Impact of fluids on coagulopathy in sepsis - sepsis is a deadly disease where a dysregulated host inflammatory response leads to inflammation, but also to acute coagulopathy

This $181,772 project grant from the National Heart, Lung and Blood Institute will support research into coagulopathy in sepsis patients. The grantee, Beth Israel Deaconess Medical Center, will conduct an ancillary study using viscoelastic monitoring to examine the effects of randomly assigned fluid resuscitation strategies on coagulation parameters in sepsis patients. Specifically, the study aims to: 1) analyze how liberal versus restrictive fluid administration impacts coagulation measurements over 24 hours; 2) determine if baseline and change in coagulation parameters predict organ dysfunction and mortality; and 3) explore the complex relationships between fluid administration, coagulopathy and outcomes. The research will leverage the infrastructure of the ongoing CRYSTALLOID Liberal or vasOpressors earLy resuscitation in Sepsis trial to randomly assign 2,320 sepsis patients to different fluid resuscitation protocols. Findings may help identify optimal treatment of sepsis-induced coagulopathy. The funding falls under the Cardiovascular Diseases Research program of the National Institutes of Health.

Patients with septic coagulopathy experience a pro-coagulant state, micro- thrombosis, and resultant microcirculatory dysfunction. This problem remains under-studied, in part because IT is difficult to detect and how to treat abnormalities and incorporate coagulopathy into decision- making remains unknown. Routine coagulation tests incompletely reflect coagulation status in vivo, and do not provide information about the contribution of platelets; other tests such as VON willebrand factor, thrombomodulin, and tissue plasminogen activator make physiologic sense and are previously reported, but current data are not compelling enough to make them routinely available by clinical labs. We aim to use viscoelastic monitoring (VCM), a bedside test of coagulation well studied and widely used in cardiac, liver, and trauma surgery, to examine coagulopathy in sepsis. To that end, we will perform an ancillary study to the ongoing crystalloid liberal or vasopressors early resuscitation in sepsis (clovers) trial, a 50-center prospective trial randomizing 2,320 patients with sepsis-induced hypotension to either a liberal fluids or restrictive fluid resuscitation protocol. The clovers study provides a unique and unparalleled infrastructure with randomly assigned treatment exposure (liberal VS restrictive fluid), offering an opportunity to examine the effect of randomly assigned fluid resuscitation strategies on the coagulation cascade in vivo in sepsis patients. We will use VCM to determine whether a randomly assigned fluid strategy influences coagulopathy in sepsis, whether degree of coagulopathy impacts outcomes, and what interactions exist between fluid administration, coagulopathy, and outcomes via the following aims: - aim 1: to study the effects of randomly assigned fluid resuscitation strategies (liberal versus restrictive) on coagulation parameters (VCM) in sepsis-induced hypotension. - aim 2: to determine if VCM parameters (baseline and change over the first 24 hours) are prognostic of organ dysfunction (sofa score) and mortality. - aim 3: to study the complex association between fluid administration, coagulopathy, and outcomes, and determine if differential treatment effects are present.