The Golden Hour of Casualty Care: Rapid Handoff to Surgical Team is Associated With Improved Survival in War-injured US Service Members.

OBJECTIVE: To examine time from injury to initiation of surgical care and association with survival in US military casualties. BACKGROUND: Although the advantage of trauma care within the "golden hour" after an injury is generally accepted, evidence is scarce. METHODS: This retrospective, population-based cohort study included US military casualties injured in Afghanistan and Iraq, January 2007 to December 2015, alive at initial request for evacuation with maximum abbreviated injury scale scores ≥2 and documented 30-day survival status after injury. Interventions: (1) handoff alive to the surgical team, and (2) initiation of first surgery were analyzed as time-dependent covariates (elapsed time from injury) using sequential Cox proportional hazards regression to assess how intervention timing might affect mortality. Covariates included age, injury year, and injury severity. RESULTS: Among 5269 patients (median age, 24 years; 97% males; and 68% battle-injured), 728 died within 30 days of injury, 68% within 1 hour, and 90% within 4 hours. Only handoffs within 1 hour of injury and the resultant timely initiation of emergency surgery (adjusted also for prior advanced resuscitative interventions) were significantly associated with reduced 24-hour mortality compared with more delayed surgical care (adjusted hazard ratios: 0.34; 95% CI: 0.14-0.82; P = 0.02; and 0.40; 95% CI: 0.20-0.81; P = 0.01, respectively). In-hospital waits for surgery (mean: 1.1 hours; 95% CI; 1.0-1.2) scarcely contributed ( P = 0.67). CONCLUSIONS: Rapid handoff to the surgical team within 1 hour of injury may reduce mortality by 66% in US military casualties. In the subgroup of casualties with indications for emergency surgery, rapid handoff with timely surgical intervention may reduce mortality by 60%. To inform future research and trauma system planning, findings are pivotal.

Finding the bleeding edge: 24-hour mortality by unit of blood product transfused in combat casualties from 2002-2020.

BACKGROUND: Transfusion studies in civilian trauma patients have tried to identify a general futility threshold. We hypothesized that in combat settings there is no general threshold where blood product transfusion becomes unbeneficial to survival in hemorrhaging patients. We sought to assess the relationship between the number of units of blood products transfused and 24-hour mortality in combat casualties. METHODS: A retrospective analysis of the Department of Defense Trauma Registry supplemented with data from the Armed Forces Medical Examiner. Combat casualties who received at least one unit of blood product at US military medical treatment facilities (MTFs) in combat settings (2002-2020) were included. The main intervention was the total units of any blood product transfused, which was measured from the point of injury until 24 hours after admission from the first deployed MTF. The primary outcome was discharge status (alive, dead) at 24 hours from time of injury. RESULTS: Of 11,746 patients included, the median age was 24 years, and most patients were male (94.2%) with penetrating injury (84.7%). The median injury severity score was 17 and 783 (6.7%) patients died by 24 hours. Median units of blood products transfused was 8. Most blood products transfused were red blood cells (50.2%), followed by plasma (41.1%), platelets (5.5%), and whole blood (3.2%). Among the 10 patients who received the most units of blood product (164 units to 290 units), 7 survived to 24 hours. The maximum amount of total blood products transfused to a patient who survived was 276 units. Of the 58 patients who received over 100 units of blood product, 20.7% died by 24 hours. CONCLUSION: While civilian trauma studies suggest the possibility of futility with ultra-massive transfusion, we report that the majority (79.3%) of combat casualties who received transfusions greater than 100 units survived to 24 hours. These results do not support a threshold for futility of blood product transfusion. Further analysis as to predictors for mortality will help in situations of blood product and resource constraints. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

The epidemiology and outcomes of prolonged trauma care (EpiC) study: methodology of a prospective multicenter observational study in the Western Cape of South Africa.

BACKGROUND: Deaths due to injuries exceed 4.4 million annually, with over 90% occurring in low-and middle-income countries. A key contributor to high trauma mortality is prolonged trauma-to-treatment time. Earlier receipt of medical care following an injury is critical to better patient outcomes. Trauma epidemiological studies can identify gaps and opportunities to help strengthen emergency care systems globally, especially in lower income countries, and among military personnel wounded in combat. This paper describes the methodology of the "Epidemiology and Outcomes of Prolonged Trauma Care (EpiC)" study, which aims to investigate how the delivery of resuscitative interventions and their timeliness impacts the morbidity and mortality outcomes of patients with critical injuries in South Africa. METHODS: The EpiC study is a prospective, multicenter cohort study that will be implemented over a 6-year period in the Western Cape, South Africa. Data collected will link pre- and in-hospital care with mortuary reports through standardized clinical chart abstraction and will provide longitudinal documentation of the patient's clinical course after injury. The study will enroll an anticipated sample of 14,400 injured adults. Survival and regression analysis will be used to assess the effects of critical early resuscitative interventions (airway, breathing, circulatory, and neurologic) and trauma-to-treatment time on the primary 7-day mortality outcome and secondary mortality (24-h, 30-day) and morbidity outcomes (need for operative interventions, secondary infections, and organ failure). DISCUSSION: This study is the first effort in the Western Cape of South Africa to build a standardized, high-quality, multicenter epidemiologic trauma dataset that links pre- and in-hospital care with mortuary data. In high-income countries and the U.S. military, the introduction of trauma databases and registries has led to interventions that significantly reduce post-injury death and disability. The EpiC study will describe epidemiology trends over time, and it will enable assessments of how trauma care and system processes directly impact trauma outcomes to ultimately improve the overall emergency care system. TRIAL REGISTRATION: Not applicable as this study is not a clinical trial.

Determining resuscitation outcomes in combat casualties: Design of the Deployed Hemostatic Emergency Resuscitation of Traumatic Exsanguinating Shock (Deployed HEROES) study.

BACKGROUND: During the course of the recent conflicts, the recommendations for resuscitation practices have evolved, but there has been no comprehensive comparative effectiveness study of these resuscitation strategies. The objective of this study was to describe the development and study design of the Deployed Hemostatic Emergency Resuscitation of Traumatic Exsanguinating Shock (Deployed HEROES) study-the first comprehensive analysis of military resuscitation practices in the deployed environment from October 2001 to October 2019. METHODS: This retrospective cohort study uses the Department of Defense Trauma Registry, Armed Services Blood Program database, and Military Trauma Mortality Review, while abstractors will use Theater Medical Data Store and Web Interface Patient Records to collect transfusion timing data. This study includes patients, who received blood products or died before receiving blood, treated at US military medical treatment facilities. The primary endpoints are survival at 6 hours, 24 hours, and 30 days postinjury. Secondary outcomes include infection, renal dysfunction, pulmonary dysfunction, and thromboembolic event. Exposure will be defined by blood product transfusion. Study groups will be frequency matched. Cox proportional hazards will compare patients who received warm fresh whole blood, low titer type-O whole blood, or only component therapy, while using adjustment for type of blood product transfused as a time-dependent covariate. Multilevel mixed-effects logistic regression will determine the effect of incompatible plasma in low titer type-O whole blood. RESULTS: An analysis plan for the Deployed HEROES study was developed with the aim of minimizing bias. CONCLUSION: This study will inform the optimal resuscitation strategies, which will potentially have a substantial impact on combat mortality. If whole blood is found to be the optimal transfusion strategy, this finding will be crucial in future operating environments involving dispersed medical assets. These results will provide critical information necessary for combat casualty care guidelines. LEVEL OF EVIDENCE: Prognostic and epidemiological; Level III.

Whole blood at the tip of the spear: A retrospective cohort analysis of warm fresh whole blood resuscitation versus component therapy in severely injured combat casualties.

BACKGROUND: Death from uncontrolled hemorrhage occurs rapidly, particularly among combat casualties. The US military has used warm fresh whole blood during combat operations owing to clinical and operational exigencies, but published outcomes data are limited. We compared early mortality between casualties who received warm fresh whole blood versus no warm fresh whole blood. METHODS: Casualties injured in Afghanistan from 2008 to 2014 who received ≥2 red blood cell containing units were reviewed using records from the Joint Trauma System Role 2 Database. The primary outcome was 6-hour mortality. Patients who received red blood cells solely from component therapy were categorized as the non-warm fresh whole blood group. Non- warm fresh whole blood patients were frequency-matched to warm fresh whole blood patients on identical strata by injury type, patient affiliation, tourniquet use, prehospital transfusion, and average hourly unit red blood cell transfusion rates, creating clinically unique strata. Multilevel mixed effects logistic regression adjusted for the matching, immortal time bias, and other covariates. RESULTS: The 1,105 study patients (221 warm fresh whole blood, 884 non-warm fresh whole blood) were classified into 29 unique clinical strata. The adjusted odds ratio of 6-hour mortality was 0.27 (95% confidence interval 0.13-0.58) for the warm fresh whole blood versus non-warm fresh whole blood group. The reduction in mortality increased in magnitude (odds ratio = 0.15, P = .024) among the subgroup of 422 patients with complete data allowing adjustment for seven additional covariates. There was a dose-dependent effect of warm fresh whole blood, with patients receiving higher warm fresh whole blood dose (>33% of red blood cell-containing units) having significantly lower mortality versus the non-warm fresh whole blood group. CONCLUSION: Warm fresh whole blood resuscitation was associated with a significant reduction in 6-hour mortality versus non-warm fresh whole blood in combat casualties, with a dose-dependent effect. These findings support warm fresh whole blood use for hemorrhage control as well as expanded study in military and civilian trauma settings.

Case-control analysis of prehospital death and prolonged field care survival during recent US military combat operations.

BACKGROUND: Quantification of medical interventions administered during prolonged field care (PFC) is necessary to inform training and planning. MATERIALS AND METHODS: Retrospective cohort study of Department of Defense Trauma Registry casualties with maximum Abbreviated Injury Scale (MAIS) score of 2 or greater and prehospital records during combat operations 2007 to 2015; US military nonsurvivors were linked to Armed Forces Medical Examiner System data. Medical interventions administered to survivors of 4 hours to 72 hours of PFC and nonsurvivors who died prehospital were compared by frequency-matching on mechanism (explosive, firearm, other), injury type (penetrating, blunt) and injured body regions with MAIS score of 3 or greater. Covariates for adjustment included age, sex, military Service, shock, Glasgow Coma Scale, transport team, MAIS and Injury Severity Score (ISS). Sensitivity analysis focused on US military subgroup with AIS/ISS assigned to nonsurvivors after autopsy. RESULTS: The total inception cohort included 16,202 casualties (5,269 US military, 10,809 non-US military), 64% Afghanistan, 36% Iraq. Of US military, 734 deaths occurred within 30 days, nearly 90% occurred within 4 hours of injury. There were 3,222 casualties (1,111 US military, 2,111 non-US military) documented for prehospital care and died prehospital (691) or survived 4 hours to 72 hours of PFC (2,531). Twenty-five percent (815/3,222) received advanced airway, 18% (583) ventilatory support, 9% (281) tourniquet. Twenty-three percent (725) received blood transfusions within 24 hours. Of the matched cohort (1,233 survivors, 490 nonsurvivors), differences were observed in care (survivors received more warming, intravenous fluids, sedation, mechanical ventilation, narcotics, antibiotics; nonsurvivors received more intubations, tourniquets, intraosseous fluids, cardiopulmonary resuscitation). Sensitivity analysis focused on US military (732 survivors, 379 nonsurvivors) showed no significant differences in prehospital interventions. Without autopsy information, the ISS of nonsurvivors significantly underestimated injury severity. CONCLUSION: Tourniquets, blood transfusion, airway, and ventilatory support are frequently required interventions for the seriously injured. Prolonged field care should direct resources, technology, and training to field technology for sustained resuscitation, airway, and breathing support in the austere environment. LEVEL OF EVIDENCE: Prognostic, Level III.

A stepped randomized trial to promote colorectal cancer screening in a nationwide sample of U.S. Veterans.

BACKGROUND: Colorectal cancer (CRC) screening (CRCS) facilitates early detection and lowers CRC mortality. OBJECTIVES: To increase CRCS in a randomized trial of stepped interventions. Step 1 compared three modes of delivery of theory-informed minimal cue interventions. Step 2 was designed to more intensively engage those not completing CRCS after Step 1. METHODS: Recruitment packets (60,332) were mailed to a random sample of individuals with a record of U.S. military service during the Vietnam-era. Respondents not up-to-date with CRCS were randomized to one of four Step 1 groups: automated telephone, telephone, letter, or survey-only control. Those not completing screening after Step 1 were randomized to one of three Step 2 groups: automated motivational interviewing (MI) call, counselor-delivered MI call, or Step 2 control. Intention-to-treat (ITT) analyses assessed CRCS on follow-up surveys mailed after each step. RESULTS: After Step 1 (n = 1784), CRCS was higher in the letter, telephone, and automated telephone groups (by 1%, 5%, 7%) than in survey-only controls (43%), although differences were not statistically significant. After Step 2 (n = 516), there were nonsignificant increases in CRCS in the two intervention groups compared with the controls. CRCS following any combination of stepped interventions overall was 7% higher (P = 0.024) than in survey-only controls (55.6%). CONCLUSIONS: In a nationwide study of Veterans, CRCS after each of two stepped interventions of varying modes of delivery did not differ significantly from that in controls. However, combined overall, the sequence of stepped interventions significantly increased CRCS.

Evidence-Based and Clinically Relevant Outcomes for Hemorrhage Control Trauma Trials.

OBJECTIVE: To address the clinical and regulatory challenges of optimal primary endpoints for bleeding patients by developing consensus-based recommendations for primary clinical outcomes for pivotal trials in patients within 6 categories of significant bleeding, (1) traumatic injury, (2) intracranial hemorrhage, (3) cardiac surgery, (4) gastrointestinal hemorrhage, (5) inherited bleeding disorders, and (6) hypoproliferative thrombocytopenia. BACKGROUND: A standardized primary outcome in clinical trials evaluating hemostatic products and strategies for the treatment of clinically significant bleeding will facilitate the conduct, interpretation, and translation into clinical practice of hemostasis research and support alignment among funders, investigators, clinicians, and regulators. METHODS: An international panel of experts was convened by the National Heart Lung and Blood Institute and the United States Department of Defense on September 23 and 24, 2019. For patients suffering hemorrhagic shock, the 26 trauma working-group members met for almost a year, utilizing biweekly phone conferences and then an in-person meeting, evaluating the strengths and weaknesses of previous high quality studies. The selection of the recommended primary outcome was guided by goals of patient-centeredness, expected or demonstrated sensitivity to beneficial treatment effects, biologic plausibility, clinical and logistical feasibility, and broad applicability. CONCLUSIONS: For patients suffering hemorrhagic shock, and especially from truncal hemorrhage, the recommended primary outcome was 3 to 6-hour all-cause mortality, chosen to coincide with the physiology of hemorrhagic death and to avoid bias from competing risks. Particular attention was recommended to injury and treatment time, as well as robust assessments of multiple safety related outcomes.

A Pilot Trial of Platelets Stored Cold versus at Room Temperature for Complex Cardiothoracic Surgery.

BACKGROUND: This pilot trial focused on feasibility and safety to provide preliminary data to evaluate the hemostatic potential of cold-stored platelets (2° to 6°C) compared with standard room temperature-stored platelets (20° to 24°C) in adult patients undergoing complex cardiothoracic surgery. This study aimed to assess feasibility and to provide information for future pivotal trials. METHODS: A single center two-stage exploratory pilot study was performed on adult patients undergoing elective or semiurgent complex cardiothoracic surgery. In stage I, a two-armed randomized trial, platelets stored up to 7 days in the cold were compared with those stored at room temperature. In the subsequent single-arm stage II, cold storage time was extended to 8 to 14 days. The primary outcome was clinical effect measured by chest drain output. Secondary outcomes were platelet function measured by multiple electrode impedance aggregometry, total blood usage, immediate and long-term (28 days) adverse events, length of stay in intensive care, and mortality. RESULTS: In stage I, the median chest drain output was 720 ml (quartiles 485 to 1,170, n = 25) in patients transfused with room temperature-stored platelets and 645 ml (quartiles 460 to 800, n = 25) in patients transfused with cold-stored platelets. No significant difference was observed. The difference in medians between the room temperature- and cold-stored up to 7 days arm was 75 ml (95% CI, -220, 425). In stage II, the median chest drain output was 690 ml (500 to 1,880, n = 15). The difference in medians between the room temperature arm and the nonconcurrent cold-stored 8 to 14 days arm was 30 ml (95% CI, -1,040, 355). Platelet aggregation in vitro increased after transfusion in both the room temperature- and cold-stored platelet study arms. Total blood usage, number of adverse events, length of stay in intensive care, and mortality were comparable among patients receiving cold-stored and room temperature-stored platelets. CONCLUSIONS: This pilot trial supports the feasibility of platelets stored cold for up to 14 days and provides critical guidance for future pivotal trials in high-risk cardiothoracic bleeding patients.

Association of time to craniectomy with survival in patients with severe combat-related brain injury.

OBJECTIVEIn combat and austere environments, evacuation to a location with neurosurgery capability is challenging. A planning target in terms of time to neurosurgery is paramount to inform prepositioning of neurosurgical and transport resources to support a population at risk. This study sought to examine the association of wait time to craniectomy with mortality in patients with severe combat-related brain injury who received decompressive craniectomy.METHODSPatients with combat-related brain injury sustained between 2005 and 2015 who underwent craniectomy at deployed surgical facilities were identified from the Department of Defense Trauma Registry and Joint Trauma System Role 2 Registry. Eligible patients survived transport to a hospital capable of diagnosing the need for craniectomy and performing surgery. Statistical analyses included unadjusted comparisons of postoperative mortality by elapsed time from injury to start of craniectomy, and Cox proportional hazards modeling adjusting for potential confounders. Time from injury to craniectomy was divided into quintiles, and explored in Cox models as a binary variable comparing early versus delayed craniectomy with cutoffs determined by the maximum value of each quintile (quintile 1 vs 2-5, quintiles 1-2 vs 3-5, etc.). Covariates included location of the facility at which the craniectomy was performed (limited-resource role 2 facility vs neurosurgically capable role 3 facility), use of head CT scan, US military status, age, head Abbreviated Injury Scale score, Injury Severity Score, and injury year. To reduce immortal time bias, time from injury to hospital arrival was included as a covariate, entry into the survival analysis cohort was defined as hospital arrival time, and early versus delayed craniectomy was modeled as a time-dependent covariate. Follow-up for survival ended at death, hospital discharge, or hospital day 16, whichever occurred first.RESULTSOf 486 patients identified as having undergone craniectomy, 213 (44%) had complete date/time values. Unadjusted postoperative mortality was 23% for quintile 1 (n = 43, time from injury to start of craniectomy 30-152 minutes); 7% for quintile 2 (n = 42, 154-210 minutes); 7% for quintile 3 (n = 43, 212-320 minutes); 19% for quintile 4 (n = 42, 325-639 minutes); and 14% for quintile 5 (n = 43, 665-3885 minutes). In Cox models adjusted for potential confounders and immortal time bias, postoperative mortality was significantly lower when time to craniectomy was within 5.33 hours of injury (quintiles 1-3) relative to longer delays (quintiles 4-5), with an adjusted hazard ratio of 0.28, 95% CI 0.10-0.76 (p = 0.012).CONCLUSIONSPostoperative mortality was significantly lower when craniectomy was initiated within 5.33 hours of injury. Further research to optimize craniectomy timing and mitigate delays is needed. Functional outcomes should also be evaluated.

Association of Prehospital Blood Product Transfusion During Medical Evacuation of Combat Casualties in Afghanistan With Acute and 30-Day Survival.

IMPORTANCE: Prehospital blood product transfusion in trauma care remains controversial due to poor-quality evidence and cost. Sequential expansion of blood transfusion capability after 2012 to deployed military medical evacuation (MEDEVAC) units enabled a concurrent cohort study to focus on the timing as well as the location of the initial transfusion. OBJECTIVE: To examine the association of prehospital transfusion and time to initial transfusion with injury survival. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of US military combat casualties in Afghanistan between April 1, 2012, and August 7, 2015. Eligible patients were rescued alive by MEDEVAC from point of injury with either (1) a traumatic limb amputation at or above the knee or elbow or (2) shock defined as a systolic blood pressure of less than 90 mm Hg or a heart rate greater than 120 beats per minute. EXPOSURES: Initiation of prehospital transfusion and time from MEDEVAC rescue to first transfusion, regardless of location (ie, prior to or during hospitalization). Transfusion recipients were compared with nonrecipients (unexposed) for whom transfusion was delayed or not given. MAIN OUTCOMES AND MEASURES: Mortality at 24 hours and 30 days after MEDEVAC rescue were coprimary outcomes. To balance injury severity, nonrecipients of prehospital transfusion were frequency matched to recipients by mechanism of injury, prehospital shock, severity of limb amputation, head injury, and torso hemorrhage. Cox regression was stratified by matched groups and also adjusted for age, injury year, transport team, tourniquet use, and time to MEDEVAC rescue. RESULTS: Of 502 patients (median age, 25 years [interquartile range, 22 to 29 years]; 98% male), 3 of 55 prehospital transfusion recipients (5%) and 85 of 447 nonrecipients (19%) died within 24 hours of MEDEVAC rescue (between-group difference, -14% [95% CI, -21% to -6%]; P = .01). By day 30, 6 recipients (11%) and 102 nonrecipients (23%) died (between-group difference, -12% [95% CI, -21% to -2%]; P = .04). For the 386 patients without missing covariate data among the 400 patients within the matched groups, the adjusted hazard ratio for mortality associated with prehospital transfusion was 0.26 (95% CI, 0.08 to 0.84, P = .02) over 24 hours (3 deaths among 54 recipients vs 67 deaths among 332 matched nonrecipients) and 0.39 (95% CI, 0.16 to 0.92, P = .03) over 30 days (6 vs 76 deaths, respectively). Time to initial transfusion, regardless of location (prehospital or during hospitalization), was associated with reduced 24-hour mortality only up to 15 minutes after MEDEVAC rescue (median, 36 minutes after injury; adjusted hazard ratio, 0.17 [95% CI, 0.04 to 0.73], P = .02; there were 2 deaths among 62 recipients vs 68 deaths among 324 delayed transfusion recipients or nonrecipients). CONCLUSIONS AND RELEVANCE: Among medically evacuated US military combat causalities in Afghanistan, blood product transfusion prehospital or within minutes of injury was associated with greater 24-hour and 30-day survival than delayed transfusion or no transfusion. The findings support prehospital transfusion in this setting.

Estimating the ratio of multivariate recurrent event rates with application to a blood transfusion study.

In comparative effectiveness studies of multicomponent, sequential interventions like blood product transfusion (plasma, platelets, red blood cells) for trauma and critical care patients, the timing and dynamics of treatment relative to the fragility of a patient's condition is often overlooked and underappreciated. While many hospitals have established massive transfusion protocols to ensure that physiologically optimal combinations of blood products are rapidly available, the period of time required to achieve a specified massive transfusion standard (e.g. a 1:1 or 1:2 ratio of plasma or platelets:red blood cells) has been ignored. To account for the time-varying characteristics of transfusions, we use semiparametric rate models for multivariate recurrent events to estimate blood product ratios. We use latent variables to account for multiple sources of informative censoring (early surgical or endovascular hemorrhage control procedures or death). The major advantage is that the distributions of latent variables and the dependence structure between the multivariate recurrent events and informative censoring need not be specified. Thus, our approach is robust to complex model assumptions. We establish asymptotic properties and evaluate finite sample performance through simulations, and apply the method to data from the PRospective Observational Multicenter Major Trauma Transfusion study.

Assessing protocol adherence in a clinical trial with ordered treatment regimens: Quantifying the pragmatic, randomized optimal platelet and plasma ratios (PROPPR) trial experience.

BACKGROUND: Medication dispensing errors are common in clinical trials, and have a significant impact on the quality and validity of a trial. Therefore, the definition, calculation and evaluation of such errors are important for supporting a trial's conclusions. A variety of medication dispensing errors can occur. In this paper, we focus on errors in trials where the intervention includes multiple therapies that must be given in a pre-specified order that varies across treatment arms and varies in duration. METHODS: The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial was a Phase III multi-site, randomized trial to compare the effectiveness and safety of 1:1:1 transfusion ratios of plasma and platelets to red blood cells with a 1:1:2 ratio. In this trial, these three types of blood products were to be transfused in a pre-defined order that differed by treatment arm. In this paper, we present approaches from the PROPPR trial that we used to define and calculate the occurrence of out of order blood transfusion errors. We applied the proposed method to calculate protocol adherence to the specified order of transfusion in each treatment arm. RESULTS: Using our proposed method, protocol adherence was greater in the 1:1:1 group than in the 1:1:2 group (96% vs 93%) (p<0.0001), although out of order transfusion errors in both groups were low. Final transfusion ratios of plasma to platelets to red blood cells for the 1:1:1 ratio group was 0.93:1.32:1, while the transfusion ratio for the 1:1:2 ratio group was 0.48:0.48:1. CONCLUSIONS: Overall, PROPPR adherence to blood transfusion order pre-specified in the protocol was high, and the required order of transfusions for the 1:1:2 group was more difficult to achieve. The approaches proposed in this manuscript were useful in evaluating the PROPPR adherence and are potentially useful for other trials where a specific treatment orders with varying durations must be maintained.

Ideal hemoglobin transfusion target for resuscitation of massive-transfusion patients.

BACKGROUND: Overtransfusion of packed red blood cells is known to increase the risk of death in stable patients. With the delineation of minimum transfusion ratios in hemorrhaging patients complete, attention must be turned to the other end of the massive transfusion spectrum-that of defining the maximum transfusion of packed red blood cells. We aimed to define the ideal hemoglobin range 24 hours after anatomic hemostasis associated with the lowest mortality. METHODS: Massive-transfusion patients (≥10 units packed red blood cells within 24 hours) were reviewed from 2010-2013. The hemoglobin 24 ± 6 hours after anatomic hemostasis was used to stratify patients into undertransfusion (<8.0 g/dL), hemoglobin transfusion target (8.0-11.9 g/dL), and overtransfusion (>12.0 g/dL) groups; patients not surviving to 24 hours were excluded. RESULTS: We identified 418 patients (351 [84%] in the hemoglobin transfusion target group, 38 [9%] in the undertransfusion group, and 29 [7%] in the overtransfusion group) with an overall mortality of 18%. Undertransfusion patients had the greatest risk of death (odds ratio 3.3; 95% confidence interval 1.6-6.7) followed by overtransfusion patients (odds ratio 2.5; 95% confidence interval 1.1-5.6). Though pretransfusion hemoglobin was similar (9.5 ± 2.2 g/dL vs 9.5 ± 2.3 g/dL), overtransfusion patients had greater hemoglobin values during massive transfusion (8.3 ± 3.0 g/dL vs 6.9 ± 1.4 g/dL), persisting until hospital dismissal/death (11.4 ± 2.3 g/dL vs 9.6 ± 1.1 g/dL). In total, 657.4 excess packed red blood cell units were transfused (1.9 ± 1.5 per patient). CONCLUSION: Overtransfusion patients had increased mortality, comparable to undertransfusion patients, despite younger age and fewer comorbidities. Shorter massive transfusion durations foster a scenario in which patients are at greater risk of overtransfusion.

Recurrent event frailty models reduced time-varying and other biases in evaluating transfusion protocols for traumatic hemorrhage.

OBJECTIVE: Transfusion research seeks to improve survival for severely injured and hemorrhaging patients using optimal plasma and platelet ratios over red blood cells (RBCs). However, most published studies comparing different ratios are plagued with serious bias and ignore time-varying effects. We applied joint recurrent event frailty models to increase validity and clinical utility. STUDY DESIGN AND SETTING: Using the PRospective Observational Multicenter Major Trauma Transfusion study data, our joint random-effects models estimated the association of (1) clinical covariates with transfusion rate intensities and (2) varying plasma:RBC and platelet:RBC ratios with survival over the 24 hours after hospital admission. Along with survival time, baseline patient vital signs, laboratory values, and longitudinal data on types and volumes of transfusions were included. RESULTS: Baseline systolic blood pressure, heart rate, pH, and hemoglobin were significantly associated with RBC transfusion rates. Increased transfusion rates (per hour) of plasma (P = 0.05), platelets (P < 0.001), or RBCs were associated with increased 24-hour mortality. Higher ratios of plasma:RBC (P = 0.107) and platelet:RBC (P < 0.001) were associated with reduced mortality in a time-varying pattern (P < 0.001). CONCLUSIONS: The proposed joint analysis of transfusion rates and ratios offers a more valid statistical approach to evaluate survival effects in the presence of informative censoring by early death.

Cardiovascular Disease Risk Factors in Hispanic Adolescents in South Texas.

OBJECTIVES: Despite a national crisis of increased prevalence of obesity and type 2 diabetes mellitus in adolescents, especially among Hispanics, there is a paucity of data on health indicators among farmworker adolescents and their peers. The main aim of this study was to estimate the prevalence of cardiovascular disease risk factors in a population of Hispanic adolescent students in south Texas. The study also aimed to compare the prevalence of these risk factors between students enrolled in the Migrant Education Program (MEP) and other students, and between boys and girls. METHODS: In partnership with the Weslaco (Texas) Independent School District and the Migrant Education Department, a cohort study was conducted from 2007 to 2010 to estimate the prevalence of overall obesity (body mass index ≥85th percentile for age and sex), abdominal obesity (waist circumference ≥75th percentile for age, sex, and ethnicity), acanthosis nigricans (AN), and high blood pressure (HBP; ≥90th percentile for age, height, and sex or systolic/diastolic BP ≥120/80 mm Hg) among MEP students compared with other students from two south Texas high schools. Multilevel logistic regression was used to assess the relation between sex and our main outcomes of interest while accounting for within-school nesting of participants. RESULTS: Among 628 sampled students, 508 (80.9%) completed the consent procedure and participated in the study. Of these, 257 were MEP students and 251 were non-MEP peers. Approximately 96.7% of participants were Hispanic and 50.0% were boys. Analyses of data across the years comparing MEP students and non-MEP students show an average prevalence of 44.8% versus 47.7% for overall obesity, 43.2% versus 43.7% for abdominal obesity, 24.7% versus 24.7% for AN, and 29.2% versus 32.8% for HBP. Across recruitment and follow-up years, the prevalence of overall obesity, abdominal obesity, and HBP was 1.3 to 1.5, 1.2 to 1.8, and 2.9 to 4.6 times higher in boys than in girls, respectively. In contrast, the prevalence of AN varied little by sex. CONCLUSIONS: The high prevalence of cardiovascular risk factors in both groups suggests a compelling need for comprehensive, culturally targeted interventions to prevent future cardiovascular diseases in these high-risk Hispanic adolescents, especially among boys. There were not, however, substantial differences between MEP students and other students. These findings also support the feasibility of conducting future epidemiologic studies among adolescent farmworkers and their families, as well as culturally appropriate school or community-based interventions.