Prospective Validation of a Plasma Transfusion Dosing Algorithm in Patients With Chronic Liver Disease

Study Overview
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Brief Summary
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This study plans to learn more about transfusion of a human blood component called plasma in patients who have liver problems. Patients are asked to be in this study because they have liver disease and therefore may require the transfusion of plasma. The dose of plasma required to reach certain blood clotting laboratory targets is usually determined by clinicians. Due to the complexity of the patient's blood clotting disorder, determining the appropriate dose of plasma is very difficult. The investigators have developed a dosing table based on information from other patients with liver disease and the investigators are testing it to see if it is a more accurate dosing tool then clinician chosen dosing of plasma in patients with liver disease who need one or more plasma transfusions

Detailed Description
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Clinicians currently transfuse plasma to International Normalized Ratio (INR) targets without an understanding of the dose response characteristics of plasma in bleeding patients with liver disease. Epidemiologic studies show that INR is infrequently corrected to target INR values after clinician chosen plasma transfusion doses in patients with liver disease. Plasma transfusion is frequently given to patients prior to procedures and during active bleeding in this patient population though there are no dosing guidelines to aid clinicians in reaching INR targets in patients with liver disease. Previous studies suggest that patients with liver disease may need more plasma then patients without liver disease to correct any given pre-transfusion INR (INR value measured before plasma transfusion) to the same post-transfusion INR target (INR value measured after plasma transfusion). Current physician dosing of plasma is variable and rarely successful at reaching stated INR targets. The INR thresholds, commonly used triggers for plasma transfusion by Gastro-Intestinal (GI), Hepatology and critical care physicians at our institution range from 1.5-3.0 in bleeding or pre-procedural patients with liver disease representing tremendous variability. When we evaluated plasma transfusion dosing practices in bleeding patients with liver disease over 8 years, we demonstrated that these same physicians rarely met stated theoretical targets. Over or under dosing plasma in these patients may lead to serious clinical complications.The target INR goal was to be within ±0.1 after the first round of FFP transfusion, and was selected because underdosing can result in prolonged bleeding, delayed procedure times, and more rounds of FFP transfusion. Furthermore, overdosing can result in excess cost, increased portal pressures, bleeding, transfusion associated circulatory overload (TACO), and transfusion related acute lung injury (TRALI).

Official Title
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Prospective Validation of a Plasma Transfusion Dosing Algorithm in Patients With Chronic Liver Disease

Conditions
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Liver Disease

Intervention / Treatment
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* Biological: Fresh Frozen Plasma
* Diagnostic Test: Pre-Transfusion International Normalized Ratio (INR)
* Diagnostic Test: Post-Transfusion International Normalized Ratio (INR)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects will be eligible to participate in the study if they meet all of the following criteria: Admission to the University of Colorado Hospital or Denver Health hospital and the clinical care team plans to transfuse the patient plasma to target a specific INR value. (reason for transfusion is not considered). Patient has chronic liver disease defined as 1 or more of the following: Previous diagnosis of chronic liver disease OR -Imaging or biopsy diagnosis of cirrhosis; or Signs of portal hypertension (ascites, varices, hypersplenism), or Laboratory evidence of synthetic dysfunction (INR>1.5, bilirubin> 2.0 mg/dL, albumin<2.5 mg/dL) 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 Patient under age 18 Patient actively taking vitamin K antagonists Inability to obtain consent Clinical team does not desire to target a specific INR value Pregnant patients and prisoners Patients with Acute Liver Failure

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Clinician Chosen Dosing<br>Admitted University of Colorado Hospital or Denver Health bleeding patients with chronic liver disease determined to receive fresh frozen plasma (FFP) for clinical indications as determined by hospital clinician. The total dose will be determined by the physician's judgment which is the current standard of care. The physician chosen dose will be utilized but physician will be unaware of which dosing strategy has been utilized. INR measurements will be performed before (pre) and after (post) transfusion of plasma has been administered. Primary and secondary outcome measures will be collected. No other transfused blood component, crystalloid or colloidal fluid will be infused between the first and second INR studies except plasma. | Biological: Fresh Frozen Plasma<br>* An INR dose-response curve with associated transfusion algorithm was generated for plasma in bleeding patients with chronic liver disease. In the intervention arm we will determine the plasma transfusion dose using the algorithm dosing table based on the pre-transfusion INR and the clinician chosen INR target. In the usual care group the dosing will be determined by the clinician.<br>* Other names: FFP;Diagnostic Test: Pre-Transfusion International Normalized Ratio (INR)<br>* INR result prior to Fresh Frozen Plasma (FFP) transfusion determined by clinical lab testing performed within 6 hours to 1 day before transfusion start time.<br>* Other names: Pre-Transfusion INR;Diagnostic Test: Post-Transfusion International Normalized Ratio (INR)<br>* INR result after Fresh Frozen Plasma (FFP) transfusion completed, determined by clinical lab testing performed within 1 hour after transfusion completed.<br>* Other names: Post-Transfusion INR;|
| Experimental: Algorithm Dosing<br>Admitted University of Colorado Hospital or Denver Health bleeding patients with chronic liver disease determined to receive fresh frozen plasma (FFP) for clinical indications as determined by hospital clinician. This group will receive plasma doses based on the study dosing algorithm table. A pre-transfusion INR (before transfusion) and a target post-transfusion INR (after transfusion) will be used to determine dose of FFP. The study table will reveal the dose in (ml/kg) of FFP to be transfused. INR measurements will be performed before (pre) and after (post) transfusion of plasma has been administered. Primary and secondary outcome measures will be collected. No other transfused blood component,crystalloid or colloidal fluid will be infused between the first and second INR studies except plasma. | Biological: Fresh Frozen Plasma<br>* An INR dose-response curve with associated transfusion algorithm was generated for plasma in bleeding patients with chronic liver disease. In the intervention arm we will determine the plasma transfusion dose using the algorithm dosing table based on the pre-transfusion INR and the clinician chosen INR target. In the usual care group the dosing will be determined by the clinician.<br>* Other names: FFP;Diagnostic Test: Pre-Transfusion International Normalized Ratio (INR)<br>* INR result prior to Fresh Frozen Plasma (FFP) transfusion determined by clinical lab testing performed within 6 hours to 1 day before transfusion start time.<br>* Other names: Pre-Transfusion INR;Diagnostic Test: Post-Transfusion International Normalized Ratio (INR)<br>* INR result after Fresh Frozen Plasma (FFP) transfusion completed, determined by clinical lab testing performed within 1 hour after transfusion completed.<br>* Other names: Post-Transfusion INR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Reached Targeted International Normalized Ratio (INR) Within ±0.1 After First Fresh Frozen Plasma (FFP) Transfusion Completed. | Ability of dosing algorithm to accurately predict necessary plasma dose (ml/kg), required to reach commonly targeted International Normalized Ratio (INR) values, compared to clinician chosen plasma transfusion dose, as determined by dose-response curve. The primary outcome was achievement of the target INR within ±0.1 after the first round of FFP transfusion. This primary outcome was selected because underdosing can result in prolonged bleeding, delayed procedure times, and more rounds of FFP transfusion. Furthermore, overdosing can result in excess cost, increased portal pressures, bleeding, transfusion associated circulatory overload (TACO), and transfusion related acute lung injury (TRALI). | within 1 hour after entire plasma transfusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time (Hours) From Initiation of First Dose of Plasma to Initiation of Planned Procedure (in Patient Undergoing Transfusion Before a Procedure) for Clinician Dosing Compared to Algorithm Dosing Strategies. | Decreased time between initiation of plasma infusion, achieving a corrected target INR and start of planned patient procedures would potentially improve care efficiency and/or allow faster intervention in unstable patients. | hours from first dose to initiation of procedure, anticipated timeframe between 1 minute to 8 hours. | 
| Dose Difference (Average # Units) Between Clinician Dosing and Algorithm Dosing (Units of FFP) Per Patient. |  | within 1 hour after entire plasma transfusion | 
| Hospital Length of Stay |  | Subjects will be followed for duration of hospital stay, anticipated within 1 Day to 28 Days |