Combat: Initial Experience with a Randomized Clinical Trial of Plasma-Based Resuscitation in the Field for Traumatic Hemorrhagic Shock

Abstract

The existing evidence shows great promise for plasma as the first resuscitation fluid in both civilian and military trauma. We embarked on the Control of Major Bleeding After Trauma (COMBAT) trial with the support of the Department of Defense to determine if plasma-first resuscitation yields hemostatic and survival benefits. The methodology of the COMBAT study represents not only 3 years of development work but also the integration of nearly two decades of technical experience with the design and implementation of other clinical trials and studies. Herein, we describe the key features of the study design, critical personnel and infrastructural elements, and key innovations. We will also briefly outline the systems engineering challenges entailed by this study. The COMBAT trial is a randomized, placebo-controlled, semiblinded, prospective, phase IIB clinical trial conducted in a ground ambulance fleet based at a level I trauma center and part of a multicenter collaboration. The primary objective of the COMBAT trial is to determine the efficacy of field resuscitation with plasma first compared with standard of care (normal saline). To date, we have enrolled 30 subjects in the COMBAT study. The ability to achieve intervention with a hemostatic resuscitation agent in the closest possible temporal proximity to injury is critical and represents an opportunity to forestall the evolution of the "bloody vicious cycle." Thus, the COMBAT model for deploying plasma in first-response units should serve as a model for randomized clinical trials of other hemostatic resuscitative agents.

Trial registration: ClinicalTrials.gov NCT01838863.

Figures

Figure 1. COMBAT Biological Sampling Timeline

Samples are drawn at 11 time points, starting in the field, immediately before randomization and the administration of the initial resuscitative fluids (FP24 or normal saline). Subsequent samples are drawn at ED arrival and hours 2, 4, 6, 12, 24, 48 and days 5 and 7 after injury. The samples comprise a comprehensive battery of coagulation and other biochemical assays detailed in figure 2, and are typical for each time point with the exception of the field sample which lacks a lactate measurement (due to sample handling constraints) and the addition of a hepatic function panel at the 72 hour time point. At 28 days post-injury, mortality, complications, and other outcomes data are finalized.

Figure 2. COMBAT Biological Sample Processing Chart

This guide is carried by the COMBAT technical staff to aid in proper sample handling and allocation. Five sodium citrate (blue top), one lithium heparin (green), one EDTA, and one protease inhibitor vacuum tube are collected at each time point. One citrate and the EDTA tube are sent to the DHMC central clinical laboratory for a CBC and conventional coagulation tests. The protease inhibitor tube is immediately chilled and centrifuged to yield plasma. The remaining tubes are processed according to this chart. Whole blood undergoes a battery of 12 channels of viscoelastic hemostatic assays on the TEG® and ROTEM® platforms, including TEG® Platelet Mapping™ as well as ROTEM® platelet aggregometry. The remaining blood is immediately chilled, centrifuged to yield platelet free plasma and flash frozen in liquid nitrogen. These plasma samples are used for coagulation factor level tests (II, V, VII, X, and XIII), cytokine and chemokine panels, proteomics, metabolomics, and ELISAs for proteins of specific interest relevant to trauma induced coagulopathy, including tPA, PAI-1, syndecan and α-enolase. Aliquots are also contributed to the Trans Agency Research Consortium for Trauma-Induced Coagulopathy (TACTIC) collaboration.

Figure 3. Field Plasma System Schematic

FP24 is stored frozen at less than -18 °C in a high performance cooler (A) passively chilled with a phase change material. This cooler is unpacked at the time of randomization and if it contains FP24 (instead of a dummy payload for the control arm) these units are transferred to the Plasmatherm™ dry warm water bath system (B) where they are thawed in approximately 3 minutes. The Plasmatherm™ is powered by a self-contained electrical system that is charged by connection to conventional 110 VAC mains power via a shore power coupling (C) when the ambulance is parked. A power inverter/battery charger (D) both charges a lithium-ion storage battery (E), which supplies power to the system while the ambulance is in the field, and converts the battery's DC power output to AC to run the Plasmatherm™.

Figure 4. Systems and Subsystems of the COMBAT Study

This highly abbreviated systems tree for the COMBAT study is excerpted from the organizational documents used during development of the study. In this view, only the “Plasma Thawing and Administration” subsystem is broken out into third and fourth order detail as an example. If all the nested systems, subsystems and component descriptions were unpacked, the document would run to several hundred pages. Such organizational trees are essential to define and organize operational elements throughout the development of a study of this complexity, and also aid in the process of quality assurance and improvement.