Immediate Transfusion in African Children with Uncomplicated Severe Anemia

Abstract

Background: The World Health Organization recommends not performing transfusions in African children hospitalized for uncomplicated severe anemia (hemoglobin level of 4 to 6 g per deciliter and no signs of clinical severity). However, high mortality and readmission rates suggest that less restrictive transfusion strategies might improve outcomes.

Methods: In this factorial, open-label, randomized, controlled trial, we assigned Ugandan and Malawian children 2 months to 12 years of age with uncomplicated severe anemia to immediate transfusion with 20 ml or 30 ml of whole-blood equivalent per kilogram of body weight, as determined in a second simultaneous randomization, or no immediate transfusion (control group), in which transfusion with 20 ml of whole-blood equivalent per kilogram was triggered by new signs of clinical severity or a drop in hemoglobin to below 4 g per deciliter. The primary outcome was 28-day mortality. Three other randomizations investigated transfusion volume, postdischarge supplementation with micronutrients, and postdischarge prophylaxis with trimethoprim-sulfamethoxazole.

Results: A total of 1565 children (median age, 26 months) underwent randomization, with 778 assigned to the immediate-transfusion group and 787 to the control group; 984 children (62.9%) had malaria. The children were followed for 180 days, and 71 (4.5%) were lost to follow-up. During the primary hospitalization, transfusion was performed in all the children in the immediate-transfusion group and in 386 (49.0%) in the control group (median time to transfusion, 1.3 hours vs. 24.9 hours after randomization). The mean (±SD) total blood volume transfused per child was 314±228 ml in the immediate-transfusion group and 142±224 ml in the control group. Death had occurred by 28 days in 7 children (0.9%) in the immediate-transfusion group and in 13 (1.7%) in the control group (hazard ratio, 0.54; 95% confidence interval [CI], 0.22 to 1.36; P = 0.19) and by 180 days in 35 (4.5%) and 47 (6.0%), respectively (hazard ratio, 0.75; 95% CI, 0.48 to 1.15), without evidence of interaction with other randomizations (P>0.20) or evidence of between-group differences in readmissions, serious adverse events, or hemoglobin recovery at 180 days. The mean length of hospital stay was 0.9 days longer in the control group.

Conclusions: There was no evidence of differences in clinical outcomes over 6 months between the children who received immediate transfusion and those who did not. The triggered-transfusion strategy in the control group resulted in lower blood use; however, the length of hospital stay was longer, and this strategy required clinical and hemoglobin monitoring. (Funded by the Medical Research Council and Department for International Development; TRACT Current Controlled Trials number, ISRCTN84086586.).

Figure 1. CONSORT diagram

Screening, Randomization, and Follow-up. In the control group (no immediate transfusion), transfusion with 20 ml of whole-blood equivalent per kilogram of body weight was triggered by the development of new signs of clinical severity, which included impaired consciousness (prostration or unconsciousness), increased difficulty in breathing (respiratory distress), hemoglobinuria (grade 6 or higher) in the current illness, or a hemoglobin level of less than 4 g per deciliter. The data regarding the children who were lost to follow-up are presented for days 0 through 28 and days 0 through 180 days (i.e., the data regarding children lost to follow-up by 28 days are a subset of the data of those lost to follow-up by 180 days). Screening did not take place on the days when there was no available blood for transfusion.

Figure 2. Key Outcomes, Admission through 180 Days.

The time window for the 180-day visit was 120 to 240 days after randomization (99.3% of the children were seen after 170 days). The inset in Panel A shows the same data on an enlarged y axis. Panel B shows the mean hemoglobin level during the first 48 hours and through 180 days. Panel C shows distribution of hemoglobin levels of less than 6 g per deciliter, 6 to 9 g per deciliter, and higher than 9 g per deciliter according to the indicated time point. Additional details are provided in Table S4A and S4B in the Supplementary Appendix. Key outcomes (a) Mortality through 180 days (b) Mean hemoglobin over 180 days (c) Proportions with hemoglobin <6g/dl, 6-9g/dl and >9g/dl over 180 days

Figure 3. Proportion transfused in control group by baseline hemoglobin

Transfusion Status among the Children in the Control Group, Stratified According to Baseline Hemoglobin Level. The percentages above the bars represent the percentage of children who received a transfusion among those who had the indicated hemoglobin level at baseline.