Out-of-hospital cardiac arrest (OHCA) occurs in more than 200,000 patients in the United States each year with an estimated mortality of greater than 90%. Guidelines from the American Heart Association (AHA) emphasize not only the importance of optimizing intra-arrest treatment, but also the management of patients during the post-arrest period. Until recently, neuromuscular blockade (NMB) was considered potentially detrimental in the critically ill, with several older case series suggesting an association with th development of muscle weakness. These concerns lead to the current AHA recommendation to limit NMB use. However, recent data from a randomized trial in acute respiratory distress syndrome (ARDS) challenged this paradigm. In this trial, patients with ARDS had improved survival when randomized to NMB therapy versus usual care. We examined NMB in a multicenter observational investigation of adult out-of-hospital cardiac arrest patients and found that patients who received early, sustained NMB had improved survival as well as a more rapid decrease in lactate compared to patients who did not receive NMB. NMB may improve outcome through a number of mechanisms including the reduction of global oxygen consumption, prevention of patient-ventilator dyssynchrony, reduction of metabolic demand, reduction of inflammation, or other unidentified pathways. Given this, we hypothesize that provision of NMB to post-CA patients will result in improved mortality. We believe the first step in the evaluation f this hypothesis is a pilot randomized trial to determine the feasibility of this intervention, explre potential mechanisms and obtain the necessary data with which to design a Phase III investigation evaluating the effect on mortality. Thus, we are performing a Phase II, multicenter, randomized trial to determine if NMB decreases lactate levels in post-CA patients. This trial (funded by the American Heart Association) forms the parent study of the current grant proposal which has the dual Aim of advancing the science of resuscitation and the pool of junior investigators entering and advancing in the field of resuscitation science. To that end, we propose three additional scientific Aims, two of which will characterize the oxygen consumption and inflammatory response between patients in the NMB arm versus placebo.
Our final Aim will include a survey and large data registry query which will evaluate both the usage patterns of NMB throughout the United States as well as the potential duration-related differences in NMB usage and their association with mortality. These additional scientific Aims will support the education/mentoring objective of the project which is to increase the quality and quantity of investigators in the field of resuscitation science. To that end, this grant will support an established mentor (Dr. Michael Donnino) as he continues to provide mentoring and structure for junior investigators in a large translational research group dedicated to resuscitation science (Center of Resuscitation Science at Beth Israel Deaconess Medical Center). The breadth of experiments in the scientific portion of this proposal (clinical trial [along with clinical sub-stuy involving global oxygen consumption], patient-related laboratory-based work [blood biomarkers and measurement of cellular oxygen consumption], creation and distribution of a survey, and a large data registry query) along with ongoing work by the group will provide the background for a comprehensive training program aimed at increasing the knowledge and expertise of junior investigators. The Center for Resuscitation Science has multiple ongoing clinical trials and observational studies thus providing excellent infrastructure for supporting the next generation of resuscitation investigators. This current proposal will bolster the resources in order to provid the necessary protected time and project support to execute an outstanding scientific and resuscitation research training program.
Cardiac arrest is associated with upwards of 350,000 deaths each year though there are limited interventions available apart from supportive care, and there are relatively few investigators in the field of resuscitation compared to other major illnesses. This application will support a sub-study of a randomized clinical trial evaluating the use of neuromuscular blocking agents after cardiac arrest. The current proposal will leverage this clinical trial (and sub-studies) to support an established investigator's mentoring program for a wide range of junior investigators in resuscitation science.
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