Deborah J. del Junco

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.

The association between the quality of inpatient care and early readmission: a meta-analysis of the evidence.

OBJECTIVES To help resolve the current controversy over the validity of early readmission as an indicator of the quality of care, the authors critically reviewed the literature using meta-analysis to derive summary estimates of effect and evaluate inter-study heterogeneity. METHODS The authors selected reports meeting five criteria: (1) presentation of new data on medical-surgical hospitalization of adults; (2) measurement of outcome as a person-specific readmission; (3) readmission within < or = 31 days; (4) examination of some aspect of the process of inpatient care; (5) inclusion of a comparison group. One meta-analysis examined 13 comparisons of readmission rates after substandard versus normative care, another examined 9 comparisons of readmission rates after normative versus exceptional care, and the third examined all 22 comparisons together. Two authors applied inclusion criteria and extracted data on methods and findings. Two others classified studies on 11 methodological variables for the heterogeneity evaluation. RESULTS The summary odds ratio for readmission after substandard care was 1.24 (0.99-1.57) relative to normative care; for readmission after normative care the summary odds ratio was 1.45 (0.90-2.33) relative to exceptional care. The individual odds ratios varied significantly (chi2, 21 df = 50.34, P = 0.0003). Most of the variance in study odds ratios could be explained by whether the study focused on the quality of patient care or the qualifications of patient care providers. The summary odds ratio for the 16 homogeneous comparisons focusing on the quality of patient care was 1.55 (1.25-1.92). CONCLUSIONS Early readmission is significantly associated with the process of inpatient care. The risk of early readmission is increased by 55% when care is of relatively low quality, that is, substandard or normative instead of normative or exceptional.

Comparison of 2-Year Weight Loss Trends in Behavioral Treatments of Obesity: Diet, Exercise, and Combination Interventions

OBJECTIVE The effects of three cognitive-behavioral weight control interventions for adults were compared: diet only, exercise only, and a combination of diet and exercise. This article reports 2-year follow-up data. DESIGN The three interventions were compared in a randomized, experimental design. SUBJECTS A total of 127 men and women who were at least 14 kg overweight (according to height-weight tables) were recruited from an urban community and assigned randomly to the experimental conditions. INTERVENTION The dietary intervention was a low-energy eating plan adjusted to produce a 1 kg/week loss of weight. The exercise component involved training in walking and a home-based program of up to five exercise periods per week. There were 12 weekly instructional sessions, followed by 3 biweekly and 8 monthly meetings. All sessions were led by registered dietitians. OUTCOME MEASURES Changes in body weight. STATISTICAL ANALYSES Analysis of variance for weight changes and repeated measures analysis of variance for weight change trends. RESULTS At 1 year, no significant differences were noted among the three groups. The diet-only group lost 6.8 kg, the exercise-only group lost 2.9 kg, and the combination group lost 8.9 kg (P=.09). During the second year, the diet-only group regained weight--reaching 0.9 kg above baseline; the combination group regained to 2.2 kg below baseline; and the exercise-only group regained slightly to 2.7 kg below baseline (P=.36). Repeated measures analysis of variance showed a group-by-time interaction (P=.001); data for the dieting groups best fit a U-shaped regain curve (P=.001). APPLICATIONS The results suggest that dieting is associated with weight loss followed by regain after treatment ends, whereas exercise alone produced smaller weight losses but better maintenance. The large outcome variability and unequal difficulty of the regimens across groups limit the generalizability of the findings.

Clinical and mechanistic drivers of acute traumatic coagulopathy.

BACKGROUND Acute traumatic coagulopathy (ATC) occurs after severe injury and shock and is associated with increased bleeding, morbidity, and mortality. The effects of ATC and hemostatic resuscitation on outcome are not well-explored. The PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study provided a unique opportunity to characterize coagulation and the effects of resuscitation on ATC after severe trauma. METHODS Blood samples were collected upon arrival on a subset of PROMMTT patients. Plasma clotting factor levels were prospectively assayed for coagulation factors. These data were analyzed with comprehensive PROMMTT clinical data. RESULTS There were 1,198 patients with laboratory results, of whom 41.6% were coagulopathic. Using international normalized ratio of 1.3 or greater, 41.6% of patients (448) were coagulopathic, while 20.5% (214) were coagulopathic using partial thromboplastin time of 35 or greater. Coagulopathy was primarily associated with a combination of an Injury Severity Score (ISS) of greater than 15 and a base deficit (BD) of less than −6 (p < 0.05). Regression modeling for international normalized ratio–based coagulopathy shows that prehospital crystalloid (odds ratio [OR], 1.05), ISS (OR, 1.03), Glasgow Coma Scale (GCS) score (OR, 0.93), heart rate (OR, 1.08), systolic blood pressure (OR, 0.96), BD (OR, 0.92), and temperature (OR, 0.84) were significant predictors of coagulopathy (all p < 0.03). A subset of 165 patients had blood samples collected and coagulation factor analysis performed. Elevated ISS and BD were associated with elevation of aPC and depletion of factors (all p < 0.05). Reductions in factors I, II, V, VIII and an increase in aPC drive ATC (all p < 0.04). Similar results were found for partial thromboplastin time–defined coagulopathy. CONCLUSION ATC is associated with the depletion of factors I, II, V, VII, VIII, IX, and X and is driven by the activation of the protein C system. These data provide additional mechanistic understanding of the drivers of coagulation abnormalities after injury. Further understanding of the drivers of ATC and the effects of resuscitation can guide factor-guided resuscitation and correction of coagulopathy after injury. LEVEL OF EVIDENCE Epidemiologic/prognostic study, level IV.

Prehospital Transfusion of Plasma and Red Blood Cells in Trauma Patients.

Abstract Objective. Earlier use of plasma and red blood cells (RBCs) has been associated with improved survival in trauma patients with substantial hemorrhage. We hypothesized that prehospital transfusion (PHT) of thawed plasma and/or RBCs would result in improved patient coagulation status on admission and survival. Methods. Adult trauma patient records were reviewed for patient demographics, shock, coagulopathy, outcomes, and blood product utilization from September 2011 to April 2013. Patients arrived by either ground or two different helicopter companies. All patients transfused with blood products (either pre- or in-hospital) were included in the study. One helicopter system (LifeFlight, LF) had thawed plasma and RBCs while the other air (OA) and ground transport systems used only crystalloid resuscitation. Patients receiving PHT were compared with all other patients meeting entry criteria to the study cohort. All comparisons were adjusted in multilevel regression models. Results. A total of 8,536 adult trauma patients were admitted during the 20-month study period, of which 1,677 met inclusion criteria. They represented the most severely injured patients (ISS = 24 and mortality = 26%). There were 792 patients transported by ground, 716 by LF, and 169 on OA. Of the LF patients, 137 (19%) received prehospital transfusion. There were 942 units (244 RBCs and 698 plasma) placed on LF helicopters, with 1.9% wastage. PHT was associated with improved acid–base status on hospital admission, decreased use of blood products over 24 hours, a reduction in the risk of death in the sickest patients over the first 6 hours after admission, and negligible blood products wastage. In this small single-center pilot study, there were no differences in 24-hour (odds ratio 0.57, p = 0.117) or 30-day mortality (odds ratio 0.71, p = 0.441) between LF and OA. Conclusions. Prehospital plasma and RBC transfusion was associated with improved early outcomes, negligible blood products wastage, but not an overall survival advantage. Similar to the data published from the ongoing war, improved early outcomes are associated with placing blood products prehospital, allowing earlier infusion of life-saving products to critically injured patients.

Clinical and Genetic Factors Predictive of Mortality in Early Systemic Sclerosis

OBJECTIVE To investigate the clinical and genetic variables at initial presentation that predict survival in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort. METHODS GENISOS is a prospective, observational study of a multiethnic early systemic sclerosis (SSc) cohort. To date, a total of 250 patients have been enrolled. In addition to clinical and laboratory data, electrocardiograms (EKGs), chest radiographs, and pulmonary function tests have been obtained from each patient. A modified Rodnan skin thickness score, HLA class II genotyping, and a Medsger Damage Index also have been collected. We performed multivariable analyses utilizing the Cox regression following a purposeful model building strategy. RESULTS The study analyzed 122 white, 47 African American, and 71 Hispanic SSc patients with an average disease duration of 2.6 years at enrollment. At the time of analysis, 52 (20.8%) of the 250 patients had died. In the final multivariable model excluding HLA genes, 7 variables emerged as significant predictors of mortality: age > or =65 years at enrollment, forced vital capacity <50% predicted, clinically significant arrhythmia on EKG, absence of anticentromere antibodies, hypertension, chest radiograph suggestive of pulmonary fibrosis, and low body mass index (BMI). In separate modeling that included HLA genes, HLA alleles DRB1*0802 and DQA1*0501 were significant predictors of mortality in addition to the predictors mentioned above. CONCLUSION A limited number of variables collected at presentation, including BMI, are able to predict mortality in patients with early SSc. In addition, some of the HLA genes associated with SSc susceptibility are useful for predicting SSc outcome.

A randomized controlled pilot trial of modified whole blood versus component therapy in severely injured patients requiring large volume transfusions.

Objectives: To determine whether resuscitation of severely injured patients with modified whole blood (mWB) resulted in fewer overall transfusions compared with component (COMP) therapy. Background: For decades, whole blood (WB) was the primary product for resuscitating patients in hemorrhagic shock. After dramatic advances in blood banking in the 1970s, blood donor centers began supplying hospitals with individual components [red blood cell (RBC), plasma, platelets] and removed WB as an available product. However, no studies of efficacy or hemostatic potential in trauma patients were performed before doing so. Methods: Single-center, randomized trial of severely injured patients predicted to large transfusion volume. Pregnant patients, prisoners, those younger than 18 years or with more than 20% total body surface area burns (TBSA) burns were excluded. Patients were randomized to mWB (1 U mWB) or COMP therapy (1 U RBC+ 1 U plasma) immediately on arrival. Each group also received 1 U platelets (apheresis or prepooled random donor) for every 6 U of mWB or 6 U of RBC + 6 U plasma. The study was performed under the Exception From Informed Consent (Food and Drug Administration 21 code of federal regulations [CFR] 50.24). Primary outcome was 24-hour transfusion volumes. Results: A total of 107 patients were randomized (55 mWB, 52 COMP therapy) over 14 months. There were no differences in demographics, arrival vitals or laboratory values, injury severity, or mechanism. Transfusions were similar between groups (intent-to-treat analysis). However, when excluding patients with severe brain injury (sensitivity analysis), WB group received less 24-hour RBC (median 3 vs 6, P = 0.02), plasma (4 vs 6, P = 0.02), platelets (0 vs 3, P = 0.09), and total products (11 vs 16, P = 0.02). Conclusions: Compared with COMP therapy, WB did not reduce transfusion volumes in severely injured patients predicted to receive massive transfusion. However, in the sensitivity analysis (patients without severe brain injuries), use of mWB significantly reduced transfusion volumes, achieving the prespecified endpoint of this initial pilot study.

Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial: Design, rationale and implementation §

BACKGROUND Forty percent of in-hospital deaths among injured patients involve massive truncal haemorrhage. These deaths may be prevented with rapid haemorrhage control and improved resuscitation techniques. The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial was designed to determine if there is a difference in mortality between subjects who received different ratios of FDA approved blood products. This report describes the design and implementation of PROPPR. STUDY DESIGN PROPPR was designed as a randomized, two-group, Phase III trial conducted in subjects with the highest level of trauma activation and predicted to have a massive transfusion. Subjects at 12 North American level 1 trauma centres were randomized into one of two standard transfusion ratio interventions: 1:1:1 or 1:1:2, (plasma, platelets, and red blood cells). Clinical data and serial blood samples were collected under Exception from Informed Consent (EFIC) regulations. Co-primary mortality endpoints of 24h and 30 days were evaluated. RESULTS Between August 2012 and December 2013, 680 patients were randomized. The overall median time from admission to randomization was 26min. PROPPR enrolled at higher than expected rates with fewer than expected protocol deviations. CONCLUSION PROPPR is the largest randomized study to enrol severely bleeding patients. This study showed that rapidly enrolling and successfully providing randomized blood products to severely injured patients in an EFIC study is feasible. PROPPR was able to achieve these goals by utilizing a collaborative structure and developing successful procedures and design elements that can be part of future trauma studies.

An Emergency Department Thawed Plasma Protocol for Severely Injured Patients

IMPORTANCE In an effort to expedite delivery of plasma for patients requiring massive transfusions, US medical centers began keeping thawed plasma (TP) in their blood banks (BBs), markedly reducing time to release of plasma; however, the time to transfusion was still excessively long. OBJECTIVE To expedite delivery and transfusion of TP through implementation of an emergency department (ED) protocol. DESIGN AND SETTING Retrospective cohort study in an American College of Surgeons-verified level I trauma center. PARTICIPANTS Using the Trauma Registry of the American College of Surgeons database, we evaluated all adult trauma patients admitted from June 1, 2009, through August 31, 2010, who arrived directly from the scene, were the institutions highest level trauma activation, and received at least 1 U of red blood cells and 1 U of plasma in the first 6 hours after admission. The protocol was initiated in February 2010 by giving 4 U of AB plasma to patients in the ED. Patients were then divided into 2 groups: those admitted 8 months before (TP-BB) and 8 months after implementing TP location change (TP-ED). MAIN OUTCOME MEASURES Primary outcome was time to first unit of plasma. Secondary outcomes included 24-hour blood use and 24-hour and 30-day mortality. RESULTS A total of 294 patients met the study criteria (130 in the TP-BB group and 164 in the TP-ED). Although the patient demographics were similar, TP-ED patients had greater anatomical injury (median Injury Severity Score, 18 vs 25; P = .02) and more physiologic disturbances (median weighted Revised Trauma Score, 6.81 vs 3.83; P = .008). The TP-ED patients had a shorter time to first plasma transfusion (89 vs 43 minutes, P < .001). The TP-ED protocol was associated with a reduction in 24-hour transfusion of RBCs (P = .04), plasma (P = .04), and platelets (P < .001). Logistic regression identified TP-ED as an independent predictor of decreased 30-day mortality (odds ratio, 0.43; 95% CI, 0.194-0.956; P = .04). CONCLUSIONS We demonstrated that implementation of an ED-TP protocol expedites transfusion of plasma to severely injured patients. This approach is associated with a reduction in overall blood product use and a 60% decreased odds in 30-day mortality.

Do Oral Contraceptives Prevent Rheumatoid Arthritis

Two studies have suggested that the risk of rheumatoid arthritis in women using oral contraceptives is less than half that of nonusers. When a third study from the Mayo Clinic failed to confirm these findings, it was criticized for inclusion of ineligible subjects, misclassification of oral contraceptive use, and inadequate statistical power. Recent expansion of the Mayo Clinics data resources provided a unique opportunity to resolve the controversy, and a new population-based case-control study was undertaken. In comparison with the previous study, the new investigation had 2.2 times as many eligible cases and more complete ascertainment of oral contraceptive use via access to the records of Planned Parenthood of Minnesota. Comparing any prior use of oral contraceptives with never having used them, the relative risk of rheumatoid arthritis estimated from 182 cases and their 182 matched controls was 1.1 (95% confidence interval 0.7 to 1.7). The relative risk for current use was 1.3 (95% confidence interval, 0.7 to 2.4). The lack of a protective effect was independent of age, disease severity, and disease end point (date of confirmed diagnosis or symptom onset).