Cirrhosis, End Stage Liver Disease, Acute Kidney Injury, Liver Transplant; Complications, Chronic Kidney Diseases, Hepatitis c, Hepatitis B, NASH - Nonalcoholic Steatohepatitis, Alcoholic Cirrhosis, Hepatocellular Carcinoma
Conditions
Keywords
Hypothermia, NGAL - Neutrophil Gelatinase-associated Lipocalin
Brief summary
Acute kidney injury (AKI), or worsening kidney function, is a common complication after liver transplantation (20-90% in published studies). Patients who experience AKI after liver transplantation have higher mortality, increased graft loss, longer hospital and intensive care unit stays, and more progression to chronic kidney disease compared with those who do not. In this study, half of the participants will have their body temperature cooled to slightly lower than normal (mild hypothermia) for a portion of the liver transplant operation, while the other half will have their body temperature maintained at normal. The study will evaluate if mild hypothermia protects from AKI during liver transplantation.
Detailed description
This study is a randomized controlled trial of mild hypothermia during liver transplantation to provide protection from AKI. Participants will be randomized to normothermia (36.5-37.5 °C) versus mild hypothermia (34-35 °C) during a portion of the liver transplant operation. The protocol is based on preliminary data from rodent models showing that hypothermia protects the kidneys from ischemia-reperfusion injury, as well as studies in deceased organ donors showing that cooling improves post-transplant organ function. Temperature will be maintained with standard techniques plus a minimally-invasive esophageal cooling device that is approved by the U.S. Food and Drug Administration. The investigators hypothesize that mild hypothermia will reduce the incidence and severity of AKI after liver transplantation(LTx). Standard surrogates (e.g., change in serum creatinine, need for initiation of dialysis) and biomarkers will be used to assess the severity of kidney injury.
Interventions
DEVICEEsophageal cooling/warming device
The EnsoETM (formerly known as Esophageal Cooling Device) is a non-sterile multilumen silicone tube placed in the esophagus for the purpose of cooling or warming a patient while allowing gastric decompression and drainage. It is placed in a manner identical to a standard orogastric tube, which is standard equipment for liver transplant surgery. It is removed at the end of surgery. Control of the patient's temperature is achieved by connecting the EnsoETM to an external heat exchanger (Gaymar Medi-Therm III or similar system). The Medi-Therm III is a standard device used in operating rooms for warming patients with a conductive table warming pad. The Medi-Therm III circulates temperature-controlled water through a closed-loop system via the two outer lumens of the EnsoETM. Water temperature ranges from 4°C - 42°C.
OTHERMild hypothermia
Cooling will be initiated after induction of anesthesia and maintained throughout the anhepatic phase of liver transplantation. In all feasible cases the surgeon will cover the peritoneal surface over the right kidney, which is exposed during the operation, with ice-cold sponges to enhance cooling of the renal parenchyma. After blood flow is completely restored to the liver, the esophageal cooling device and other standard measures (forced-air, fluid, and table warmers, plus a heated anesthesia circuit) will be used to actively re-warm the patient (expected warming rate ≥ 1 deg C/hour). The goal is to achieve normothermia by case end.
OTHERNormothermia
After induction of anesthesia, the esophageal cooling/warming device and standard warming measures will be used to maintain normothermia throughout the operation.
Sponsors
University of Colorado, Denver
The Methodist Hospital Research Institute
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Liver transplantation from a donor after neurologic determination of death
Exclusion criteria
* Liver transplantation from a donor after cardiac death * Acute liver failure * Living-donor liver transplantation * Simultaneous liver-kidney transplantation * Preoperative renal replacement therapy * Preoperative intubation * Portopulmonary hypertension * Machine perfusion of liver graft
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acute Kidney Injury (AKI) | 72 hours from the end of surgery | Acute Kidney Injury (AKI) is defined according to the International Club for Ascites (ICA) 2015 criteria, a revision of the Kidney Disease Improving Global Outcome (KDIGO) criteria for patients with cirrhosis (Angeli P, Ginès P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Gut. 2015 Apr;64(4):531-7). AKI is defined as an increase in sCr ≥ 0.3 mg/dL within 48 hours, or a percentage increase ≥ 50% from baseline, or the initiation of renal replacement therapy. Baseline creatinine is defined as the most recent value obtained prior to liver transplantation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Persistent Renal Dysfunction | 90 days and 1 year | Presence of a reduction in GFR by ≥ 25 mL/min or ≥ 50% from baseline at the time of follow-up. If patient died before the indicated follow-up time, the outcome was counted as positive (patient had persistent renal dysfunction). |
| Distribution of the Stages of Acute Kidney Injury (AKI) | 72 hours from the end of surgery | The International Club for Ascites (ICA) 2015 criteria, a revision of the Kidney Disease Improving Global Outcome (KDIGO) criteria for patients with cirrhosis (Angeli P, Ginès P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Gut. 2015 Apr;64(4):531-7), will be used to define the stage of AKI (Stage 1, 2, or 3). The distribution of the stages of AKI within 72 hours after liver transplantation. The stages of AKI are defined as follows based on the serum creatinine (sCr): AKI Stage 1: increase in sCr ≥ 0.3 mg/dL, or an increase in sCr ≥ 1.5-fold and ≤ 2-fold from baseline. AKI Stage 2: increase in sCr \> 2-fold and ≤ 3-fold from baseline. AKI Stage 3: increase in sCr \> 3-fold from baseline, or sCr ≥ 4.0 with an acute increase of ≥ 0.3 mg/dL, or initiation of renal replacement therapy. |
| Duration of Intensive Care Unit (ICU) Stay | Time from end of liver transplant to ICU discharge, approximately 1 to 3 days | Time after liver transplantation until patient is discharged from the ICU to a regular hospital bed. |
| Duration of Hospital Stay | Time from liver transplant to hospital discharge, approximately 1-2 weeks. | From the date of liver transplantation until the date patient is discharged from the hospital. |
| Need for Renal Replacement Therapy | 72 hours, 30 days, and 1 year. The original protocol specified assessment at 1 week after surgery. However, this data was unable to be collected and we are only able to determine the outcome at 72 hours, 30 days, and 1 year. | Patient is receiving continuous renal replacement therapy or dialysis at the time of follow-up. If patient died before the indicated follow-up time, the outcome was counted as positive (patient was on renal replacement therapy). |
| Serum Neutrophil Gelatinase-associated Lipocalin (NGAL) | Baseline (start of surgery) and 2 hours after reperfusion of the portal vein | Change in serum NGAL levels from baseline to 2 hours after reperfusion of the portal vein (final - initial). |
| Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) | Baseline (start of surgery) and 2 hours after reperfusion of the portal vein | Change in urine NGAL levels from baseline to 2 hours after reperfusion of the portal vein (final - initial). |
| Patient Survival | up to 1 year | From the date of liver transplantation until the date of death from any cause. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Blood Product Transfusions | During surgery | The number of units of packed red blood cells, fresh frozen plasma, platelets, and cryoprecipitate transfused during surgery. We had originally proposed to measure up until 72 hours after surgery, but we were not able to collect this data at all centers. Therefore, only blood product transfusions during surgery are reported. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited between July 2018 and August 2023 from patients scheduled for deceased donor liver transplantation at three transplant centers.
Pre-assignment details
Participants were enrolled after liver transplantation was scheduled but before entering the operating room for surgery. Before proceeding with randomization, it was necessary for the attending surgeon to verify that the liver graft was suitable for transplantation. If that was not the case, the transplant could be aborted before randomization.
Participants by arm
| Arm | Count |
|---|---|
| Mild Hypothermia & Esophageal Cooling/Warming Device The target core temperature is 34-35 °C.
Esophageal cooling/warming device: The EnsoETM (formerly known as Esophageal Cooling Device) is a non-sterile multilumen silicone tube placed in the esophagus for the purpose of cooling or warming a patient while allowing gastric decompression and drainage. It is placed in a manner identical to a standard orogastric tube and is removed at the end of surgery. Control of the patient's temperature is achieved by connecting the EnsoETM to an external heat exchanger (Gaymar Medi-Therm III or similar system). The Medi-Therm III circulates temperature-controlled water through a closed-loop system via the two outer lumens of the EnsoETM. Water temperature ranges from 4°C - 42°C.
Mild hypothermia: Cooling will be initiated after induction of anesthesia and maintained throughout the anhepatic phase of liver transplantation. In all feasible cases the surgeon will cover the peritoneal surface over the right kidney, which is exposed during the operation, with ice-cold sponges to enhance cooling of the renal parenchyma. After blood flow is completely restored to the liver, the esophageal cooling device and other standard measures (forced-air, fluid, and table warmers, plus a heated anesthesia circuit) will be used to actively re-warm the patient (expected warming rate ≥ 1 deg C/hour). The goal is to achieve normothermia by case end. | 86 |
| Normothermia & Esophageal Cooling/Warming Device The target core temperature is 36.5-37.5 °C.
Esophageal cooling/warming device: The EnsoETM (formerly known as Esophageal Cooling Device) is a non-sterile multilumen silicone tube placed in the esophagus for the purpose of cooling or warming a patient while allowing gastric decompression and drainage. It is placed in a manner identical to a standard orogastric tube, which is standard equipment for liver transplant surgery. It is removed at the end of surgery. Control of the patient's temperature is achieved by connecting the EnsoETM to an external heat exchanger (Gaymar Medi-Therm III or similar system). The Medi-Therm III is a standard device used in operating rooms for warming patients with a conductive table warming pad. The Medi-Therm III circulates temperature-controlled water through a closed-loop system via the two outer lumens of the EnsoETM. Water temperature ranges from 4°C - 42°C.
Normothermia: After induction of anesthesia, the esophageal cooling/warming device and standard warming measures will be used to maintain normothermia throughout the operation. | 85 |
| Total | 171 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Enrolled in other clinical trial | 1 | 0 |
| Overall Study | Liver graft explanted due to surgical issue | 0 | 1 |
| Overall Study | Liver transplant aborted after randomization | 0 | 2 |
Baseline characteristics
| Characteristic | Mild Hypothermia & Esophageal Cooling/Warming Device | Total | Normothermia & Esophageal Cooling/Warming Device |
|---|---|---|---|
| Age, Continuous | 58 years | 59 years | 59 years |
| Body Mass Index | 27.6 kg/m^2 | 27.3 kg/m^2 | 27.2 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 26 Participants | 54 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 60 Participants | 117 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Etiology of liver disease Alcoholic | 22 Participants | 52 Participants | 30 Participants |
| Etiology of liver disease Cryptogenic | 2 Participants | 10 Participants | 8 Participants |
| Etiology of liver disease Hepatitis B | 6 Participants | 9 Participants | 3 Participants |
| Etiology of liver disease Hepatitis C | 17 Participants | 30 Participants | 13 Participants |
| Etiology of liver disease Nonalcoholic steatohepatitis (NASH) | 20 Participants | 41 Participants | 21 Participants |
| Etiology of liver disease Other | 19 Participants | 29 Participants | 10 Participants |
| Model for End-stage Liver Disease-Sodium score | 21 units on a scale | 22 units on a scale | 22 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 13 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 15 Participants | 34 Participants | 19 Participants |
| Race (NIH/OMB) White | 57 Participants | 112 Participants | 55 Participants |
| Region of Enrollment United States | 86 participants | 171 participants | 85 participants |
| Sex: Female, Male Female | 35 Participants | 62 Participants | 27 Participants |
| Sex: Female, Male Male | 51 Participants | 109 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 86 | 7 / 85 |
| other Total, other adverse events | 15 / 86 | 15 / 85 |
| serious Total, serious adverse events | 5 / 86 | 3 / 85 |
Outcome results
Primary
Acute Kidney Injury (AKI)
Acute Kidney Injury (AKI) is defined according to the International Club for Ascites (ICA) 2015 criteria, a revision of the Kidney Disease Improving Global Outcome (KDIGO) criteria for patients with cirrhosis (Angeli P, Ginès P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Gut. 2015 Apr;64(4):531-7). AKI is defined as an increase in sCr ≥ 0.3 mg/dL within 48 hours, or a percentage increase ≥ 50% from baseline, or the initiation of renal replacement therapy. Baseline creatinine is defined as the most recent value obtained prior to liver transplantation.
Time frame: 72 hours from the end of surgery
Population: Intention-to-treat population. Excludes participants that were withdrawn after randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mild Hypothermia & Esophageal Cooling/Warming Device | Acute Kidney Injury (AKI) | 56 Participants |
| Normothermia & Esophageal Cooling/Warming Device | Acute Kidney Injury (AKI) | 47 Participants |
Secondary
Distribution of the Stages of Acute Kidney Injury (AKI)
The International Club for Ascites (ICA) 2015 criteria, a revision of the Kidney Disease Improving Global Outcome (KDIGO) criteria for patients with cirrhosis (Angeli P, Ginès P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Gut. 2015 Apr;64(4):531-7), will be used to define the stage of AKI (Stage 1, 2, or 3). The distribution of the stages of AKI within 72 hours after liver transplantation. The stages of AKI are defined as follows based on the serum creatinine (sCr): AKI Stage 1: increase in sCr ≥ 0.3 mg/dL, or an increase in sCr ≥ 1.5-fold and ≤ 2-fold from baseline. AKI Stage 2: increase in sCr \> 2-fold and ≤ 3-fold from baseline. AKI Stage 3: increase in sCr \> 3-fold from baseline, or sCr ≥ 4.0 with an acute increase of ≥ 0.3 mg/dL, or initiation of renal replacement therapy.
Time frame: 72 hours from the end of surgery
Population: Intention-to-treat population. Excludes participants that were withdrawn after randomization.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mild Hypothermia & Esophageal Cooling/Warming Device | Distribution of the Stages of Acute Kidney Injury (AKI) | No AKI | 30 Participants |
| Mild Hypothermia & Esophageal Cooling/Warming Device | Distribution of the Stages of Acute Kidney Injury (AKI) | AKI Stage 1 | 32 Participants |
| Mild Hypothermia & Esophageal Cooling/Warming Device | Distribution of the Stages of Acute Kidney Injury (AKI) | AKI Stage 2 | 13 Participants |
| Mild Hypothermia & Esophageal Cooling/Warming Device | Distribution of the Stages of Acute Kidney Injury (AKI) | AKI Stage 3 | 11 Participants |
| Normothermia & Esophageal Cooling/Warming Device | Distribution of the Stages of Acute Kidney Injury (AKI) | AKI Stage 3 | 18 Participants |
| Normothermia & Esophageal Cooling/Warming Device | Distribution of the Stages of Acute Kidney Injury (AKI) | No AKI | 38 Participants |
| Normothermia & Esophageal Cooling/Warming Device | Distribution of the Stages of Acute Kidney Injury (AKI) | AKI Stage 2 | 9 Participants |
| Normothermia & Esophageal Cooling/Warming Device | Distribution of the Stages of Acute Kidney Injury (AKI) | AKI Stage 1 | 20 Participants |
Secondary
Duration of Hospital Stay
From the date of liver transplantation until the date patient is discharged from the hospital.
Time frame: Time from liver transplant to hospital discharge, approximately 1-2 weeks.
Population: Intention-to-treat population. Excludes participants that were withdrawn after randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mild Hypothermia & Esophageal Cooling/Warming Device | Duration of Hospital Stay | 7 days |
| Normothermia & Esophageal Cooling/Warming Device | Duration of Hospital Stay | 7 days |
Secondary
Duration of Intensive Care Unit (ICU) Stay
Time after liver transplantation until patient is discharged from the ICU to a regular hospital bed.
Time frame: Time from end of liver transplant to ICU discharge, approximately 1 to 3 days
Population: Intention-to-treat population. Excludes participants that were withdrawn after randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mild Hypothermia & Esophageal Cooling/Warming Device | Duration of Intensive Care Unit (ICU) Stay | 36 hours |
| Normothermia & Esophageal Cooling/Warming Device | Duration of Intensive Care Unit (ICU) Stay | 37 hours |
Secondary
Need for Renal Replacement Therapy
Patient is receiving continuous renal replacement therapy or dialysis at the time of follow-up. If patient died before the indicated follow-up time, the outcome was counted as positive (patient was on renal replacement therapy).
Time frame: 72 hours, 30 days, and 1 year. The original protocol specified assessment at 1 week after surgery. However, this data was unable to be collected and we are only able to determine the outcome at 72 hours, 30 days, and 1 year.
Population: Intention-to-treat population. Excludes participants that were withdrawn after randomization.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mild Hypothermia & Esophageal Cooling/Warming Device | Need for Renal Replacement Therapy | Renal replacement therapy within 72 hours after liver transplant. | 8 Participants |
| Mild Hypothermia & Esophageal Cooling/Warming Device | Need for Renal Replacement Therapy | Renal replacement therapy at 30 days after liver transplant. | 8 Participants |
| Mild Hypothermia & Esophageal Cooling/Warming Device | Need for Renal Replacement Therapy | Renal replacement therapy at 1 year after liver transplant. | 7 Participants |
| Normothermia & Esophageal Cooling/Warming Device | Need for Renal Replacement Therapy | Renal replacement therapy within 72 hours after liver transplant. | 13 Participants |
| Normothermia & Esophageal Cooling/Warming Device | Need for Renal Replacement Therapy | Renal replacement therapy at 30 days after liver transplant. | 5 Participants |
| Normothermia & Esophageal Cooling/Warming Device | Need for Renal Replacement Therapy | Renal replacement therapy at 1 year after liver transplant. | 9 Participants |
Secondary
Patient Survival
From the date of liver transplantation until the date of death from any cause.
Time frame: up to 1 year
Population: Intention-to-treat population. Excludes participants that were withdrawn after randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mild Hypothermia & Esophageal Cooling/Warming Device | Patient Survival | 81 Participants |
| Normothermia & Esophageal Cooling/Warming Device | Patient Survival | 78 Participants |
Secondary
Persistent Renal Dysfunction
Presence of a reduction in GFR by ≥ 25 mL/min or ≥ 50% from baseline at the time of follow-up. If patient died before the indicated follow-up time, the outcome was counted as positive (patient had persistent renal dysfunction).
Time frame: 90 days and 1 year
Population: Intention-to-treat population. Excludes participants that were withdrawn after randomization.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mild Hypothermia & Esophageal Cooling/Warming Device | Persistent Renal Dysfunction | Persistent renal dysfunction at 90 days after liver transplant. | 24 Participants |
| Mild Hypothermia & Esophageal Cooling/Warming Device | Persistent Renal Dysfunction | Persistent renal dysfunction at 1 year after liver transplant. | 28 Participants |
| Normothermia & Esophageal Cooling/Warming Device | Persistent Renal Dysfunction | Persistent renal dysfunction at 90 days after liver transplant. | 25 Participants |
| Normothermia & Esophageal Cooling/Warming Device | Persistent Renal Dysfunction | Persistent renal dysfunction at 1 year after liver transplant. | 32 Participants |
Secondary
Serum Neutrophil Gelatinase-associated Lipocalin (NGAL)
Change in serum NGAL levels from baseline to 2 hours after reperfusion of the portal vein (final - initial).
Time frame: Baseline (start of surgery) and 2 hours after reperfusion of the portal vein
Population: Serum for NGAL determination was only collected at the coordinating center. It was not feasible to collect serum for all patients due to research personnel being unavailable during some off-hours and weekend liver transplants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mild Hypothermia & Esophageal Cooling/Warming Device | Serum Neutrophil Gelatinase-associated Lipocalin (NGAL) | 20.8 ng/mL |
| Normothermia & Esophageal Cooling/Warming Device | Serum Neutrophil Gelatinase-associated Lipocalin (NGAL) | 26.15 ng/mL |
Secondary
Urine Neutrophil Gelatinase-associated Lipocalin (NGAL)
Change in urine NGAL levels from baseline to 2 hours after reperfusion of the portal vein (final - initial).
Time frame: Baseline (start of surgery) and 2 hours after reperfusion of the portal vein
Population: Urine for NGAL determination was only collected at the coordinating center. It was not feasible to collect urine for all patients due to research personnel being unavailable during some off-hours and weekend liver transplants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mild Hypothermia & Esophageal Cooling/Warming Device | Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) | 156.3 ng/mL |
| Normothermia & Esophageal Cooling/Warming Device | Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) | 81.85 ng/mL |
Other Pre-specified
Blood Product Transfusions
The number of units of packed red blood cells, fresh frozen plasma, platelets, and cryoprecipitate transfused during surgery. We had originally proposed to measure up until 72 hours after surgery, but we were not able to collect this data at all centers. Therefore, only blood product transfusions during surgery are reported.
Time frame: During surgery
Population: Intention-to-treat population. Excludes participants that were withdrawn after randomization.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Mild Hypothermia & Esophageal Cooling/Warming Device | Blood Product Transfusions | Packed red blood cells | 4 Units of blood product transfused |
| Mild Hypothermia & Esophageal Cooling/Warming Device | Blood Product Transfusions | Fresh frozen plasma | 8.5 Units of blood product transfused |
| Mild Hypothermia & Esophageal Cooling/Warming Device | Blood Product Transfusions | Platelets | 2 Units of blood product transfused |
| Mild Hypothermia & Esophageal Cooling/Warming Device | Blood Product Transfusions | Cryoprecipitate | 0 Units of blood product transfused |
| Normothermia & Esophageal Cooling/Warming Device | Blood Product Transfusions | Cryoprecipitate | 0 Units of blood product transfused |
| Normothermia & Esophageal Cooling/Warming Device | Blood Product Transfusions | Packed red blood cells | 5 Units of blood product transfused |
| Normothermia & Esophageal Cooling/Warming Device | Blood Product Transfusions | Platelets | 2 Units of blood product transfused |
| Normothermia & Esophageal Cooling/Warming Device | Blood Product Transfusions | Fresh frozen plasma | 9 Units of blood product transfused |