Brian G. Leroux

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.

Maximum-likelihood estimation for hidden Markov models

Hidden Markov models assume a sequence of random variables to be conditionally independent given a sequence of state variables which forms a Markov chain. Maximum-likelihood estimation for these models can be performed using the EM algorithm. In this paper the consistency of a sequence of maximum-likelihood estimators is proved. Also, the conclusion of the Shannon-McMillan-Breiman theorem on entropy convergence is established for hidden Markov models.

Early versus Later Rhythm Analysis in Patients with Out-of-Hospital Cardiac Arrest

BACKGROUND In a departure from the previous strategy of immediate defibrillation, the 2005 resuscitation guidelines from the American Heart Association-International Liaison Committee on Resuscitation suggested that emergency medical service (EMS) personnel could provide 2 minutes of cardiopulmonary resuscitation (CPR) before the first analysis of cardiac rhythm. We compared the strategy of a brief period of CPR with early analysis of rhythm with the strategy of a longer period of CPR with delayed analysis of rhythm. METHODS We conducted a cluster-randomized trial involving adults with out-of-hospital cardiac arrest at 10 Resuscitation Outcomes Consortium sites in the United States and Canada. Patients in the early-analysis group were assigned to receive 30 to 60 seconds of EMS-administered CPR and those in the later-analysis group were assigned to receive 180 seconds of CPR, before the initial electrocardiographic analysis. The primary outcome was survival to hospital discharge with satisfactory functional status (a modified Rankin scale score of ≤3, on a scale of 0 to 6, with higher scores indicating greater disability). RESULTS We included 9933 patients, of whom 5290 were assigned to early analysis of cardiac rhythm and 4643 to later analysis. A total of 273 patients (5.9%) in the later-analysis group and 310 patients (5.9%) in the early-analysis group met the criteria for the primary outcome, with a cluster-adjusted difference of -0.2 percentage points (95% confidence interval, -1.1 to 0.7; P=0.59). Analyses of the data with adjustment for confounding factors, as well as subgroup analyses, also showed no survival benefit for either study group. CONCLUSIONS Among patients who had an out-of-hospital cardiac arrest, we found no difference in the outcomes with a brief period, as compared with a longer period, of EMS-administered CPR before the first analysis of cardiac rhythm. (Funded by the National Heart, Lung, and Blood Institute and others; ROC PRIMED ClinicalTrials.gov number, NCT00394706.).

Estimation of Disease Rates in Small Areas: A new Mixed Model for Spatial Dependence

In this paper, a new model is proposed for spatial dependence that includes separate parameters for overdispersion and the strength of spatial dependence. The new dependence structure is incorporated into a generalized linear mixed model useful for the estimation of disease incidence rates in small geographic regions. The mixed model allows for log-linear covariate adjustment and local smoothing of rates through estimation of the spatially correlated random effects. Computer simulation studies compare the new model with the following sub-models: intrinsic autoregression, an independence model, and a model with no random effects. The major finding was that regression coefficient estimates based on fitting intrinsic autoregression to independent data can have very low precision compared with estimates based on the full model. Additional simulation studies demonstrate that penalized quasi-likelihood (PQL) estimation generally performs very well although the estimates are slightly biased for very small counts.

Maximum-Penalized-Likelihood Estimation for Independent and Markov-Dependent Mixture Models

This paper concerns the use and implementation of maximum-penalized-likelihood procedures for choosing the number of mixing components and estimating the parameters in independent and Markov-dependent mixture models. Computation of the estimates is achieved via algorithms for the automatic generation of starting values for the EM algorithm. Computation of the information matrix is also discussed. Poisson mixture models are applied to a sequence of counts of movements by a fetal lamb in utero obtained by ultrasound. The resulting estimates are seen to provide plausible mechanisms for the physiological process.

A Trial of an Impedance Threshold Device in Out-of-Hospital Cardiac Arrest

BACKGROUND The impedance threshold device (ITD) is designed to enhance venous return and cardiac output during cardiopulmonary resuscitation (CPR) by increasing the degree of negative intrathoracic pressure. Previous studies have suggested that the use of an ITD during CPR may improve survival rates after cardiac arrest. METHODS We compared the use of an active ITD with that of a sham ITD in patients with out-of-hospital cardiac arrest who underwent standard CPR at 10 sites in the United States and Canada. Patients, investigators, study coordinators, and all care providers were unaware of the treatment assignments. The primary outcome was survival to hospital discharge with satisfactory function (i.e., a score of ≤3 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating greater disability). RESULTS Of 8718 patients included in the analysis, 4345 were randomly assigned to treatment with a sham ITD and 4373 to treatment with an active device. A total of 260 patients (6.0%) in the sham-ITD group and 254 patients (5.8%) in the active-ITD group met the primary outcome (risk difference adjusted for sequential monitoring, -0.1 percentage points; 95% confidence interval, -1.1 to 0.8; P=0.71). There were also no significant differences in the secondary outcomes, including rates of return of spontaneous circulation on arrival at the emergency department, survival to hospital admission, and survival to hospital discharge. CONCLUSIONS Use of the ITD did not significantly improve survival with satisfactory function among patients with out-of-hospital cardiac arrest receiving standard CPR. (Funded by the National Heart, Lung, and Blood Institute and others; ROC PRIMED ClinicalTrials.gov number, NCT00394706.).

Identification of Body Fat Mass as a Major Determinant of Metabolic Rate in Mice

OBJECTIVE Analysis of energy expenditure (EE) in mice is essential to obesity research. Since EE varies with body mass, comparisons between lean and obese mice are confounded unless EE is normalized to account for body mass differences. We 1) assessed the validity of ratio-based EE normalization involving division of EE by either total body mass (TBM) or lean body mass (LBM), 2) compared the independent contributions of LBM and fat mass (FM) to EE, and 3) investigated whether leptin contributes to the link between FM and EE. RESEARCH DESIGN AND METHODS We used regression modeling of calorimetry and body composition data in 137 mice to estimate the independent contributions of LBM and FM to EE. Subcutaneous administration of leptin or vehicle to 28 obese ob/ob mice and 32 fasting wild-type mice was used to determine if FM affects EE via a leptin-dependent mechanism. RESULTS Division of EE by either TBM or LBM is confounded by body mass variation. The contribution of FM to EE is comparable to that of LBM in normal mice (expressed per gram of tissue) but is absent in leptin-deficient ob/ob mice. When leptin is administered at physiological doses, the plasma leptin concentration supplants FM as an independent determinant of EE in both ob/ob mice and normal mice rendered leptin-deficient by fasting. CONCLUSIONS The contribution of FM to EE is substantially greater than predicted from the metabolic cost of adipose tissue per se, and the mechanism underlying this effect is leptin dependent. Regression-based approaches that account for variation in both FM and LBM are recommended for normalization of EE in mice.

Trial of Continuous or Interrupted Chest Compressions during CPR

BACKGROUND During cardiopulmonary resuscitation (CPR) in patients with out-of-hospital cardiac arrest, the interruption of manual chest compressions for rescue breathing reduces blood flow and possibly survival. We assessed whether outcomes after continuous compressions with positive-pressure ventilation differed from those after compressions that were interrupted for ventilations at a ratio of 30 compressions to two ventilations. METHODS This cluster-randomized trial with crossover included 114 emergency medical service (EMS) agencies. Adults with non-trauma-related cardiac arrest who were treated by EMS providers received continuous chest compressions (intervention group) or interrupted chest compressions (control group). The primary outcome was the rate of survival to hospital discharge. Secondary outcomes included the modified Rankin scale score (on a scale from 0 to 6, with a score of ≤3 indicating favorable neurologic function). CPR process was measured to assess compliance. RESULTS Of 23,711 patients included in the primary analysis, 12,653 were assigned to the intervention group and 11,058 to the control group. A total of 1129 of 12,613 patients with available data (9.0%) in the intervention group and 1072 of 11,035 with available data (9.7%) in the control group survived until discharge (difference, -0.7 percentage points; 95% confidence interval [CI], -1.5 to 0.1; P=0.07); 7.0% of the patients in the intervention group and 7.7% of those in the control group survived with favorable neurologic function at discharge (difference, -0.6 percentage points; 95% CI, -1.4 to 0.1, P=0.09). Hospital-free survival was significantly shorter in the intervention group than in the control group (mean difference, -0.2 days; 95% CI, -0.3 to -0.1; P=0.004). CONCLUSIONS In patients with out-of-hospital cardiac arrest, continuous chest compressions during CPR performed by EMS providers did not result in significantly higher rates of survival or favorable neurologic function than did interrupted chest compressions. (Funded by the National Heart, Lung, and Blood Institute and others; ROC CCC ClinicalTrials.gov number, NCT01372748.).

Efficiency of regression estimates for clustered data.

Statistical methods for clustered data, such as generalized estimating equations (GEE) and generalized least squares (GLS), require selecting a correlation or convariance structure to specify the dependence between observations within a cluster. Valid regression estimates can be obtained that do not depend on correct specification of the true correlation, but inappropriate specifications can result in a loss of efficiency. We derive general expressions for the asymptotic relative efficiency of GEE and GLS estimators under nested correlation structures. Efficiency is shown to depend on the covariate distribution, the cluster sizes, the response variable correlation, and the regression parameters. The results demonstrate that efficiency is quite sensitive to the between- and within-cluster variation of the covariates, and provide useful characterizations of models for which upper and lower efficiency bounds are attained. Efficiency losses for simple working correlation matrices, such as independence, can be large even for small to moderate correlations and cluster sizes.

Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest

BACKGROUND Antiarrhythmic drugs are used commonly in out-of-hospital cardiac arrest for shock-refractory ventricular fibrillation or pulseless ventricular tachycardia, but without proven survival benefit. METHODS In this randomized, double-blind trial, we compared parenteral amiodarone, lidocaine, and saline placebo, along with standard care, in adults who had nontraumatic out-of-hospital cardiac arrest, shock-refractory ventricular fibrillation or pulseless ventricular tachycardia after at least one shock, and vascular access. Paramedics enrolled patients at 10 North American sites. The primary outcome was survival to hospital discharge; the secondary outcome was favorable neurologic function at discharge. The per-protocol (primary analysis) population included all randomly assigned participants who met eligibility criteria and received any dose of a trial drug and whose initial cardiac-arrest rhythm of ventricular fibrillation or pulseless ventricular tachycardia was refractory to shock. RESULTS In the per-protocol population, 3026 patients were randomly assigned to amiodarone (974), lidocaine (993), or placebo (1059); of those, 24.4%, 23.7%, and 21.0%, respectively, survived to hospital discharge. The difference in survival rate for amiodarone versus placebo was 3.2 percentage points (95% confidence interval [CI], -0.4 to 7.0; P=0.08); for lidocaine versus placebo, 2.6 percentage points (95% CI, -1.0 to 6.3; P=0.16); and for amiodarone versus lidocaine, 0.7 percentage points (95% CI, -3.2 to 4.7; P=0.70). Neurologic outcome at discharge was similar in the three groups. There was heterogeneity of treatment effect with respect to whether the arrest was witnessed (P=0.05); active drugs were associated with a survival rate that was significantly higher than the rate with placebo among patients with bystander-witnessed arrest but not among those with unwitnessed arrest. More amiodarone recipients required temporary cardiac pacing than did recipients of lidocaine or placebo. CONCLUSIONS Overall, neither amiodarone nor lidocaine resulted in a significantly higher rate of survival or favorable neurologic outcome than the rate with placebo among patients with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT01401647.).