INR-Triggered Transfusion In GI Bleeders From ER (I-TRIGER)
|Respiratory Distress Syndrome, Adult Gastrointestinal Hemorrhage Liver Diseases Transfusion Related Lung Injury||Other: Transfuse plasma to High INR target Other: Transfuse plasma to Low INR target||Phase 3|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Outcomes Assessor
Primary Purpose: Prevention
|Official Title:||Transfusion-related Acute Lung Injury in Patients With Liver Disease|
- Mean change in PaO2/fraction of inspired oxygen (FiO2) ratio [ Time Frame: Enrollment to 6 hours after the cessation of the transfusion protocol (54 hours) ]The development of hypoxemia will not distinguish between hydrostatic edema and TRALI, but investigators believe a significant change in oxygenation is clinically relevant and a more sensitive outcome variable for all transfusion-related pulmonary complications and therefore appropriate for use in this clinical trial.
- Bleeding complication (y/n) [ Time Frame: 120 hour from admission ]Baveno V consensus conference definition for failure to control bleeding
- Transfusion-related acute lung injury [ Time Frame: enrollment to 54 hours post-enrollment ]The development of consensus definition ALI within 6 hours of a transfused blood component.
- 28 day and ICU Mortality [ Time Frame: enrollment to 28 days ]Mortality in ICU (y/n); Mortality at 28 days post enrollment (y/n)
- ICU and Hospital length of Stay [ Time Frame: days ]We will measure number of days subjects are alive and in the ICU or hospital
- Change in oxygen saturation (SPO2)/FiO2 ratio (∆S/F) before and after transfusion [ Time Frame: enrollment to 54 hours post enrollment ]The mean ∆S/F ratio immediately before and 60 minutes after transfusion of plasma vs. (RBCs or platelets) will allow investigators to analyze changes in oxygenation over time to further delineate which blood components are most temporarily associated with pulmonary edema.
- Ventilator-free days [ Time Frame: enrollment to 28 days ]Investigators will determine how many days a patient is alive and off mechanical ventilation at day 28 from enrollment.
|Study Start Date:||July 2011|
|Study Completion Date:||August 2015|
|Primary Completion Date:||August 2015 (Final data collection date for primary outcome measure)|
Experimental: High INR
Transfuse plasma to High INR target. Plasma will be transfused to reach a target INR=2.5 for 48 hours while patient is actively bleeding.
Other: Transfuse plasma to High INR target
Using a dosing algorithm we will bolus plasma to reach an INR target (2.5) while patient is actively bleeding or 48 hours whichever comes first
Active Comparator: Low INR
Transfuse plasma to Low INR target. Plasma will be transfused to reach a target INR=1.8 for 48 hours while patient is actively bleeding.
Other: Transfuse plasma to Low INR target
Using a dosing algorithm we will bolus plasma to reach an INR target (1.8) while patient is actively bleeding or 48 hours whichever comes first
Advances in the understanding of the coagulation imbalance in liver disease have experts questioning the clinical efficacy of current plasma transfusion practices in patients with liver disease. Having recently discovered a large previously unrecognized risk (TRALI) of plasma transfusion in this patient population, the investigators now believe the current clinical transfusion paradigm under-recognizes risk and overvalues the benefit of plasma transfusion in bleeding patients with liver disease. Though experts have recommended more judicious use of plasma, clinical practice remains variable. Transfusion triggers and thresholds are often arbitrarily set based on conventional coagulation studies and evidence to guide clinicians on plasma dosing required to achieve these laboratory thresholds does not exist. The investigators hypothesize that a restrictive plasma transfusion strategy in critically ill chronic liver disease patients with acute gastrointestinal bleeding will decrease a surrogate measure of TRALI without increasing bleeding complications (figure 1). With the collaborative support of the pulmonary/critical care, hepatology, and transfusion medicine services, the investigators will conduct a randomized controlled trial comparing a restrictive versus liberal strategy of plasma transfusion in bleeding patients with liver disease. In addition, investigators will refine and validate our plasma transfusion dosing algorithm so clinicians will have the tools to appropriately dose plasma to reach evidence-based transfusion targets.
The development of TRALI is believed to require two pathophysiologic events. First, a pro-inflammatory stimulus, such as sepsis, leads to exposure of endothelial surface adhesion proteins and consequent capture of polymorphonuclear leukocytes (PMNs) within the pulmonary microvasculature. Second, these adherent PMNs are activated by mediators within transfused blood components, leading to neutrophilic inflammation and TRALI. Emerging evidence suggests that the process of neutrophil adhesion in the lung involves degradation of the endothelial glycocalyx, a thin layer of glycosaminoglycans (GAGs) lining the vascular lumen(S). In mice, sepsis results in pulmonary glycocalyx loss, neutrophil adhesion and subsequent development of ALI(S). Glycocalyx degradation is also associated with organ injury in humans, as evidenced by an increase in circulating GAG fragments (e.g. heparinoids) in septic shock. Circulating heparinoids can be detected quickly and accurately by a point of care heparinase-I modified thromboelastogram (TEG) study26-27. Detection of heparinoids by TEG may therefore indicate pulmonary microvasculature propensity for PMN adhesion (first event) and be utilized as a predictive biomarker for TRALI. Restrictive plasma transfusion strategies could then be individualized to high risk patients to decrease the probability of a second event resulting in the clinical syndrome of TRALI. In conjunction with the clinical trial, investigators will perform a translational observational study to assess whether detection of systemic heparinoids predict the subsequent development of a TRALI surrogate, post-transfusion hypoxemia. These clinical studies will pave the way for larger clinical trials guiding future plasma transfusion practice and decreasing the significant TRALI burden in the critically ill.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01461889
|United States, Colorado|
|University of Colorado Hospital|
|Aurora, Colorado, United States, 80045|
|Denver Health Hospitals|
|Denver, Colorado, United States, 80204|
|Principal Investigator:||Marc Moss, MD||University of Colorado, Denver|