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INR-Triggered Transfusion In GI Bleeders From ER (I-TRIGER)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by University of Colorado, Denver
Sponsor:
Information provided by (Responsible Party):
University of Colorado, Denver
ClinicalTrials.gov Identifier:
NCT01461889
First received: October 26, 2011
Last updated: January 16, 2015
Last verified: April 2014
  Purpose

Transfusion-related acute lung injury (TRALI) is the most common cause of transfusion-related morbidity and mortality in the United States. It is very common and often unrecognized in the critically ill with the greatest incidence occurring in bleeding patients with liver disease. Plasma is the most blood component associated with this deadly complication and therefore patients with liver disease who frequently receive transfused plasma are at increased risk. The optimal plasma transfusion strategy for bleeding patients with liver disease is unknown and we will evaluate this clinical question in a small pilot randomized controlled trial. We hypothesize that targetting a more restrictive INR Target (2.5) vs. an INR Target (1.8) will result in less hypoxemia, a TRALI surrogate without increasing bleeding complications.


Condition Intervention Phase
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 Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Transfusion-related Acute Lung Injury in Patients With Liver Disease

Resource links provided by NLM:


Further study details as provided by University of Colorado, Denver:

Primary Outcome Measures:
  • 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) ] [ Designated as safety issue: Yes ]
    The development of hypoxemia will not distinguish between hydrostatic edema and TRALI, but we 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.


Secondary Outcome Measures:
  • Bleeding complication (y/n) [ Time Frame: 120 hour from admission ] [ Designated as safety issue: Yes ]
    Baveno V consensus conference definition for failure to control bleeding

  • Transfusion-related acute lung injury [ Time Frame: enrollment to 54 hours post-enrollment ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    Mortality in ICU (y/n); Mortality at 28 days post enrollment (y/n)

  • ICU and Hospital length of Stay [ Time Frame: days ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    The mean ∆S/F ratio immediately before and 60 minutes after transfusion of plasma vs. (RBCs or platelets) will allow us 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 ] [ Designated as safety issue: No ]
    We will determine how many days a patient is alive and off mechanical ventilation at day 28 from enrollment.


Estimated Enrollment: 72
Study Start Date: July 2011
Estimated Study Completion Date: August 2016
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

Detailed Description:

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 disease17-18. Having recently discovered a large previously unrecognized risk (TRALI) of plasma transfusion in this patient population, we 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 variable18. 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. We 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, we will conduct a randomized controlled trial comparing a restrictive versus liberal strategy of plasma transfusion in bleeding patients with liver disease. In addition, we 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) 22-23. 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 shock22, 24-25. 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 our clinical trial, we 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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria: Subjects will be eligible to participate in the study if they meet all of the following criteria:

  1. Admit to an ICU due to gastrointestinal bleeding AND an INR in first 12 hours >1.8; (INR ≥ 1.6 if received ≥ 2 units plasma)
  2. Patient has chronic liver disease defined as 1 or more of the three following diagnostic criteria:

    • Previous diagnosis of chronic liver disease OR Imaging or biopsy diagnosis of cirrhosis
    • Signs of portal hypertension (ascites, varices, hypersplenism)
    • Laboratory evidence of synthetic dysfunction (INR>1.5, Bilirubin> 2.0, Albumin< 2.5) AND ≥2 physical exam findings on admission associated with chronic liver disease (palmar erythema, spider angiomata, asterixis, caput medusa, gynecomastia)

Exclusion Criteria:Subjects will be ineligible to participate in the study if they meet any of the following criteria:

  1. Patient under age 18 OR pregnant OR incarcerated
  2. Patient meets criteria for acute respiratory distress syndrome (ARDS) (PaO2/FiO2<165)41
  3. Patient admitted to ICU for re-bleed on same hospital admission OR has already received >4 units of plasma.
  4. Patient already underwent therapeutic endoscopy with noted hemostasis
  5. History of inheritable or acquired clotting or bleeding disorder (hemophilia A or B or acquired clotting factor inhibitor)
  6. Patient is being actively anticoagulated with vitamin K antagonists, direct thrombin inhibitors, heparins or anti-Xa antagonists
  7. Inability to obtain consent OR clinical team believes one of the transfusion strategies will be harmful to the patient
  8. Congestive heart failure (previous clinical diagnosis or Ejection Fraction (EF) <50%)
  9. Patient is do-not-resuscitate (DNR) or unexpected to live > 72 hours
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01461889

Contacts
Contact: Marc Moss, MD 303-724-6074 Marc.Moss@ucdenver.edu

Locations
United States, Colorado
University of Colorado Hospital Recruiting
Aurora, Colorado, United States, 80045
Contact: Marc Moss, MD    303-724-6074    marc.moss@ucdenver.edu   
Principal Investigator: Marc Moss, MD         
Sub-Investigator: Steven Purtle, MD         
Denver Health Hospitals Recruiting
Denver, Colorado, United States, 80204
Contact: Marc Moss, MD    303-724-6074    marc.moss@ucdenver.edu   
Principal Investigator: Marc Moss, MD         
Sub-Investigator: Steven Purtle, MD         
Sponsors and Collaborators
University of Colorado, Denver
Investigators
Principal Investigator: Marc Moss, MD University of Colorado, Denver
  More Information

Publications:
Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT01461889     History of Changes
Other Study ID Numbers: 10-1453
Study First Received: October 26, 2011
Last Updated: January 16, 2015
Health Authority: United States: Institutional Review Board

Keywords provided by University of Colorado, Denver:
transfusion-related acute lung injury
Blood Component Transfusion
Gastrointestinal Hemorrhage
Cirrhosis
Fresh frozen plasma

Additional relevant MeSH terms:
Gastrointestinal Hemorrhage
Acute Lung Injury
Liver Diseases
Lung Injury
Respiratory Distress Syndrome, Adult
Respiratory Distress Syndrome, Newborn
Digestive System Diseases
Gastrointestinal Diseases
Hemorrhage
Infant, Newborn, Diseases
Infant, Premature, Diseases
Lung Diseases
Pathologic Processes
Respiration Disorders
Respiratory Tract Diseases
Thoracic Injuries
Wounds and Injuries

ClinicalTrials.gov processed this record on March 01, 2015