Publications

OBJECTIVES: To evaluate the feasibility of conducting a large international electronic health record-enabled randomized controlled trial (RCT) designed to compare two strategies for RBC transfusion (RBCT) in almost all anemic critically ill children, and the ability to support data abstraction from electronic medical data monitoring systems (eMDMSs).

DESIGN: Two-arm parallel design pilot RCT.

SETTING: Four university-affiliated PICUs in Canada, France, and United Kingdom.

PATIENTS: Non-cyanotic critically ill children with hemoglobin (Hb) less than or equal to 9.5 g/dL.

INTERVENTIONS: Participants were randomly allocated to a restrictive strategy (no RBCT if Hb ≥ 7.0 g/dL) or to usual care (clinician discretion for RBCT).

MEASUREMENTS AND MAIN RESULTS: Feasibility outcomes were recruitment, adherence, separation of pre-RBCT Hb, and electronic data extraction from eMDMS. The proportion of patients with Hb less than or equal to 9.5 g/dL who were eligible for consent to participate in Pilot-Optimizing Transfusion Therapy in Critically Ill Children With Anemia (P-OpTTICCA) was 83% (feasibility criterion: ≥ 80%). We enrolled 120 patients, 63 in the restrictive and 57 in the usual care arms. We reached the planned recruitment rate (≥ 2 participants/wk in sites with > 800 admissions/yr, ≥ 1 in other sites). The pre-RBCT Hb concentration was 6.6 ± 7 and 6.7 ± 1.3 g/dL in the restrictive and usual care arms, respectively (separation = 0.1 g/dL; desired difference ≥ 1.0 g/dL). The pre-transfusion Hb concentration was greater than or equal to 7.0 g/dL for 6 of 20 RBCT (30%) given to patients allocated to the restrictive arm (success criterion for protocol adherence: < 20%). There were two protocol deviations, but no protocol violation. Using eMDMS, 87.7% of the 390 data elements in the case report form were extracted and/or calculated electronically (success criterion: > 80%).

CONCLUSIONS: P-OpTTICCA demonstrated the feasibility of recruitment, adherence, and electronic data extraction, but we did not get a good separation of pre-RBCT Hb. Future trials need to clearly define transfusion Hb thresholds in both trial arms (NCT03871244).

INTRODUCTION: Blue light (peak wavelength 442 nm) has been shown to modulate the immune response in preclinical models of intra-abdominal sepsis and pneumonia. In vivo pathways involve optic nerve stimulation with transmission to the central nervous system, activation of parasympathetic pathways terminating at the spleen, and downstream immune effects including decreased inflammatory tissue damage and improved pathogen clearance. Related effects on pain mediators including proinflammatory cytokines (interleukin 6, TNF- α) and autonomic tone (increased parasympathetic outflow) suggest possible analgesic properties that would be highly relevant to a trauma population.

METHODS AND ANALYSIS: This is a randomised controlled trial in which adult trauma inpatients (≥18 years) with painful rib fractures will be allocated 1:1:1 to three arms: bright blue light intervention (peak 442 nm,  1400 lux), bright full-spectrum light comparison ( 1400 lux) and usual ambient light control. Bright light exposures will be administered for 4 consecutive hours daily for up to 3 days. The primary outcome will be any measurable changes in chest wall pain intensity during deep breathing, quantified using an 11-point Numerical Rating Scale. Secondary outcomes will assess chest wall pain intensity at rest, opioid requirements, delirium incidence, pulmonary complication incidence, hospital-free and intensive care unit-free days, and physiological markers of autonomic nervous system, circadian, and immune activation. Sample size analysis yields a total of 75 participants needed to detect a 2-point difference in pain scores with >80% power and assuming a 20% non-completion rate.

ETHICS AND DISSEMINATION: Full ethical approval for this trial has been granted by the University of Pittsburgh Institutional Review Board. On study completion, results will be published in the peer-reviewed literature and at ClinicalTrials.gov.

TRIAL REGISTRATION NUMBER: NCT06626334.

OBJECTIVE: The underrepresentation of female patients in key trials results in a lack of sex-based guidelines regarding appropriate evaluation, diagnosis and management of the female vascular patient. As a result, recent literature has found a difference in the amputation and mortality rates in female patients following treatment for acute limb ischemia. However, the reasons for outcome variability are unknown. The objectives of this study were to identify sex specific predictors of major amputation and mortality following intervention for acute limb ischemia and sex specific differences in presentation, management and outcome of patients who undergo revascularization for acute limb ischemia.

METHODS: We included all adults who underwent revascularization for ALI at a multihospital healthcare system (2016-2023), excluding those who presented secondary to trauma, dissection, iatrogenic injury, popliteal aneurysms or COVID. The terms "male" and "female" were used to delineate patient's sex assignment at birth, were obtained from electronic health records and were assumed to be congruent with gender references. Survival and amputation were evaluated using Kaplan-Meier and multivariable Cox regression with a priori and empirically selected covariates. Comprehensive subgroup analyses were conducted to assess risk of mortality and amputation.

RESULTS: 548 patients were identified, of which 252 (46%) were female. Male patients were younger (64.4±11.5 vs. 67.0 ±15.3; p=0.023), more likely to have CAD (p=0.014), smoking history (p<0.001), and prior revascularization (p<0.001). Female patients were more likely to be hypercoagulable (p=0.001) and less likely to present with acute on chronic disease (p<0.001). Female patients were less frequently on a preoperative statin (p<0.001) or antiplatelet agent (p=0.004). While there was no sex-based difference in Rutherford ALI classification upon presentation, female patients were more likely to go to the OR within 24 hours (p=0.024). There were no differences in the initial surgical approach (endovascular vs. open). Female patients had an increased rate of death on univariable (p=.009) and multivariable (aHR=1.6; 95% CI [1.07-2.33]) analysis. On subgroup analyses, female patients who were medically optimized on presentation achieved mortality rates similar to male patients. Although there was no difference in overall amputation rates, female patients who underwent an endovascular first approach were twice as likely to undergo amputation in comparison to males (OR 2.6, pinteraction=0.01).

CONCLUSIONS: Female patients who presented with ALI had higher mortality following revascularization, except for those medically optimized. They also had notably higher amputation rates following endovascular intervention. Further exploration of these disparities may allow for tailored intervention strategies by sex.

BACKGROUND: Social determinants of health impact outcomes after traumatic injury. Little is known regarding if and how this impact of social determinants of health in trauma varies across different geographic settings. Our objective was to evaluate whether social determinants of health associated with injury-related mortality vary based on geographic region.

METHODS: We conducted a retrospective cohort study using the Pennsylvania Trauma Study Outcomes database merged with data from the Association for Healthcare, Research, and Quality social determinants of health database. Bootstrapped elastic net regression determined the association between risk-adjusted mortality and social determinants of health factors in urban, suburban, and rural areas.

RESULTS: A total of 374,136 patients were included in the study (285,062 urban, 71,847 suburban, and 17,227 rural). Economic context and physical infrastructure were the most important domains for urban populations, whereas social context was the most important domain for suburban and rural populations. In urban populations, the increasing proportion of White race was most strongly associated with lower morality risk (coefficient: -0.045; 95% confidence interval: -0.044, -0.046), whereas income/poverty, transportation, and health insurance were the most common features associated with mortality. In suburban and rural communities, US born citizens were most strongly associated with lower mortality risk (coefficient: -0.024; 95% confidence interval: -0.023, -0.025), while demographics and housing were most commonly associated with mortality.

CONCLUSION: The social determinants of health associated with mortality after injury vary across geographic settings. This may inform risk stratification and more effectively target policy and community interventions by geography to reduce the burden of injury.

Copper-catalyzed radical C(sp3)‒N coupling has become a major focus in synthetic catalysis over the past decade. However, achieving this reaction manifold by using enzymes has remained elusive. In this study, we introduce a photobiocatalytic approach for radical benzylic C(sp3)‒N coupling using a copper-substituted nonheme enzyme. Using rhodamine B as a photoredox catalyst, we identified a copper-substituted phenylalanine hydroxylase that facilitates enantioconvergent decarboxylative amination between N-hydroxyphthalimide esters and anilines. Directed evolution remodeled the active site, resulting in high enantioselectivities for most substrates. On the basis of molecular modeling and mechanistic studies, we propose that the enzyme accommodates a copper-anilide complex that reacts with a benzylic radical. This study expands the scope of non-natural biocatalytic transition metal catalysis to copper-catalyzed radical coupling.

The FDA recently licensed 14-day cold-stored platelets for bleeding patients. This policy change represents a reversal from the 1970s when cold-stored platelets were discontinued because of their short circulation time in healthy humans. This change will increase their availability in US hospitals with large trauma populations and in remote and rural settings in the U.S. In some of these hospitals, cold-stored platelets will be the only platelets available. It is currently unclear whether patients with hypoproliferative thrombocytopenia who need platelet transfusion for prophylaxis benefit from cold-stored platelets. However, it is noteworthy that in recent clinical trials using room temperature-stored platelets, the transfusion interval in hematology-oncology patients can be as short as one transfusion per day, very similar to what one would expect to achieve with cold-stored platelets. Furthermore, the emphasis on the post-transfusion count increment and the platelet count as transfusion trigger per se is questionable. In the PLADO trial, there was only a poor correlation between the morning platelet count and bleeding events, implicating other factors, such as red blood cells, coagulation factors, and vascular health, as possible culprits. In this perspective article, we review the history of cold platelets and the reason for their discontinuation, focus on recent clinical trial data using room temperature-stored platelets, and review the platelet count as a transfusion trigger. Overall, using cold platelets for prophylaxis may seem counterintuitive, but a closer look at the available data suggests that the indication expansion may hold more promise.

Traumatic injury has the highest burden on morbidity and mortality in the United States. Early deaths from trauma are most frequently due to hemorrhage and could be prevented with more timely and efficacious treatments. A hallmark of trauma-induced coagulopathy (TIC) is hypofibrinogenemia, which is treated with fibrinogen concentrates (FibCon) or cryoprecipitate (Cryo). Pathogen reduction (PR) of Cryo (PR-CryoFC) enables extended storage after thaw at room temperature, permitting immediate availability for patients with bleeding. As Cryo contains additional concentrated plasma proteins involved in hemostasis compared with FibCon, we hypothesized that Cryo and PR-CryoFC would result in more rapid and effective clot formation. To evaluate the hemostatic capacity of these adjuncts, we simulated TIC (dilution, hyperfibrinolysis) in an ex vivo model and administered Cryo, PR-CryoFC, and FibCon, then performed hemostatic assessment to include viscoelastometry, thrombin generation, and a microfluidic model of vessel injury. Cryo and PR-CryoFC had similar resuscitation capacity in assays without flow (viscoelastometry, thrombin generation), whereas in the dynamic microfluidic model, Cryo had faster von Willebrand factor (VWF)-mediated platelet recruitment. There was no difference in intrinsic VWF function between adjuncts in static, nonflowing assays, yet in a flow-dependent vortexing assay, PR reduced VWF cleavage by ADAMTS13, despite equivalent ADAMTS13 activity, suggesting impaired biophysical elongation and extension of VWF in PR-CryoFC, resulting in reduced cleavage and platelet binding capacity. Herein, we show ex vivo simulation of coagulopathy and resuscitation differentiated hemostatic function under flow among Cryo, PR-CryoFC, and FibCon. Further exploration of effects of PR on plasma proteins is warranted as well as effects on clinical outcomes.

In May 2024, the Division of Blood Diseases and Resources of the National Heart, Lung, and Blood Institute (NHLBI) hosted a hybrid workshop on "Extracorporeal membrane oxygenation (ECMO)-induced coagulopathy: strategic initiatives for research and clinical practice." The event brought together clinicians, scientists, bioengineers, and policymakers to address the challenges of ECMO-associated coagulopathy and explore novel therapeutic approaches. Through expert presentations and collaborative discussions, the workshop focused on innovative anticoagulation strategies, precision medicine, and advanced diagnostics to enhance patient care. The discussions also identified critical research gaps and opportunities for future interdisciplinary collaboration. This summary reviews the current state of knowledge and outlines future research directions for improving ECMO-induced coagulopathy management.