Jeffrey D. Kerby

Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma: The PROPPR Randomized Clinical Trial

IMPORTANCE Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. OBJECTIVE To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. DESIGN, SETTING, AND PARTICIPANTS Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. INTERVENTIONS Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). MAIN OUTCOMES AND MEASURES Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. RESULTS No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, -4.2% [95% CI, -9.6% to 1.1%]; P = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, -3.7% [95% CI, -10.2% to 2.7%]; P = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, -5.4% [95% CI, -10.4% to -0.5%]; P = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P < .001) and platelets (12 U vs 6 U, P < .001) and similar amounts of red blood cells (9 U) over the first 24 hours, no differences between the 2 groups were found for the 23 prespecified complications, including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications. CONCLUSIONS AND RELEVANCE Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01545232.

Cecal ligation and puncture.

The model of cecal ligation and puncture (CLP) in rodents has been used extensively to investigate the clinical settings of sepsis and septic shock. This model produces a hyperdynamic, hypermetabolic state that can lead to a hypodynamic, hypometabolic stage, and eventual death. Blood cultures are positive for enteric organisms very early after CLP. The model has been widely used over the past 26 years and is highly versatile in adapting to a range of severity and testing objectives. It is inexpensive to prepare and technically straightforward. Aspects of sepsis research investigated using CLP include energetics, metabolism, resuscitation, antibiotic therapy, microbial factors, cardiovascular responses, immune function, mediator release, and cytokine expression patterns. The challenge of the small circulating blood volume in rodents can be overcome by using micromethods that enable analysis of small volumes, or alternatively, by using a large number of animals to obtain serial samples.

The relationship of blood product ratio to mortality: survival benefit or survival bias?

BACKGROUND Recent studies show an apparent survival advantage associated with the administration of higher cumulative ratios of fresh frozen plasma (FFP) to packed red blood cells (PRBC). It remains unclear how temporal factors and survival bias may influence these results. The objective of this study was to evaluate the temporal relationship between blood product ratios and mortality in massively transfused trauma patients. METHODS Patients requiring massive transfusion (>10 units of PRBC within 24 hours of admission) between 2005 and 2007 were identified (n = 134). In-hospital mortality was compared between patients receiving high (>1:2) versus low (<1:2) FFP:PRBC ratios with a regression model, using the FFP:PRBC ratio as a fixed value at 24 hours (method I) and as a time-varying covariate (method II). RESULTS The FFP:PRBC ratio for all patients was low early and increased over time. Sixty-eight percent of total blood products were given and 54% of deaths occurred during the first 6 hours. Using method I, patients receiving a high FFP:PRBC ratio (mean, 1:1.3) by 24 hours had a 63% lower risk of death (RR, 0.37; 95% CI, 0.22-0.64) compared with those receiving a low ratio (mean, 1:3.7). However, this association was no longer statistically significant (RR, 0.84; 95% CI, 0.47-1.50) when the timing of component product transfusion was taken into account (method II). CONCLUSIONS Similar to previous studies, an association between higher FFP:PRBC ratios at 24 hours and improved survival was observed. However, after adjustment for survival bias in the analysis, the association was no longer statistically significant. Prospective trials are necessary to evaluate whether hemostatic resuscitation is clinically beneficial.

Out-of-Hospital Hypertonic Resuscitation Following Severe Traumatic Brain Injury: A Randomized Controlled Trial

CONTEXT Hypertonic fluids restore cerebral perfusion with reduced cerebral edema and modulate inflammatory response to reduce subsequent neuronal injury and thus have potential benefit in resuscitation of patients with traumatic brain injury (TBI). OBJECTIVE To determine whether out-of-hospital administration of hypertonic fluids improves neurologic outcome following severe TBI. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, randomized, placebo-controlled clinical trial involving 114 North American emergency medical services agencies within the Resuscitation Outcomes Consortium, conducted between May 2006 and May 2009 among patients 15 years or older with blunt trauma and a prehospital Glasgow Coma Scale score of 8 or less who did not meet criteria for hypovolemic shock. Planned enrollment was 2122 patients. INTERVENTION A single 250-mL bolus of 7.5% saline/6% dextran 70 (hypertonic saline/dextran), 7.5% saline (hypertonic saline), or 0.9% saline (normal saline) initiated in the out-of-hospital setting. MAIN OUTCOME MEASURE Six-month neurologic outcome based on the Extended Glasgow Outcome Scale (GOSE) (dichotomized as >4 or ≤4). RESULTS The study was terminated by the data and safety monitoring board after randomization of 1331 patients, having met prespecified futility criteria. Among the 1282 patients enrolled, 6-month outcomes data were available for 1087 (85%). Baseline characteristics of the groups were equivalent. There was no difference in 6-month neurologic outcome among groups with regard to proportions of patients with severe TBI (GOSE ≤4) (hypertonic saline/dextran vs normal saline: 53.7% vs 51.5%; difference, 2.2% [95% CI, -4.5% to 9.0%]; hypertonic saline vs normal saline: 54.3% vs 51.5%; difference, 2.9% [95% CI, -4.0% to 9.7%]; P = .67). There were no statistically significant differences in distribution of GOSE category or Disability Rating Score by treatment group. Survival at 28 days was 74.3% with hypertonic saline/dextran, 75.7% with hypertonic saline, and 75.1% with normal saline (P = .88). CONCLUSION Among patients with severe TBI not in hypovolemic shock, initial resuscitation with either hypertonic saline or hypertonic saline/dextran, compared with normal saline, did not result in superior 6-month neurologic outcome or survival. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00316004.

Transfusions in the less severely injured: does age of transfused blood affect outcomes?

BACKGROUND Prior studies have demonstrated that transfusion of older stored blood is associated with an increased risk of multiple organ failure, infection, and death. These reports were primarily comprised of severely injured patients, and it remains unknown whether this phenomenon is observed in relatively less injured patients. The purpose of this study was to evaluate the association between the age of stored blood and the morbidity and mortality in a mild to moderately injured patient cohort. METHODS Blunt trauma patients with Injury Severity Score <25 admitted to a Trauma Intensive Care Unit during 7.5 years who received no blood during the first 48 hours of hospitalization were selected for inclusion. Patients who died within 48 hours of admission were excluded from analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the association between morbidity or mortality and the age and amount of blood transfused (>48 hours postadmission), adjusted for age, sex, injury severity, thoracic injury, mechanical ventilation, and transfusion volume. RESULTS During 7.5 years, 1,624 patients met the study criteria. The mean Injury Severity Score was 14.4. Receipt of blood stored beyond 2 weeks was associated with mortality (OR 1.12 [CI 1.02-1.23]), renal failure (OR 1.18 [CI 1.07-1.29]), and pneumonia (OR 1.10 [CI 1.04-1.17]). No such associations were identified, however, concerning the transfusion of blood with a lesser storage age. CONCLUSION In a mild to moderately injured intensive care unit patient cohort, the receipt of blood stored beyond 2 weeks was independently associated with mortality, renal failure, and pneumonia. The deleterious effect of older blood on patient outcome does not appear to be limited to the severely injured.

Identifying risk for massive transfusion in the relatively normotensive patient: utility of the prehospital shock index.

BACKGROUND In the prehospital environment, the failure of medical providers to recognize latent physiologic derangement in patients with compensated shock may risk undertriage. We hypothesized that the shock index (SI; heart rate divided by systolic blood pressure [SBP]), when used in the prehospital setting, could facilitate the identification of such patients. The objective of this study was to assess the association between the prehospital SI and the risk of massive transfusion (MT) in relatively normotensive blunt trauma patients. METHODS Admissions to a Level I trauma center between January 2000 and October 2008 with blunt mechanism of injury and prehospital SBP>90 mm Hg were identified. Patients were categorized by SI, calculated for each patient from prehospital vital signs. Risk ratios (RRs) and 95% confidence intervals (CI) for requiring MT (>10 red blood cell units within 24 hours of admission) were calculated using SI>0.5 to 0.7 (normal range) as the referent for all comparisons. RESULTS A total of 8,111 patients were identified, of whom 276 (3.4%) received MT. Compared with patients with normal SI, there was no significant increased risk for MT for patients with a SI of ≤0.5 (RR, 1.41; 95% CI, 0.90-2.21) or>0.7 to 0.9 (RR, 1.06; 95% CI, 0.77-1.45). However, a significantly increased risk for MT was observed for patients with SI>0.9. Specifically, patients with SI>0.9 to 1.1 were observed to have a 1.5-fold increased risk for MT (RR, 1.61; 95% CI, 1.13-2.31). Further increases in SI were associated with incrementally higher risks for MT, with an more than fivefold increase in patients with SI>1.1 to 1.3 (RR, 5.57; 95% CI, 3.74-8.30) and an eightfold risk in patients with SI>1.3 (RR, 8.13; 95% CI, 4.60-14.36). CONCLUSION Prehospital SI>0.9 identifies patients at risk for MT who would otherwise be considered relatively normotensive under current prehospital triage protocols. The risk for MT rises substantially with elevation of SI above this level. Further evaluation of SI in the context of trauma system triage protocols is warranted to analyze whether it triage precision might be augmented among blunt trauma patients with SBP>90 mm Hg.

Gender differences in acute response to trauma-hemorrhage.

To understand the pathogenesis of a disease, experimental models are needed. A good experimental model is the one that simulates responses observed in the clinical setting. In recent years, clinical studies have indicated that gender might be a factor that plays a significant role in the outcome of patients with shock, trauma, and sepsis. These observations are now being evaluated in experimental setting. Studies performed in a rodent model of trauma-hemorrhage have concluded that alterations in immune and cardiac functions after trauma-hemorrhage are more markedly depressed in adult males, and ovariectomized and aged females. However, both are maintained in castrated males and in proestrus females. Moreover, the survival rate of proestrus females subjected to sepsis after trauma-hemorrhage is significantly higher than age-matched males or ovariectomized females. Although these observations suggest gender-specific response after trauma-hemorrhage, the mechanisms responsible for gender specificity remain largely unknown. Furthermore, in other injuries such as burn, experimental studies dealing with sexual dimorphism are limited. Therefore, more studies in clinical and experimental settings are required to determine whether gender-specific responses are global across the injuries or are observed in specific injury situations. Studies are also needed to delineate underlying mechanisms responsible for differences between males and females after trauma-hemorrhage. The information gained from the experimental studies will help in designing innovative therapeutic approaches for the treatment of trauma patients.

Lactate Is a Better Predictor than Systolic Blood Pressure for Determining Blood Requirement and Mortality: Could Prehospital Measures Improve Trauma Triage?

BACKGROUND Standard hemodynamic evaluation of patients in shock may underestimate severity of hemorrhage given physiologic compensation. Blood lactate (BL) is an important adjunct in characterizing shock, and point-of-care devices are currently available for use in the prehospital (PH) setting. The objective of this study was to determine if BL levels have better predictive value when compared with systolic blood pressure (SBP) for identifying patients with an elevated risk of significant transfusion and mortality in a hemodynamically indeterminant cohort. STUDY DESIGN We selected trauma patients admitted to a level I trauma center over a 9-year period with SBP between 90 and 110 mmHg. The predictive capability of initial emergency department (ED) BL for needing > or =6 units packed RBCs within 24 hours postinjury and mortality was compared with PH-SBP and ED-SBP by comparing estimated area under the receiver operator curve (AUC). RESULTS We identified 2,413 patients with ED-SBP and 787 patients with PH-SBP and ED-BL. ED-BL was statistically better than PH-SBP (p = 0.0025) and ED-SBP (p < 0.0001) in predicting patients who will need > or = 6 U packed RBCs within 24 hours postinjury (AUC: ED-BL, 0.72 vs PH-SBP, 0.61; ED-BL, 0.76 vs ED-SBP, 0.60). ED-BL was also a better predictor than both PH-SBP (p = 0.0235) and ED-SBP (p < 0.0001) for mortality (AUC: ED-BL, 0.74 vs PH-SBP, 0.60; ED-BL, 0.76 vs ED-SBP, 0.61). CONCLUSIONS ED-BL is a better predictor than SBP in identifying patients requiring significant transfusion and mortality in this cohort with indeterminant SBP. These findings suggest that point-of-care BL measurements could improve trauma triage and better identify patients for enrollment in interventional trials. Further studies using BL measurement in the PH environment are warranted.

Duration of red cell storage influences mortality after trauma.

BACKGROUND Although previous studies have identified an association between the transfusion of relatively older red blood cells (RBCs) (storage ≥ 14 days) and adverse outcomes, they are difficult to interpret because the majority of patients received a combination of old and fresh RBC units. To overcome this limitation, we compared in-hospital mortality among patients who received exclusively old versus fresh RBC units during the first 24 hours of hospitalization. METHODS Patients admitted to a Level I trauma center between January 2000 and May 2009 who received ≥ 1 unit of exclusively old (≥ 14 days) vs. fresh (< 14 days) RBCs during the first 24 hours of hospitalization were identified. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for the association between mortality and RBC age, adjusted for patient age, Injury Severity Score, gender, receipt of fresh frozen plasma or platelets, RBC volume, brain injury, and injury mechanism (blunt or penetrating). RESULTS One thousand six hundred forty-seven patients met the study inclusion criteria. Among patients who were transfused 1 or 2 RBC units, no difference in mortality with respect to RBC age was identified (adjusted RR, 0.97; 95% CI, 0.72-1.32). Among patients who were transfused 3 or more RBC units, receipt of old versus fresh RBCs was associated with a significantly increased risk of mortality, with an adjusted RR of 1.57 (95% CI, 1.14-2.15). No difference was observed concerning the mean number of old versus fresh units transfused to patients who received 3 or more units (6.05 vs. 5.47, respectively; p = 0.11). CONCLUSION In trauma patients undergoing transfusion of 3 or more RBC units within 24 hour of hospital arrival, receipt of relatively older blood was associated with a significantly increased mortality risk. Reservation of relatively fresh RBC units for the acutely injured may be advisable.

Sex differences in mortality after burn injury: Results of analysis of the National Burn Repository of the American Burn Association

Clinical and experimental studies have shown a decreased mortality for women after nonthermal injury. However, recently published data from this institution showed an increased mortality for female patients younger than 60 years of age with thermal injury. This study extended these observations to evaluate outcomes related to sex in thermal injury in a larger population of patients. The National Burn Repository (NBR) was used for this analysis. Patients admitted to burn centers between 1991 and 2001 were selected for inclusion (n = 49,079). Sex differences in demographic, injury, clinical, and outcome characteristics were compared. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the association between mortality and sex, both overall and stratified by age. In total, 34,470 men and 14,609 women were included in this study. Women had a 50% increased risk of death when compared with men (OR 1.5; 95% CI 1.3–1.6), which diminished slightly when adjustments were made for age, race, TBSA burn, and inhalation injury (OR 1.3; 95% CI 1.2–1.5). When stratified by age, women had an increased risk of death for all age groups between 10 and 70 years. This study confirmed earlier studies showing an association between sex and burn mortality. Further prospective studies analyzing differences in immune responses between men and women after burn injury may provide insight into the mechanism behind these divergent outcomes and identify targets for future therapy.