EMS World

OCT 2018

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16 OCTOBER 2018 | EMSWORLD.com W hen leaders and stakehold- ers use research to develop things like evidence-based guidelines, they must weigh that research's quality. What they evaluate is often called strength of evidence or level of evidence. When making recommenda- tions it is important to use the highest-level evidence available, and randomized trials are right at the top of the list. In randomized trials subjects are assigned by chance to an experiment or control group. Randomization helps reduce bias, which is when results are influenced by factors unre- lated to what's being tested. This month we review an interesting and important study funded by the U.S. Depart- ment of Defense. This study was part of the Control of Major Bleeding After Trauma trial, or COMBAT. COMBAT tested prehos- pital administration of plasma for control of major bleeding after injury. Its authors compared prehospital plasma administra- tion to the standard of care, administration of normal saline. This study was necessary because a 2016 review of the literature indicated a random- ized, controlled trial was needed. Previously the military reported increased survival when plasma was administered during the Iraq war from 2003–2005. This was followed by ret- rospective studies that showed increased survival with early plasma administration. However, some early clinical trials did not show any benefits to survival. Further, the authors indicated that prior to this study, the U.S. Food and Drug Administration was anticipated to approve lyophilized plasma, which prompted the Department of Defense to fund several randomized, controlled trials with the goal of producing robust evidence on early plasma resuscitation. COMBAT was a pragmatic, randomized, placebo-controlled, single-center trial. A pragmatic trial is one designed to evaluate the effectiveness of interventions in real- world, routine-practice conditions. The trial took place within the paramedic division of Denver Health Medical Center from April 1, 2014 to March 31, 2017. The outcome of interest was mortality within 28 days. The authors tested the hypothesis that mor- tality would be lower among patients who received plasma before arrival at a Level 1 trauma facility than among those who received standard care with normal saline. Consecutive hemorrhagic shock patients were randomized to receive either plasma or normal saline. Hemorrhagic shock was defined as systolic blood pressure less than or equal to 70 mm Hg or 71–90 mm Hg plus a heart rate of 108 bpm or more. Patients were excluded if they were less than 18 years old, were a prisoner, were pregnant, had an isolated gunshot wound to the head, were in asystole or had CPR performed before randomization, had a known objection to blood products, wore an opt-out bracelet or necklace, or if a family member objected to the patient's enrollment. Once paramed- ics determined a patient was eligible, they began plasma or normal saline adminis- tration based on the contents of assigned coolers. Coolers were randomized to contain either plasma or frozen water by research coordinators. If the cooler contained frozen water, normal saline was administered based on hemodynamic need. Sample Size Prior to beginning the study, the authors performed a sample size calculation to determine the number of patients needed to detect a meaningful difference between the experiment and control groups. That calculation indicated 150 patients needed to be enrolled in the study. During the study period there were 144 potentially eligible patients identified and randomized to a group. Of these, 75 were initially assigned to the plasma group, and 69 were initially assigned to the saline control group. However, 8 patients from the plasma group and 11 from the saline group met exclusion criteria. Recall the authors' sample size calculation required them to enroll 150 patients. There's an interesting reason why they didn't get there, which we'll return to shortly. The authors chose to perform two sta- tistical assessments. They performed an "as-treated" assessment that assessed patients based on whether they actually received plasma or normal saline. They also performed an "intent-to-treat" analy- sis. Intent-to-treat analyses are common in randomized trials. Essentially they analyze the subject based on the group to which they were assigned, whether or not they actually received plasma or normal saline. This is necessary in some trials due to noncompli- ance or missing data. This analysis generally gives a more conservative estimate of the treatment effect and helps researchers run statistical analyses without having to worry about protocol deviations, withdrawals, and anything else that could happen after randomization. For example, in this study two patients were randomized to receive plasma but instead received normal saline because the paramedics misidentified the contents of the cooler. So the intent-to-treat analysis included the 75 patients initially assigned to the plasma group and the 69 assigned to the saline control group, while the as-treated assessment removed those who met exclu- Did plasma's apparent benefi t hold up in a randomized, controlled trial? By Antonio R. Fernandez, PhD, NRP, FAHA THE TRIP REPORT: TURNING RESEARCH INTO PRACTICE Look for PCRF research podcasts based on the topics featured in this column at www.pcrfpodcast.org. REVIEWED THIS MONTH Plasma-First Resuscitation to Treat Haemorrhagic Shock During Emergency Ground Transportation in an Urban Area: A Randomised Trial. Authors: Moore HB, Moore EE, Chapman MP, et al. Published in: Lancet, 2018 Jul 28; 392(10,144): 283–91. Plasma vs. Saline for Hemorrhagic Shock

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