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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01461889
Recruitment Status : Terminated
First Posted : October 28, 2011
Last Update Posted : March 27, 2017
Information provided by (Responsible Party):
University of Colorado, Denver

Brief Summary:
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 the investigators will evaluate this clinical question in a small pilot randomized controlled trial. The invstigators 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 or disease Intervention/treatment 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

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 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Transfusion-related Acute Lung Injury in Patients With Liver Disease
Study Start Date : July 2011
Actual Primary Completion Date : August 2015
Actual Study Completion Date : August 2015

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. Bleeding complication (y/n) [ Time Frame: 120 hour from admission ]
    Baveno V consensus conference definition for failure to control bleeding

  2. 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.

  3. 28 day and ICU Mortality [ Time Frame: enrollment to 28 days ]
    Mortality in ICU (y/n); Mortality at 28 days post enrollment (y/n)

  4. ICU and Hospital length of Stay [ Time Frame: days ]
    We will measure number of days subjects are alive and in the ICU or hospital

  5. 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.

  6. 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.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01461889

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United States, Colorado
University of Colorado Hospital
Aurora, Colorado, United States, 80045
Denver Health Hospitals
Denver, Colorado, United States, 80204
Sponsors and Collaborators
University of Colorado, Denver
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Principal Investigator: Marc Moss, MD University of Colorado, Denver
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Responsible Party: University of Colorado, Denver Identifier: NCT01461889    
Other Study ID Numbers: 10-1453
First Posted: October 28, 2011    Key Record Dates
Last Update Posted: March 27, 2017
Last Verified: March 2017
Keywords provided by University of Colorado, Denver:
transfusion-related acute lung injury
Blood Component Transfusion
Gastrointestinal Hemorrhage
Fresh frozen plasma
Additional relevant MeSH terms:
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Liver Diseases
Gastrointestinal Hemorrhage
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Lung Injury
Acute Lung Injury
Transfusion-Related Acute Lung Injury
Wounds and Injuries
Pathologic Processes
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Thoracic Injuries
Gastrointestinal Diseases
Transfusion Reaction
Hematologic Diseases
Immune System Diseases