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The Impact of Restrictive Transfusion Practices on Hemodynamically Stable Critically Ill Children Without Heart Disease: A Secondary Analysis of the Age of Blood in Children in the PICU Trial
Steffen KM, Tucci M, Doctor A, Reeder R, Caro JJ, Muszynski JA, Spinella PC
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2023;24(2):84-92
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Editor's Choice
Abstract
OBJECTIVES Guidelines recommend against RBC transfusion in hemodynamically stable (HDS) children without cardiac disease, if hemoglobin is greater than or equal to 7 g/dL. We sought to assess the clinical and economic impact of compliance with RBC transfusion guidelines. DESIGN A nonprespecified secondary analysis of noncardiac, HDS patients in the randomized trial Age of Blood in Children (NCT01977547) in PICUs. Costs analyzed included ICU stay and physician fees. Stabilized inverse propensity for treatment weighting was used to create a cohort balanced with respect to potential confounding variables. Weighted regression models were fit to evaluate outcomes based on guideline compliance. SETTING Fifty international tertiary care centers. PATIENTS Critically ill children 3 days to 16 years old transfused RBCs at less than or equal to 7 days of ICU admission. Six-hundred eighty-seven subjects who met eligibility criteria were included in the analysis. INTERVENTIONS Initial RBC transfusions administered when hemoglobin was less than 7 g/dL were considered "compliant" or "non-compliant" if hemoglobin was greater than or equal to 7 g/dL. MEASUREMENTS AND MAIN RESULTS Frequency of new or progressive multiple organ system dysfunction (NPMODS), ICU survival, and associated costs. The hypothesis was formulated after data collection but exposure groups were masked until completion of planned analyses. Forty-nine percent of patients (338/687) received a noncompliant initial transfusion. Weighted cohorts were balanced with respect to confounding variables (absolute standardized differences < 0.1). No differences were noted in NPMODS frequency (relative risk, 0.86; 95% CI, 0.61-1.22; p = 0.4). Patients receiving compliant transfusions had more ICU-free days (mean difference, 1.73; 95% CI, 0.57-2.88; p = 0.003). Compliance reduced mean costs in ICU by $38,845 U.S. dollars per patient (95% CI, $65,048-$12,641). CONCLUSIONS Deferring transfusion until hemoglobin is less than 7 g/dL is not associated with increased organ dysfunction in this population but is independently associated with increased likelihood of live ICU discharge and lower ICU costs.
PICO Summary
Population
A subgroup of haemodynamically stable critically ill children without heart disease, enrolled in the Age of Blood in Children (ABC-PICU trial) at 50 international tertiary care centers (n= 687).
Intervention
Initial red blood cells (RBCs) transfusion when haemoglobin was less than 7 g/dL (Compliant, n= 349).
Comparison
Initial RBCs transfusion when haemoglobin was greater than or equal to 7 g/dL (Non-compliant, n= 338).
Outcome
This secondary analysis of the ABC-PICU trial assessed the clinical and economic impact of compliance with RBCs transfusion guidelines. 49% of patients (338/687) received a non-compliant initial transfusion, and 51% (349/687) received a compliant initial transfusion. Weighted cohorts were balanced with respect to confounding variables. No differences were noted in new or progressive multiple organ system dysfunction frequency (relative risk, 0.86, 95% CI: 0.61-1.22). Patients receiving compliant transfusions had more ICU-free days (mean difference, 1.73, 95% CI: 0.57-2.88). Compliance reduced mean costs in ICU by $38,845 U.S. dollars per patient (95% CI: $65,048-$12,641).
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Transfusion-Associated Delirium in Children: No Difference Between Short Storage Versus Standard Issue RBCs
Traube C, Tucci M, Nellis ME, Avery KL, McQuillen PS, Fitzgerald JC, Muszynski JA, Cholette JM, Schwarz AJ, Stalets EL, et al
Critical care medicine. 2022;50(2):173-182
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Editor's Choice
Abstract
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.
PICO Summary
Population
Critically ill children from 20 paediatric intensive care units enrolled in the (TAD-ABC-PICU) trial (n= 146).
Intervention
Red blood cells (RBCs) stored for up to seven days, (short storage RBCs, n= 69).
Comparison
Standard RBCs (n= 77).
Outcome
The study 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.
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The Immunologic Effect of Early Intravenous Two and Four Gram Bolus Dosing of Tranexamic Acid Compared to Placebo in Patients With Severe Traumatic Bleeding (TAMPITI): A Randomized, Double-Blind, Placebo-Controlled, Single-Center Trial
Spinella PC, Thomas KA, Turnbull IR, Fuchs A, Bochicchio K, Schuerer D, Reese S, Coleoglou Centeno AA, Horn CB, Baty J, et al
Frontiers in immunology. 2020;11:2085
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Editor's Choice
Abstract
BACKGROUND The hemostatic properties of tranexamic acid (TXA) are well described, but the immunological effects of TXA administration after traumatic injury have not been thoroughly examined. We hypothesized TXA would reduce monocyte activation in bleeding trauma patients with severe injury. METHODS This was a single center, double-blinded, randomized controlled trial (RCT) comparing placebo to a 2 g or 4 g intravenous TXA bolus dose in trauma patients with severe injury. Fifty patients were randomized into each study group. The primary outcome was a reduction in monocyte activation as measured by human leukocyte antigen-DR isotype (HLA-DR) expression on monocytes 72 h after TXA administration. Secondary outcomes included kinetic assessment of immune and hemostatic phenotypes within the 72 h window post-TXA administration. RESULTS The trial occurred between March 2016 and September 2017, when data collection ended. 149 patients were analyzed (placebo, n = 50; 2 g TXA, n = 49; 4 g TXA, n = 50). The fold change in HLA-DR expression on monocytes [reported as median (Q1-Q3)] from pre-TXA to 72 h post-TXA was similar between placebo [0.61 (0.51-0.82)], 2 g TXA [0.57 (0.47-0.75)], and 4 g TXA [0.57 (0.44-0.89)] study groups (p = 0.82). Neutrophil CD62L expression was reduced in the 4 g TXA group [fold change: 0.73 (0.63-0.97)] compared to the placebo group [0.97 (0.78-1.10)] at 24 h post-TXA (p = 0.034). The fold decrease in plasma IL-6 was significantly less in the 4 g TXA group [1.36 (0.87-2.42)] compared to the placebo group [0.46 (0.19-1.69)] at 72 h post-TXA (p = 0.028). There were no differences in frequencies of myeloid or lymphoid populations or in classical complement activation at any of the study time points. CONCLUSION In trauma patients with severe injury, 4 g intravenous bolus dosing of TXA has minimal immunomodulatory effects with respect to leukocyte phenotypes and circulating cytokine levels. CLINICAL TRIAL REGISTRATION www.ClinicalTrials.gov, identifier NCT02535949.
PICO Summary
Population
Bleeding trauma patients with severe injury from the TAMPITI trial (n= 149).
Intervention
Intravenous tranexamic acid (TXA) 2 g bolus dose (n=49).
Comparison
Intravenous tranexamic acid 4 g bolus dose (n= 50); Placebo (n= 50).
Outcome
The median fold change in human leukocyte antigen-DR isotype (HLA-DR) expression on monocytes from pre-TXA to 72 h post-TXA was similar between placebo: 0.61, 2 g TXA: 0.57, and 4 g TXA: 0.57 study groups. Neutrophil CD62L expression was reduced in the 4 g TXA group (fold change: 0.73) compared to the placebo group: 0.97 at 24 h post-TXA. The fold decrease in plasma IL-6 was significantly less in the 4 g TXA group: 1.36 compared to the placebo group: 0.46 at 72 h post-TXA. There were no differences in frequencies of myeloid or lymphoid populations or in classical complement activation at any of the study time points.
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Effect of Fresh vs Standard-issue Red Blood Cell Transfusions on Multiple Organ Dysfunction Syndrome in Critically Ill Pediatric Patients: A Randomized Clinical Trial
Spinella PC, Tucci M, Fergusson DA, Lacroix J, Hebert PC, Leteurtre S, Schechtman KB, Doctor A, Berg RA, Bockelmann T, et al
Jama. 2019;322(22):2179-2190
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Editor's Choice
Abstract
Importance: The clinical consequences of red blood cell storage age for critically ill pediatric patients have not been examined in a large, randomized clinical trial. Objective: To determine if the transfusion of fresh red blood cells (stored ≤7 days) reduced new or progressive multiple organ dysfunction syndrome compared with the use of standard-issue red blood cells in critically ill children. Design, Setting, and Participants: The Age of Transfused Blood in Critically-Ill Children trial was an international, multicenter, blinded, randomized clinical trial, performed between February 2014 and November 2018 in 50 tertiary care centers. Pediatric patients between the ages of 3 days and 16 years were eligible if the first red blood cell transfusion was administered within 7 days of intensive care unit admission. A total of 15568 patients were screened, and 13308 were excluded. Interventions: Patients were randomized to receive either fresh or standard-issue red blood cells. A total of 1538 patients were randomized with 768 patients in the fresh red blood cell group and 770 in the standard-issue group. Main Outcomes and Measures: The primary outcome measure was new or progressive multiple organ dysfunction syndrome, measured for 28 days or to discharge or death. Results: Among 1538 patients who were randomized, 1461 patients (95%) were included in the primary analysis (median age, 1.8 years; 47.3% girls), in which there were 728 patients randomized to the fresh red blood cell group and 733 to the standard-issue group. The median storage duration was 5 days (interquartile range [IQR], 4-6 days) in the fresh group vs 18 days (IQR, 12-25 days) in the standard-issue group (P < .001). There were no significant differences in new or progressive multiple organ dysfunction syndrome between fresh (147 of 728 [20.2%]) and standard-issue red blood cell groups (133 of 732 [18.2%]), with an unadjusted absolute risk difference of 2.0% (95% CI, -2.0% to 6.1%; P = .33). The prevalence of sepsis was 25.8% (160 of 619) in the fresh group and 25.3% (154 of 608) in the standard-issue group. The prevalence of acute respiratory distress syndrome was 6.6% (41 of 619) in the fresh group and 4.8% (29 of 608) in the standard-issue group. Intensive care unit mortality was 4.5% (33 of 728) in the fresh group vs 3.5 % (26 of 732) in the standard-issue group (P = .34). Conclusions and Relevance: Among critically ill pediatric patients, the use of fresh red blood cells did not reduce the incidence of new or progressive multiple organ dysfunction syndrome (including mortality) compared with standard-issue red blood cells. Trial Registration: ClinicalTrials.gov Identifier: NCT01977547.
PICO Summary
Population
Critically ill paediatric patients between the ages of 3 days and 16 years, (n=1461).
Intervention
Red blood cells stored </=y days (Fresh red blood cell group, (n=728).
Comparison
Delivery of oldest compatible red cell units available (Standard-issue red blood cells, (n=733).
Outcome
There were no significant differences in new or progressive multiple organ dysfunction syndrome between fresh (147 of 728 [20.2%]) and standard-issue red blood cell groups (133 of 732 [18.2%]), with an unadjusted absolute risk difference of 2.0%; P = .33). The prevalence of sepsis was 25.8% (160 of 619) in the fresh group and 25.3% (154 of 608) in the standard-issue group. The prevalence of acute respiratory distress syndrome was 6.6% (41 of 619) in the fresh group and 4.8% (29 of 608) in the standard-issue group. Intensive care unit mortality was 4.5% (33 of 728) in the fresh group vs 3.5 % (26 of 732) in the standard-issue group.