Publications

AIMS: The aim of this study is to describe the disposition of tranexamic acid (TXA) in adult trauma patients and derive a dosing regimen that optimizes exposure based on a predefined exposure target.

METHODS: We performed a population pharmacokinetic (popPK) analysis of participants enrolled in the Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury (TAMPITI) trial (≥18 years with traumatic injury, given ≥1 blood product and/or requiring immediate transfer to the operating room) who were randomized to a single dose of either 2 or 4 g of TXA ≤2 h from time of injury. PopPK analysis was conducted using nonlinear mixed-effects modelling (NONMEM). Simulations were then performed using the final model to generate estimated plasma TXA concentrations in 1000 simulated participants. Dosing schemes were evaluated to determine maintenance of TXA plasma concentrations >10 mg/L for ≥8 h after administration of the initial dose.

RESULTS: TXA PK was best described by a two-compartment model with proportional residual error and allometric scaling on all parameters. Platelet count, skeletal muscle oxygen saturation measured by near-infrared spectroscopy and interleukin-8 concentration were significant covariates on TXA clearance. Based on simulations, a 2 g IV bolus dose, repeated 3 h later, best achieved the target exposure.

CONCLUSIONS: According to simulations from a popPK model of TXA, a 2 g IV bolus with a repeated dose 3 h later would be most likely to maintain concentrations >10 mg/L for 8 h in >95% of adult trauma patients and should be considered for patients with ongoing haemorrhage.

Improvements have been made in optimizing initial care of trauma patients, both in prehospital systems as well as in the emergency department, and these have also favorably affected longer term outcomes. However, as specific treatments for bleeding are largely lacking, many patients continue to die from hemorrhage. Also, major knowledge gaps remain on the impact of tissue injury on the host immune and coagulation response, which hampers the development of interventions to treat or prevent organ failure, thrombosis, infections or other complications of trauma. Thereby, trauma remains a challenge for intensivists. This review describes the most pressing research questions in trauma, as well as new approaches to trauma research, with the aim to bring improved therapies to the bedside within the twenty-first century.

Balanced hemostatic resuscitation has been associated with improved outcomes in patients with both pediatric and adult trauma. Cold-stored, low-titer group O whole blood (LTOWB) has been increasingly used as a primary resuscitation product in trauma in recent years. Benefits of LTOWB include rapid, balanced resuscitation in one product, platelets stored at 4°C, fewer additives and fewer donor exposures. The major theoretical risk of LTOWB transfusion is hemolysis, however this has not been shown in the literature. LTOWB use in injured pediatric populations is increasing but is not yet widespread. Seven studies to date have described the use of LTOWB in pediatric trauma cohorts. Safety of LTOWB use in both group O and non-group O pediatric patients has been shown in several studies, as indicated by the absence of hemolysis and acute transfusion reactions, and comparable risk of organ failure. Reported benefits of LTOWB included faster resolution of shock and coagulopathy, lower volumes of transfused blood products, and an independent association with increased survival in massively transfused patients. Overall, pediatric data are limited by small sample sizes and mostly single center cohorts. Multicenter randomized controlled trials are needed.

BACKGROUND: Platelet (PLT) product transfusion is a life-saving therapy for actively bleeding patients. There is an urgent need to maintain PLT function and extend shelf life to improve outcomes in these patients. Cold-stored PLT (CS-PLT) maintain hemostatic potential better than room temperature-stored PLT (RT-PLT). However, whether function in long-term CS-PLT is maintained under physiological flow regimes and/or determined by cold-induced metabolic changes is unknown.

OBJECTIVES: This study aimed to (i) compare the function of RT-PLT and CS-PLT under physiological flow conditions, (ii) determine whether CS-PLT maintain function after 3 weeks of storage, and (iii) identify metabolic pathways associated with the CS-PLT lesion.

METHODS: We performed phenotypic and functional assessments of RT- and CS-PLT (22 °C and 4 °C storage, respectively; N = 10 unique donors) at storage days 0, 5, and/or 21 via metabolomics, flow cytometry, aggregation, thrombin generation, viscoelastic testing, and a microfluidic assay to measure primary hemostatic function.

RESULTS: Day 21 4 °C PLT formed an occlusive thrombus under arterial shear at a similar rate to day 5 22 °C PLT. Day 21 4 °C PLTs had enhanced thrombin generation capacity compared with day 0 PLT and maintained functionality comparable to day RT-PLT across all assays performed. Key metrics from microfluidic assessment, flow cytometry, thrombin generation, and aggregation were associated with 4 °C storage, and metabolites involved in taurine and purine metabolism significantly correlated with these metrics. Taurine supplementation of PLT during storage improved hemostatic function under flow.

CONCLUSION: CS-PLT stored for 3 weeks maintain hemostatic activity, and storage-induced phenotype and function are associated with taurine and purine metabolism.

BACKGROUND: Some studies in both children and adults have shown a mortality benefit for the use of low titer group O whole blood (LTOWB) compared with component therapy for traumatic resuscitation. Although LTOWB is not widely available at pediatric trauma centers, its use is increasing. We hypothesized that in children who received whole blood after injury, the proportion of whole blood in relation to the total blood product resuscitation volume would impact survival.

METHODS: The trauma database from a single academic pediatric Level I trauma center was queried for pediatric (age <18 years) recipients of LTOWB after injury (years 2015-2022). Weight-based blood product (LTOWB, red blood cells, plasma, and platelet) transfusion volumes during the first 24 hours of admission were recorded. The ratio of LTOWB to total transfusion volume was calculated. The primary outcome was in-hospital mortality. Multivariable logistic regression model adjusted for the following variables: age, sex, mechanism of injury, Injury Severity Score, shock index, and Glasgow Coma Scale score. Adjusted odds ratio representing the change in the odds of mortality by a 10% increase in the LTOWB/total transfusion volume ratio was reported.

RESULTS: There were 95 pediatric LTOWB recipients included in the analysis, with median (interquartile range [IQR]) age of 10 years (5-14 years), 58% male, median (IQR) Injury Severity Score of 26 (17-35), 25% penetrating mechanism. The median (IQR) volume of LTOWB transfused was 17 mL/kg (15-35 mL/kg). Low titer group O whole blood comprised a median (IQR) of 59% (33-100%) of the total blood product resuscitation. Among patients who received LTOWB, there was a 38% decrease in in-hospital mortality for each 10% increase in the proportion of WB within total transfusion volume ( p < 0.001) after adjusting for age, sex, mechanism of injury, Injury Severity Score, shock index, and Glasgow Coma Scale score.

CONCLUSION: Increased proportions of LTOWB within the total blood product resuscitation was independently associated with survival in injured children. Based on existing data that suggests safety and improved outcomes with whole blood, consideration may be given to increasing the use of LTOWB over CT resuscitation in pediatric trauma resuscitation.

LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

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 <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 <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.

Extracorporeal membrane oxygenation (ECMO) is a high-risk and low-volume life support with increasing clinical study. However, heterogenous outcome definitions impede data assimilation into evidence to guide practice. The Academic Research Consortium (ARC), an international collaborative forum committed to facilitating the creation of stakeholder-driven consensus nomenclature and outcomes for clinical trials of medical devices, supported the ECMO Core Elements Needed for Trials Regulation And quality of Life (ECMO-CENTRAL) ARC. The ECMO-CENTRAL ARC was assembled to develop definitions of paediatric ECMO adverse events for use in clinical trials and regulatory device evaluation. An initial candidate list of ECMO adverse events derived from the mechanical circulatory support ARC was supplemented with a review of ECMO-relevant adverse event definitions collated from literature published between Jan 1, 1988, and Feb 20, 2023. Distinct teams of international topic experts drafted separate adverse event definitions that were harmonised to existing literature when appropriate. Draft definitions were revised for paediatric ECMO relevance with input from patients, families, and an international expert panel of trialists, clinicians, statisticians, biomedical engineers, device developers, and regulatory agencies. ECMO-CENTRAL ARC was revised and disseminated across research societies and professional organisations. Up to three rounds of internet-based anonymous surveys were planned as a modified Delphi process. The expert panel defined 13 adverse event definitions: neurological, bleeding, device malfunction, acute kidney injury, haemolysis, infection, vascular access-associated injury, non-CNS thrombosis, hepatic dysfunction, right heart failure, left ventricular overload, lactic acidaemia, and hypoxaemia. Definitional structure varied. Among 165 expert panel members, 114 were eligible to vote and 111 voted. Consensus was achieved for all proposed definitions. Agreement ranged from 82% to 95%. ECMO-CENTRAL ARC paired rigorous development with methodical stakeholder involvement and dissemination to define paediatric ECMO adverse events. These definitions will facilitate new research and the assimilation of data across clinical trials and ECMO device evaluation in children.

OBJECTIVE: To determine the feasibility, efficacy, and safety of early cold stored platelet transfusion compared with standard care resuscitation in patients with hemorrhagic shock.

BACKGROUND: Data demonstrating the safety and efficacy of early cold stored platelet transfusion are lacking following severe injury.

METHODS: A phase 2, multicenter, randomized, open label, clinical trial was performed at 5 US trauma centers. Injured patients at risk of large volume blood transfusion and the need for hemorrhage control procedures were enrolled and randomized. The intervention was the early transfusion of a single apheresis cold stored platelet unit, stored for up to 14 days versus standard care resuscitation. The primary outcome was feasibility and the principal clinical outcome for efficacy and safety was 24-hour mortality.

RESULTS: Mortality at 24 hours was 5.9% in patients who were randomized to early cold stored platelet transfusion compared with 10.2% in the standard care arm (difference, -4.3%; 95% CI, -12.8% to 3.5%; P =0.26). No significant differences were found for any of the prespecified ancillary outcomes. Rates of arterial and/or venous thromboembolism and adverse events did not differ across treatment groups.

CONCLUSIONS AND RELEVANCE: In severely injured patients, early cold stored platelet transfusion is feasible, safe and did not result in a significant lower rate of 24-hour mortality. Early cold stored platelet transfusion did not result in a higher incidence of arterial and/or venous thrombotic complications or adverse events. The storage age of the cold stored platelet product was not associated with significant outcome differences.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04667468.

BACKGROUND: To measure the impact of the COVID-19 pandemic on the management of patients with carotid artery stenosis.

METHODS: We prospectively collected data from 25 centers (19 centers in the United States and 6 centers internationally) on postponed carotid artery operations between March 2020 and January 2022. We describe the characteristics of these patients and their planned operations, along with outcomes including mortality and neurological deterioration during the period of operative delay due to the COVID-19 pandemic.

RESULTS: A total of 1,220 vascular operations were postponed during the pandemic, of them 96 patients presented with significant carotid stenosis (median stenosis of 71%; interquartile range; 70-80) and 80% of them were planned for carotid endarterectomy. Most patients were asymptomatic (69%), and 31% of patients were symptomatic (16% of patients had a stroke, 15% of patients had a transient ischemic attack, and 1% of patients experienced amaurosis fugax). The median length of surgical delay was 71 days (interquartile range: 45.5, 115.5). At the data entry time, 62% of patients had their carotid operations postponed and successfully completed. Most postponements (72%) were due to institutional policies aimed at resource conservation. During the delay, no patient decompensated or required an urgent operation. A total of 5 patients (5%) with carotid stenosis died while awaiting operations due to COVID-19.

CONCLUSIONS: Our study of a cohort of patients with carotid artery stenosis who underwent a median delay of 71 days during the COVID-19 pandemic showed a disparate operation delay between US regions and internationally, most postponements were due to hospital policy, and none of the patients deteriorated or required an emergency surgery during the delay.