Spinella, Philip C.

Importance Patients undergoing cardiac surgery with cardiopulmonary bypass often require platelet transfusions for bleeding. Platelets are routinely stored at room temperature (20-24 °C) for up to 5 to 7 days; however, cold storage (1-6 °C) may allow for increased storage duration without loss of hemostatic function. Objective To determine the maximum cold-storage duration, up to 21 days, for which cold-stored platelets (CSPs) are noninferior or superior in hemostatic efficacy to room-temperature platelets (RTPs) when transfused in actively bleeding patients undergoing cardiac surgery with cardiopulmonary bypass. Design, Setting, and Participants A phase 3, multicenter, randomized, partially blinded, adaptive, noninferiority, storage duration–ranging trial conducted in pediatric and adult patients undergoing cardiac surgery with planned cardiopulmonary bypass at 27 sites in the US and Australia from December 2021 to March 2025. Statistical analysis was conducted from September 9 to October 3, 2025. Intervention Patients were randomized 2:1 to receive CSPs with a maximum of 21 days of storage vs RTPs with a maximum of 7 days of storage. Main Outcomes and Measures The primary outcome was a hemostatic efficacy score with values ranging from 1 to 5 and higher values indicating greater bleeding. The noninferiority margin was 1 point. The success criterion was met if at least 1 cold-storage duration of 7 days or more had a posterior probability of noninferiority of at least 97.5%. The secondary outcome was 24-hour chest tube output. Results Of the 1000 patients who underwent platelet transfusion, 989 were included in the primary analysis (650 CSPs and 339 RTPs). The cohort had a mean (SD) age of 42.1 (30.1) years and 67.8% were male. CSPs were noninferior to RTPs for the primary outcome, with a probability of greater than 99.9% for all cold-storage durations. Pooled across storage durations, CSPs had a mean difference from RTPs of 0.09 (95% credible interval, −0.06 to 0.23). Median (IQR) chest tube output at 24 hours (8.9 mL/kg [5.2-15.4] for CSPs vs 8.4 mL/kg [5.5-15.9] for RTPs; difference in medians, 0.4 [95% CI, −1.0 to 1.5]) was not statistically different between study groups. In a post hoc analysis, as all storage durations were noninferior, considering the CSPs as a single group, the hemostatic efficacy score was similar between both groups: mean (SD) of 3.08 (1.15) CSPs vs 2.99 (1.10) RTPs. There were no differences in venous or arterial thrombotic events, transfusion-associated adverse events, acute respiratory distress syndrome, kidney failure, septic shock, and mortality between the study groups, except for increased reexploration rates in the CSP group. Conclusions and Relevance For patients undergoing cardiac surgery, CSPs stored up to 21 days are noninferior to RTPs for the control of active surgical bleeding. Use of CSPs may allow for increased availability of platelets by reducing wastage and shortages and may allow for incorporation of platelets into inventory at locations where platelets cannot be maintained due to the 5- to 7-day shelf life of RTPs. Trial Registration ClinicalTrials.gov Identifier: NCT04834414

Abstract Hemorrhagic shock is a common emergency that accounts for more than 10% of global mortality and up to 40% of trauma-related mortality. The Advanced Trauma Life Support (ATLS) guidelines outline resuscitation strategies in patients with massive hemorrhage based on clinical trial and observational data. Early intervention with fluids and/or blood products is recommended during resuscitation as key to maintaining vascular patency, stabilizing a patient’s blood pressure, maintaining tissue oxygenation, and limiting shock. From a transfusion perspective, there is wide heterogeneity in the quality of blood products due to donor and manufacturing variation. The optimal transfusion strategy for massive hemorrhage remains unclear. In silico models of resuscitation may offer a means to evaluate the effectiveness and safety of various resuscitation protocols. Here we describe a stochastic multicompartment model of fluid balance and resuscitation that includes (i) cardiovascular hemodynamics, (ii) body fluid compartments and capillary solute exchange, (iii) the ability to alter hemorrhage, resuscitation, and hemostasis parameters, and (iv) tissue oxygenation and capillary-alveolar gas exchange. Building upon deterministic frameworks, this stochastic model more faithfully reflects the clinical heterogeneity of bleeding patients at a level I trauma center. This allows for a proof of concept in silico trial comparing crystalloids, conventional component therapy (CCT), i.e. red cell, platelet and plasma components, to cold-stored low titer group O whole blood (LTOWB). In an in silico cohort of ATLS class III (>30% and ≤40% blood volume lost) hemorrhage, LTOWB resuscitation reduced the time spent in the critical hemostatic window (platelet count <50x109/L, INR≥2, hemoglobin (Hgb) <8 g/dL and fibrinogen <150 mg/dL) compared with CCT (90.59 vs. 147.62 minutes; p=0.04), with no difference in predicted event-free survival (t = 240 minutes; cardiac < 1.5, fluid overload > 10% or SBP > 150% of the starting SBP, or Hgb < 3.0 g/dL). In a separate cohort of ATLS class IV (>40% blood volume lost) hemorrhage, LTOWB yielded a higher predicted event-free survival (74%) versus the CCT arm (69%, p < 0.01). We demonstrate how this in silico platform can function as a digital twin for hemorrhagic trauma enabling precision transfusion strategies, and in parallel, an operational twin to support blood banks to forecast blood product demand and inform massive transfusion protocols and clinical trial design.

Abstract Background Substituting group A whole blood (GAWB) might relieve some of the burden on the low titer group O whole blood (LTOWB) inventory. This simulation examined the effect of implementing GAWB at a large trauma hospital. Study Design and Methods A civilian trauma center with LTOWB and GAWB par levels set to 22 and 10 units, respectively, was modeled as the baseline. The average daily number of WB recipients was 0.5 who received an average of four WB units per patient. LTOWB was issued in packages of five and all had to be consumed before a group A patient could be switched to GAWB. Several variations on the baseline simulation were also modeled. Results In the baseline simulation, there was a median (interquartile range, IQR) of 1 (0–2) GAWB and 16 (13–19) LTOWB recipients per month. The median (IQR) GAWB and LTOWB units transfused per month was 2 (0–9) and 56 (42–72), respectively. Fourteen percent of group A patients received any quantity of GAWB. The variations that had the most impact on GAWB usage included increasing the number of WB recipients to 2.5 per day where the median (IQR) monthly number of GAWB recipients and units transfused increased to 4 (3–5) recipients and 21 (12–29) units, respectively, and when the average WB requirements increased to eight units per patient resulting in transfusing a median (IQR) of 10 (5–15) GAWB units per month to 3 (1–4) recipients. Discussion Under routine civilian hospital circumstances, implementing GAWB will have a modest impact on LTOWB inventory.

Abstract Background We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care. Methods Fifty-five hospitals in 30 US states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients &lt;21 years admitted 12 March 2020–30 December 2021 to the pediatric intensive care unit (PICU) or high-acuity unit for acute COVID-19 were included. Results Of 1274 patients, 105 (8.2%) had an ICC, including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid-organ transplantation, 16 (15.2%) solid tumors, and 13 (12.4%) autoimmune disorders. Patients with ICCs were older, had more underlying renal conditions, and had lower white blood cell and platelet counts than those without ICCs, but had similar clinical disease severity upon admission. In-hospital mortality from COVID-19 was higher (11.4% vs 4.6%, P = .005) and hospitalization was longer (P = .01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, P = .40). In patients with ICCs, bacterial coinfection was more common in those with life-threatening COVID-19. Conclusions In this national case series of patients &lt;21 years of age with acute COVID-19 admitted for intensive care, existence of a prior ICCs were associated with worse clinical outcomes. Reassuringly, most patients with ICCs hospitalized in the PICU for severe acute COVID-19 survived and were discharged home without new severe morbidities.

Abstract Patients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen–reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded expert adjudication. The incidence of TEAMV-PD in all patients (1068 PRPC and 1223 CPC) was less for PRPC (1.7 %) than CPC (3.1%) with a treatment difference of –1.5% (95% confidence interval [CI], –2.7 to –0.2). In patients requiring ≥2 PCs, the incidence of TEAMV-PD was reduced for PRPC recipients compared with CPC recipients (treatment difference, –2.4%; 95% CI, –4.2 to –0.6). CSPAE increased with increasing PC exposure but were not significantly different between the cohorts. For patients receiving ≥2 platelet transfusions, TEARDS occurred in 1.3% PRPC and 2.6% CPC recipients (P = .086). Bayesian analysis demonstrated PRPC may be superior in reducing TEAMV-PD and TEARDS for platelet transfusion recipients compared with CPC recipients, with 99.2% and 88.8% probability, respectively. In this study, PRPC compared with CPC demonstrated high probability of reduced severe pulmonary injury requiring assisted mechanical ventilation in patients with hematology disorders dependent on platelet transfusion. This trial was registered at www.ClinicalTrials.gov as #NCT02549222.

AbstractBackgroundUsing low titer group O whole blood (LTOWB) is increasingly popular for resuscitating trauma patients. LTOWB is often RhD‐positive, which might cause D‐alloimmunization and hemolytic disease of the fetus and newborn (HDFN) if transfused to RhD‐negative females of childbearing potential (FCP). This simulation determined the number of life years gained by the FCP and her future children if she was resuscitated with LTOWB compared with conventional component therapy (CCT).MethodsThe model simulated 500,000 injured FCPs of each age between 0 and 49 years with LTOWB mortality relative reductions (MRRs) compared with components between 0.1% and 25%. For each surviving FCP, number of life years gained was calculated using her age at injury and average life expectancy for American women. The number of expected future pregnancies for FCPs that did not survive was also based on her age at injury; each future child was assigned the maximum lifespan unless they suffered perinatal mortality or serious neurological events from HDFN.ResultsThe LTOWB group with an MRR 25% compared with CCT had the largest total life years gained. The point of equivalence for RhD‐positive LTOWB compared to CCT, where life years lost due to severe HDFN was equivalent to life years gained due to FCP survival/future childbearing, occurred at an MRR of approximately 0.1%.ConclusionIn this model, RhD‐positive LTOWB resulted in substantial gains in maternal and child life years compared with CCT. A >0.1% relative mortality reduction from LTOWB offset the life years lost to HDFN mortality and severe neurological events.

Background The use of low-titer group O whole blood is increasing. To reduce wastage, unused units can be converted to packed red blood cells. Supernatant is currently discarded post-conversion; however, it could be a valuable transfusable product. The aim of this study was to evaluate supernatant prepared from late-storage low-titer group O whole blood being converted to red blood cells, hypothesizing it will have higher hemostatic activity compared to fresh never-frozen liquid plasma. Methods Low-titer group O whole blood supernatant (n = 12) prepared on storage day 15 was tested on days 15, 21, and 26 and liquid plasma (n = 12) on 3, 15, 21, and 26. Same-day assays included cell counts, rotational thromboelastometry, and thrombin generation. Centrifuged plasma from units was banked for microparticle characterization, conventional coagulation, clot structure, hemoglobin, and additional thrombin generation assays. Results Low-titer group O whole blood supernatant contained more residual platelets and microparticles compared to liquid plasma. At day 15, low-titer group O whole blood supernatant elicited a faster intrinsic clotting time compared to liquid plasma (257 ± 41 vs . 299 ± 36 s, P = 0.044), and increased clot firmness (49 ± 9 vs . 28 ± 5 mm, P < 0.0001). Low-titer group O whole blood supernatant showed more significant thrombin generation compared to liquid plasma (day 15 endogenous thrombin potential 1,071 ± 315 vs . 285 ± 221 nM·min, P < 0.0001). Flow cytometry demonstrated low-titer group O whole blood supernatant contained significantly more phosphatidylserine and CD41 + microparticles. However, thrombin generation in isolated plasma suggested residual platelets in low-titer group O whole blood supernatant were a greater contributor than microparticles. Additionally, low-titer group O whole blood supernatant and liquid plasma showed no difference in clot structure, despite higher CD61 + microparticle presence. Conclusions Plasma supernatant produced from late-storage low-titer group O whole blood shows comparable, if not enhanced, in vitro hemostatic efficacy to liquid plasma. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

AbstractBackgroundCommunity-onset bacterial coinfection in adults hospitalized with coronavirus disease 2019 (COVID-19) is reportedly uncommon, though empiric antibiotic use has been high. However, data regarding empiric antibiotic use and bacterial coinfection in children with critical illness from COVID-19 are scarce.MethodsWe evaluated children and adolescents aged &lt;19 years admitted to a pediatric intensive care or high-acuity unit for COVID-19 between March and December 2020. Based on qualifying microbiology results from the first 3 days of admission, we adjudicated whether patients had community-onset bacterial coinfection. We compared demographic and clinical characteristics of those who did and did not (1) receive antibiotics and (2) have bacterial coinfection early in admission. Using Poisson regression models, we assessed factors associated with these outcomes.ResultsOf the 532 patients, 63.3% received empiric antibiotics, but only 7.1% had bacterial coinfection, and only 3.0% had respiratory bacterial coinfection. In multivariable analyses, empiric antibiotics were more likely to be prescribed for immunocompromised patients (adjusted relative risk [aRR], 1.34 [95% confidence interval {CI}, 1.01–1.79]), those requiring any respiratory support except mechanical ventilation (aRR, 1.41 [95% CI, 1.05–1.90]), or those requiring invasive mechanical ventilation (aRR, 1.83 [95% CI, 1.36–2.47]) (compared with no respiratory support). The presence of a pulmonary comorbidity other than asthma (aRR, 2.31 [95% CI, 1.15–4.62]) was associated with bacterial coinfection.ConclusionsCommunity-onset bacterial coinfection in children with critical COVID-19 is infrequent, but empiric antibiotics are commonly prescribed. These findings inform antimicrobial use and support rapid de-escalation when evaluation shows coinfection is unlikely.

AbstractBackgroundA specialized international multidisciplinary group of investigators wanted to determine the performance and impact of publications presented at an annual conference over a 6 year period. Specifically, the group wanted to know if the influence of the conference publications extended beyond conference publication authors and attendees. Bibliometric methods and network analyses were used to evaluate the performance and impact of 100 peer‐reviewed publications presented at the Trauma Hemostasis and Oxygenation Research (THOR) Network Remote Damage Control Resuscitation (RCDR) Symposia from 2012 to 2017 (published 2013–2018). Further analysis was performed on the affiliations of conference attendees who attended from the years of 2012 to 2017.Study Design and MethodsThis project used normative and relative bibliometric measures and social network analysis to evaluate the performance and impact of 100 peer‐reviewed publications presented at the Trauma Hemostasis and Oxygenation Research (THOR) Network RDCR Symposia from 2012 to 2017. Publication and citation data were from Elsevier Scopus, a bibliographic citation database. Metrics from Elsevier SciVal were selected for the project to normalize for group size, year of publication, and document type. A six‐year period of publications presented at the Symposia, published from 2013 to 2018, was selected for analysis. The publication and citation data were further analyzed using Elsevier SciVal and the iCite database from the National Institutes of Health Office of Portfolio Analysis. Sci2, VOSviewer, and Gephi were used for social network analyses and visualization.ResultsThe 100 publications presented at the Trauma Hemostasis and Oxygenation Research (THOR) Network Remote Damage Control Resuscitation (RCDR) Symposia from 2012 to 2017 demonstrate reach and influence beyond the authors of the THOR publications or the THOR attendees. Citations to the THOR publications were published in 10 languages and 313 unique journals, with author affiliations from 62 countries. Citation metrics for the THOR publications exceed global averages with 65% of the THOR publications being in the 25% citation percentiles. When benchmarking the THOR publications using six homogenous comparator groups, the THOR publications demonstrate higher citation metrics than any of the comparator groups with more citations per publication, a higher average of cited publications, higher FWCI and outputs in the top citation percentiles among the six groups. The Office of Portfolio Analysis (OPA) iCite database was used to calculate potential to translate for the THOR publications with 57 of the THOR publications cited by clinical articles with an average approximate potential to translate score of 65.3%.ConclusionsThe value of international groups with sharing of research and knowledge are instrumental in enhancing the uptake for best practices for in medicine and treatment of hemorrhagic shock resuscitation. The use of bibliometric methods and network analyses, along with benchmarking, demonstrated reach and impact beyond the THOR Network. Limitations include use of a single source for analysis of publication and citation; and that publication data alone does not provide a full overview of research performance. Despite these limitations, bibliometric methods, social network analyses, and benchmarking can help centers better understand their impact.