Liver Disease
Conditions
Brief summary
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
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).
Interventions
BIOLOGICALFresh Frozen Plasma
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.
DIAGNOSTIC_TESTPre-Transfusion International Normalized Ratio (INR)
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.
DIAGNOSTIC_TESTPost-Transfusion International Normalized Ratio (INR)
INR result after Fresh Frozen Plasma (FFP) transfusion completed, determined by clinical lab testing performed within 1 hour after transfusion completed.
Sponsors
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Subjects will be eligible to participate in the study if they meet all of the following criteria: 1. 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). 2. 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 3. Signs of portal hypertension (ascites, varices, hypersplenism), or 4. 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 1. Patient under age 18 2. Patient actively taking vitamin K antagonists 3. Inability to obtain consent 4. Clinical team does not desire to target a specific INR value 5. Pregnant patients and prisoners 6. Patients with Acute Liver Failure
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants That Reached Targeted International Normalized Ratio (INR) Within ±0.1 After First Fresh Frozen Plasma (FFP) Transfusion Completed. | within 1 hour after entire plasma transfusion | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | hours from first dose to initiation of procedure, anticipated timeframe between 1 minute to 8 hours. | 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. |
| 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 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Clinician Chosen Dosing Usual Care arm: Physician determined fresh frozen plasma (FFP) dosing. Bleeding patients admitted to study hospitals,with chronic liver disease determined to receive fresh frozen plasma (FFP) for clinical indications as determined by hospital clinician. Total dose determined by physician's judgment (current standard of care). Physician chosen dose will be utilized but physician will be unaware of which dosing strategy utilized.
International Normalized Ratio (INR) measurement will be performed within 1 hour after entire plasma transfusion administered. No other transfused blood component, crystalloid or colloidal fluid infused between first and second INR studies except plasma. | 24 |
| Algorithm Dosing Intervention arm: Plasma transfusion dose determined using algorithm dosing table based on the (pre-transfusion INR) and clinician chosen INR target. Bleeding patients admitted to study hospitals with chronic liver disease determined to receive fresh frozen plasma (FFP) for clinical indications as determined by hospital clinician.
Pre-transfusion INR and target post-transfusion INR used to determine FFP dose. The study table determines dose in (ml/kg) of FFP. INR measurement will be performed within 1 hour after entire plasma transfusion administered. No other transfused blood component,crystalloid or colloidal fluid will be infused between the first and second INR studies except plasma. | 26 |
| Total | 50 |
Baseline characteristics
| Characteristic | Clinician Chosen Dosing | Algorithm Dosing | Total |
|---|---|---|---|
| Age, Continuous | 53.7 years STANDARD_DEVIATION 11.1 | 53.3 years STANDARD_DEVIATION 10.7 | 53.5 years STANDARD_DEVIATION 10.8 |
| APACHE II Score | 13.9 units on a scale STANDARD_DEVIATION 6.7 | 13.9 units on a scale STANDARD_DEVIATION 3.5 | 13.9 units on a scale STANDARD_DEVIATION 5.3 |
| Hospital Service Medical Floor | 23 participants | 22 participants | 45 participants |
| Hospital Service Other | 1 participants | 4 participants | 5 participants |
| MELD Score | 25.9 units on a scale STANDARD_DEVIATION 8.4 | 25.4 units on a scale STANDARD_DEVIATION 5.4 | 25.6 units on a scale STANDARD_DEVIATION 7 |
| Physician target International Normalized Ratio (INR) | 1.7 ratio STANDARD_DEVIATION 0.2 | 1.8 ratio STANDARD_DEVIATION 0.2 | 1.7 ratio STANDARD_DEVIATION 0.2 |
| Pre-Transfusion International Normalzied Ratio (INR) | 2.4 ratio STANDARD_DEVIATION 0.5 | 2.3 ratio STANDARD_DEVIATION 0.4 | 2.3 ratio STANDARD_DEVIATION 0.5 |
| Race/Ethnicity, Customized Asian | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Caucasian | 13 participants | 16 participants | 29 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 9 participants | 8 participants | 17 participants |
| Serum Creatinine | 1.3 mg/dL | 1.2 mg/dL | 1.3 mg/dL |
| Sex: Female, Male Female | 9 Participants | 10 Participants | 19 Participants |
| Sex: Female, Male Male | 15 Participants | 16 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 24 | 0 / 26 |
| serious Total, serious adverse events | 0 / 24 | 0 / 26 |
Outcome results
Primary
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).
Time frame: within 1 hour after entire plasma transfusion
Population: At goal INR after first transfusion.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clinician Chosen Dosing | Number of Participants That Reached Targeted International Normalized Ratio (INR) Within ±0.1 After First Fresh Frozen Plasma (FFP) Transfusion Completed. | 7 Participants |
| Algorithm Dosing | Number of Participants That Reached Targeted International Normalized Ratio (INR) Within ±0.1 After First Fresh Frozen Plasma (FFP) Transfusion Completed. | 17 Participants |
Secondary
Dose Difference (Average # Units) Between Clinician Dosing and Algorithm Dosing (Units of FFP) Per Patient.
Time frame: within 1 hour after entire plasma transfusion
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Clinician Chosen Dosing | Dose Difference (Average # Units) Between Clinician Dosing and Algorithm Dosing (Units of FFP) Per Patient. | 2.4 units |
| Algorithm Dosing | Dose Difference (Average # Units) Between Clinician Dosing and Algorithm Dosing (Units of FFP) Per Patient. | 3.1 units |
Secondary
Hospital Length of Stay
Time frame: Subjects will be followed for duration of hospital stay, anticipated within 1 Day to 28 Days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Clinician Chosen Dosing | Hospital Length of Stay | 13.8 days |
| Algorithm Dosing | Hospital Length of Stay | 11.0 days |
Secondary
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.
Time frame: hours from first dose to initiation of procedure, anticipated timeframe between 1 minute to 8 hours.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Clinician Chosen Dosing | 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. | 4.9 hours |
| Algorithm Dosing | 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. | 3.5 hours |