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

• ClinicalTrials.gov Identifier: NCT01461889
• Recruitment Status: Terminated
• First Posted: October 28, 2011
• Last Update Posted: March 27, 2017
• Sponsor: University of Colorado, Denver
• Information provided by (Responsible Party): University of Colorado, Denver

Tracking Information

• First Submitted Date: October 26, 2011
• First Posted Date: October 28, 2011
• Last Update Posted Date: March 27, 2017
• Study Start Date: July 2011
• Actual Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 22, 2016)

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.

Original Primary Outcome Measures (submitted: October 27, 2011)

Mean change in PaO2/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 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.

Current Secondary Outcome Measures (submitted: July 22, 2016)

• 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.

Original Secondary Outcome Measures (submitted: October 27, 2011)

• 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 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 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 ]
  We will determine how many days a patient is alive and off mechanical ventilation at day 28 from enrollment.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: INR-Triggered Transfusion In GI Bleeders From ER
• Official Title: Transfusion-related Acute Lung Injury in Patients With Liver Disease
• 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.

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Outcomes Assessor); Primary Purpose: Prevention

Condition

• Respiratory Distress Syndrome, Adult
• Gastrointestinal Hemorrhage
• Liver Diseases
• Transfusion Related Lung Injury

Intervention

• 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
• 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

Study Arms

• 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.
  Intervention: Other: Transfuse plasma to High INR target
• 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.
  Intervention: Other: Transfuse plasma to Low INR target

• Publications *: Benson AB, Austin GL, Berg M, McFann KK, Thomas S, Ramirez G, Rosen H, Silliman CC, Moss M. Transfusion-related acute lung injury in ICU patients admitted with gastrointestinal bleeding. Intensive Care Med. 2010 Oct;36(10):1710-7. doi: 10.1007/s00134-010-1954-x. Epub 2010 Jul 24.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: July 22, 2016): 50
• Original Estimated Enrollment (submitted: October 27, 2011): 72
• Actual Study Completion Date: August 2015
• Actual Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01461889
• Other Study ID Numbers: 10-1453
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: University of Colorado, Denver
• Study Sponsor: University of Colorado, Denver
• Collaborators: Not Provided

Investigators

• Principal Investigator: Marc Moss, MD; University of Colorado, Denver

• PRS Account: University of Colorado, Denver
• Verification Date: March 2017