

Editor's Choice
  • Saito-Benz M
  • Bennington K
  • Gray CL
  • Murphy WG
  • Flanagan P
  • et al.
JAMA Pediatr. 2022 May 1;176(5):e220152 doi: 10.1001/jamapediatrics.2022.0152.
POPULATION:

Preterm infants with anaemia (n= 42, 64 transfusion episodes).

INTERVENTION:

Transfusion of red blood cells (RBCs) freshly irradiated on the day of transfusion (n= 31).

COMPARISON:

Transfusion of RBCs irradiated and stored for up to 14 days (n= 33).

OUTCOME:

The prespecified primary outcome was the change in cerebral regional oxygen saturation (crSO2) from baseline (immediately before) to immediately after the transfusion. The prespecified secondary outcomes were the change in cerebral fractional tissue oxygen extraction (cFTOE) at different time points. Compared to infants in the control group, those in the intervention group showed a covariate-adjusted mean increase in crSO2 (2.0 percentage points; 95% CI [1.2, 2.8]) and a mean decrease in cFTOE (0.02; 95% CI [0.01, 0.04]) immediately after transfusion. These differences were sustained up to 120 hours or 5 days after transfusion. There were negligible mean changes in crSO2 or cFTOE in infants in the control group at any of the follow-up time points.

IMPORTANCE:

Gamma irradiation of leukoreduced red blood cells (RBCs) prevents transfusion-associated graft-vs-host disease but also exacerbates storage lesion formation in RBCs. It is unknown whether freshly irradiated RBCs are more efficacious than irradiated and stored RBCs in preterm infants with high transfusion requirements.

OBJECTIVE:

To examine whether transfusion of freshly irradiated vs irradiated and stored RBC components improves cerebral oxygen delivery in preterm infants with anemia.

DESIGN, SETTING, AND PARTICIPANTS:

This single-center, double-blinded, proof-of-concept randomized clinical trial was conducted at the neonatal intensive care unit of Wellington Regional Hospital in Wellington, New Zealand, between December 1, 2017, and November 30, 2018. Participants were preterm infants (<34 weeks' gestation at birth) who were at least 14 days of age and had anemia. Participants underwent nonurgent transfusions, and these episodes were randomized to the intervention group (in which the infants received a transfusion of RBCs that were freshly irradiated on the day of transfusion) or control group (in which the infants received a transfusion of RBCs that were irradiated and stored for up to 14 days). Data were analyzed using the evaluable population approach.

INTERVENTION:

Transfusion of freshly irradiated RBCs.

MAIN OUTCOMES AND MEASURES:

The prespecified primary outcome was the change in cerebral regional oxygen saturation (crSO2) from baseline (immediately before) to immediately after the transfusion. The prespecified secondary outcomes were the change in cerebral fractional tissue oxygen extraction (cFTOE) at different time points (immediately after, 24 hours after, and 120 hours or 5 days after transfusion). Outcomes were measured by blinded clinicians using near-infrared spectroscopy. A covariate-adjusted linear mixed model was used to quantify mean treatment effects and account for multiple transfusions in some infants.

RESULTS:

A total of 42 infants (mean [SD] gestational age, 26 [10] weeks and 3 days; 29 [69%] boys) were enrolled in the trial and underwent 64 transfusion episodes, which were randomized to the intervention (n = 31) or control (n = 33) group. Compared with infants in the control group, those in the intervention group showed a covariate-adjusted mean increase in crSO2 (2.0 percentage points; 95% CI, 1.2-2.8 percentage points) and a mean decrease in cFTOE (0.02; 95% CI, 0.01-0.04) immediately after transfusion. These differences were sustained up to 120 hours or 5 days after transfusion. There were negligible mean changes in crSO2 or cFTOE in infants in the control group at any of the follow-up time points.

CONCLUSIONS AND RELEVANCE:

Results of this trial showed that transfusion of freshly irradiated RBCs conferred a small advantage in cerebral oxygenation for at least 5 days after transfusion compared with transfusion of irradiated and stored RBC components. On-demand irradiation of RBC components may be considered to optimize oxygen delivery in the recipient, but this physiological finding requires further research.

TRIAL REGISTRATION:

ANZCTR Identifier: ACTRN12617001581358.

Editor's Choice
  • George EC
  • Uyoga S
  • M'baya B
  • Kyeyune Byabazair D
  • Kiguli S
  • et al.
Lancet Glob Health. 2022 Mar;10(3):e360-e368 doi: 10.1016/S2214-109X(21)00565-9.
POPULATION:

Children between 2 months and 12 years old admitted to hospital with severe anaemia, enrolled in the TRACT trial in 3 hospitals in Uganda and 1 hospital in Malawi (n= 3,188).

INTERVENTION:

Whole blood (n= 1,404).

COMPARISON:

Red cell concentrates: packed cells (n= 692), settled cells (n= 1,092).

OUTCOME:

This study is a secondary analysis of the TRACT trial data restricted to those who received an immediate transfusion (using whole blood or red cell concentrates). Haemoglobin recovery at 8 hours was significantly lower in those who received packed cells or settled cells than those who received whole blood. Compared to whole blood, children who received blood as packed or settled cells in their first transfusion had higher odds of receiving a second transfusion for packed and settled cells, and longer hospital stays. There was no association between the type of blood supplied for the first transfusion and mortality at 28 days or 180 days, or readmission to hospital for any cause.

BACKGROUND:

The TRACT trial established the timing of transfusion in children with uncomplicated anaemia (haemoglobin 4-6 g/dL) and the optimal volume (20 vs 30 mL/kg whole blood or 10 vs 15 mL/kg red cell concentrates) for transfusion in children admitted to hospital with severe anaemia (haemoglobin <6 g/dL) on day 28 mortality (primary endpoint). Because data on the safety of blood components are scarce, we conducted a secondary analysis to examine the safety and efficacy of different pack types (whole blood vs red cell concentrates) on clinical outcomes.

METHODS:

This study is a secondary analysis of the TRACT trial data restricted to those who received an immediate transfusion (using whole blood or red cell concentrates). TRACT was an open-label, multicentre, factorial, randomised trial conducted in three hospitals in Uganda (Soroti, Mbale, and Mulago) and one hospital in Malawi (Blantyre). The trial enrolled children aged between 2 months and 12 years admitted to hospital with severe anaemia (haemoglobin <6 g/dL). The pack type used (supplied by blood banks) was based only on availability at the time. The outcomes were haemoglobin recovery at 8 h and 180 days, requirement for retransfusion, length of hospital stay, changes in heart and respiratory rates until day 180, and the main clinical endpoints (mortality until day 28 and day 180, and readmission until day 180), measured using multivariate regression models.

FINDINGS:

Between Sept 17, 2014, and May 15, 2017, 3199 children with severe anaemia were enrolled into the TRACT trial. 3188 children were considered in our secondary analysis. The median age was 37 months (IQR 18-64). Whole blood was the first pack provided for 1632 (41%) of 3992 transfusions. Haemoglobin recovery at 8 h was significantly lower in those who received packed cells or settled cells than those who received whole blood, with a mean of 1·4 g/dL (95% CI -1·6 to -1·1) in children who received 30 mL/kg and -1·3 g/dL (-1·5 to -1·0) in those who received 20 mL/kg packed cells versus whole blood, and -1·5 g/dL (-1·7 to -1·3) in those who received 30 mL/kg and -1·0 g/dL (-1·2 to -0·9) in those who received 20 mL/kg settled cells versus whole blood (overall p<0·0001). Compared to whole blood, children who received blood as packed or settled cells in their first transfusion had higher odds of receiving a second transfusion (odds ratio 2·32 [95% CI 1·30 to 4·12] for packed cells and 2·97 [2·18 to 4·05] for settled cells; p<0·001) and longer hospital stays (hazard ratio 0·94 [95% CI 0·81 to 1·10] for packed cells and 0·86 [0·79 to 0·94] for settled cells; p=0·0024). There was no association between the type of blood supplied for the first transfusion and mortality at 28 days or 180 days, or readmission to hospital for any cause. 823 (26%) of 3188 children presented with severe tachycardia and 2077 (65%) with tachypnoea, but these complications resolved over time. No child developed features of confirmed cardiopulmonary overload.

INTERPRETATION:

Our study suggests that the use of packed or settled cells rather than whole blood leads to additional transfusions, increasing the use of a scarce resource in most of sub-Saharan Africa. These findings have substantial cost implications for blood transfusion and health services. Nevertheless, a clinical trial comparing whole blood transfusion with red cell concentrates might be needed to inform policy makers.

FUNDING:

UK Medical Research Council (MRC) and the Department for International Development.

TRANSLATION:

For the French translation of the abstract see Supplementary Materials section.

Editor's Choice
  • Traube C
  • Tucci M
  • Nellis ME
  • Avery KL
  • McQuillen PS
  • et al.
Crit Care Med. 2022 Feb 1;50(2):173-182 doi: 10.1097/CCM.0000000000005393.
POPULATION:

Critically ill children from 20 paediatric intensive care units (n= 146).

INTERVENTION:

Red blood cells (RBCs) stored for up to seven days, (short storage RBCs, n= 69).

COMPARISON:

Standard RBCs (n= 77).

OUTCOME:

This ancillary study for the ABC-PICU trial, Transfusion Associated Delirium (TAD-ABC-PICU) had two stages. In stage I, patients receiving short storage RBCs were compared with those receiving standard RBCs. No significant difference in delirium/coma development was found between the two groups. In stage II, all transfused patients were compared with a single-centre cohort of non-transfused patients matched for confounders of delirium/coma. Adjusted odds for delirium in the transfused cohort was more than eight-fold higher than in the non-transfused matched cohort, even after controlling for haemoglobin.

OBJECTIVES:

Primary objective is to determine if transfusion of short storage RBCs compared with standard issue RBCs reduced risk of delirium/coma in critically ill children. Secondary objective is to assess if RBC transfusion was independently associated with delirium/coma.

DESIGN:

This study was performed in two stages. First, we compared patients receiving either short storage or standard RBCs in a multi-institutional prospective randomized controlled trial. Then, we compared all transfused patients in the randomized controlled trial with a single-center cohort of nontransfused patients matched for confounders of delirium/coma.

SETTING:

Twenty academic PICUs who participated in the Age of Transfused Blood in Critically Ill Children trial.

PATIENTS:

Children 3 days to 16 years old who were transfused RBCs within the first 7 days of admission.

INTERVENTIONS:

Subjects were randomized to either short storage RBC study arm (defined as RBCs stored for up to seven days) or standard issue RBC study arm. In addition, subjects were screened for delirium prior to transfusion and every 12 hours after transfusion for up to 3 days.

MEASUREMENTS AND MAIN RESULTS:

Primary outcome measure was development of delirium/coma within 3 days of initial transfusion. Additional outcome measures were dose-response relationship between volume of RBCs transfused and delirium/coma, and comparison of delirium/coma rates between transfused patients and individually matched nontransfused patients. We included 146 subjects in the stage I analysis; 69 were randomized to short storage RBCs and 77 to standard issue. There was no significant difference in delirium/coma development between study arms (79.5% vs 70.1%; p = 0.184). In the stage II analysis, adjusted odds for delirium in the transfused cohort was more than eight-fold higher than in the nontransfused matched cohort, even after controlling for hemoglobin (adjusted odds ratio, 8.9; CI, 2.8-28.4; p < 0.001).

CONCLUSIONS:

RBC transfusions (and not anemia) are independently associated with increased odds of subsequent delirium/coma. However, storage age of RBCs does not affect delirium risk.