Ischemia Reperfusion Injury, Liver Transplantation, Tissue Donors
Conditions
Keywords
remote ischemic preconditioning, liver donors
Brief summary
Liver transplantation is the gold standard treatment for patients with end-stage liver disease. Despite its outstanding success, liver transplantation still entails certain complications including ischemia-reperfusion injury. Remote ischemic preconditioning is a novel and simple therapeutic method to lessen the harmful effects of ischemia-reperfusion injury, however, the majority of remote ischemic preconditioning studies on hepatic ischemia-reperfusion injury have been animal studies. Therefore, our aim was to assess the effects of remote ischemic preconditioning on postoperative liver function in living donor hepatectomy.
Detailed description
Liver transplantation(LT) is the gold standard treatment for patients with end-stage liver disease. In light of advancements in surgical techniques, immunosuppressive agents, and perioperative critical care, the overall 3-year survival of patients undergoing LT has exceeded 80%. Despite its outstanding success, LT still entails certain complications including ischemia-reperfusion injury (IRI). IRI occurs when the blood supply to an organ or tissue is temporarily cut-off and then restored, and it is well-known as an underlying cause of primary non-function, biliary complications, and eventual graft loss after LT. Despite many attempts to ameliorate hepatic IRI, no definitive therapies have been established. In addition, the mechanisms of IRI remain largely unclear. Remote ischemic preconditioning (RIPC) is a novel and simple therapeutic method to lessen the harmful effects of IRI. RIPC indicate that brief episodes of ischemia with intermittent reperfusion are introduced at a remote site, leading to systemic protection against subsequent insults as evinced on kidney, heart, liver, and other tissues. While RIPC has been shown to reduce hepatic IRI in several small animal studies, the beneficial effects of RIPC in hepatic IRI have been inconsistent. By far, the majority of RIPC studies on hepatic IRI have been animal studies; hence, there are limitations relating to the lack of human clinical trials. Therefore, our aim was to assess the effects of RIPC on postoperative liver function in living donor hepatectomy.
Interventions
PROCEDUREremote ischemic preconditioning
Remote ischemic preconditioning was performed following anesthesia induction in donors. The protocol involves 3 cycles of 5-minute inflation of a blood pressure cuff to 200 mm Hg to one upper arm, followed by 5-minute reperfusion with the cuff deflated
Sponsors
Asan Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Intervention model description
study group : remote ischemic preconditioning control group : none
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Donors who plan to have living right hepatectomy for liver transplantation. * age : between 18 to 60 years.
Exclusion criteria
* donors who plan to donate left lobe * donors who plan to have laparoscopic right hepatectomy * donors who cannot proceed remote ischemic preconditioning
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Postopera The Maximal Aspartate Aminotransferase Level Within 7 Postoperative Days | within 7 days after operation | The serial assessments of routine laboratory values were used as early markers for postoperative liver function. The maximal aspartate aminotransferase level within 7 postoperative days were assessed following RIPC in living donor hepatectomy. |
| The Maximal Alanine Aminotransferase Level Within 7 Postoperative Days | within 7 days after operation | The serial assessments of routine laboratory values were used as early markers for postoperative liver function. The maximal alanine aminotransferase level within 7 postoperative days were assessed following RIPC in living donor hepatectomy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Delayed Recovery of Liver Function | postoperative 7 days | The incidence of delayed recovery of hepatic function (DRHF) were used as surrogate parameters indicating the possible benefits of RIPC. DRHF was defined based on a proposal by the International Study Group of Liver Surgery, as follows: an impaired ability of the liver to maintain its synthetic, excretory, and detoxifying functions, which are characterized by an increased PT INR and concomitant hyperbilirubinemia (considering the normal limits of the local laboratory) on or after postoperative day 5. The normal upper limits of PT and bilirubin in our institutional laboratory were 1.30 INR and 1.2 mg/dL, respectively. If either the PT INR or serum bilirubin concentration was preoperatively elevated, DRHF was defined by an increasing PT INR and increasing serum bilirubin concentration on or after postoperative day 5 (compared with the values of the previous day). |
| Postoperative Liver Regeneration | 1 month | The postoperative liver regeneration index (LRI) at postoperative 1 month ) was used as surrogate parameters indicating the possible benefits of RIPC. The LRI was defined as \[(VLR - VFLR)/VFLR)\] × 100, where VLR is the volume of the liver remnant and VFLR is the volume of the future liver remnant. Liver volume was calculated by CT volumetry using 3-mm-thick dynamic CT images. The graft weight was subtracted from the total liver volume to define the future liver remnant. |
Countries
South Korea
Participant flow
Recruitment details
For the donor group, adult (aged 18-60 years) liver donors scheduled for elective donor right hepatectomy from August 2016 to July 2017 at Asan Medical Center in Seoul, Korea, were screened for eligibility.
Participants by arm
| Arm | Count |
|---|---|
| RIPC intervention: RIPC groups receive remote ischaemic preconditioning after anaesthesia induction and before surgery started.
remote ischemic preconditioning: Remote ischemic preconditioning was performed following anesthesia induction in donors. The protocol involves 3 cycles of 5-minute inflation of a blood pressure cuff to 200 mm Hg to one upper arm, followed by 5-minute reperfusion with the cuff deflated | 75 |
| Control In the control group, the same maneuver was applied but without cuff inflation. | 73 |
| Total | 148 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 5 | 7 |
Baseline characteristics
| Characteristic | RIPC | Control | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 75 Participants | 73 Participants | 148 Participants |
| Body mass index | 23.7 kg/m^2 STANDARD_DEVIATION 2.6 | 24.1 kg/m^2 STANDARD_DEVIATION 2.7 | 23.9 kg/m^2 STANDARD_DEVIATION 2.7 |
| Race/Ethnicity, Customized Asian | 75 Participants | 73 Participants | 148 Participants |
| Region of Enrollment South Korea | 75 Participants | 73 Participants | 148 Participants |
| Sex: Female, Male Female | 21 Participants | 22 Participants | 43 Participants |
| Sex: Female, Male Male | 54 Participants | 51 Participants | 105 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 73 |
| other Total, other adverse events | 0 / 75 | 0 / 73 |
| serious Total, serious adverse events | 0 / 75 | 0 / 73 |
Outcome results
Primary
Postopera The Maximal Aspartate Aminotransferase Level Within 7 Postoperative Days
The serial assessments of routine laboratory values were used as early markers for postoperative liver function. The maximal aspartate aminotransferase level within 7 postoperative days were assessed following RIPC in living donor hepatectomy.
Time frame: within 7 days after operation
| Arm | Measure | Value (MEAN) |
|---|---|---|
| RIPC | Postopera The Maximal Aspartate Aminotransferase Level Within 7 Postoperative Days | 145 IU/L |
| Control | Postopera The Maximal Aspartate Aminotransferase Level Within 7 Postoperative Days | 152 IU/L |
Primary
The Maximal Alanine Aminotransferase Level Within 7 Postoperative Days
The serial assessments of routine laboratory values were used as early markers for postoperative liver function. The maximal alanine aminotransferase level within 7 postoperative days were assessed following RIPC in living donor hepatectomy
Time frame: within 7 days after operation
| Arm | Measure | Value (MEAN) |
|---|---|---|
| RIPC | The Maximal Alanine Aminotransferase Level Within 7 Postoperative Days | 148 IU/L |
| Control | The Maximal Alanine Aminotransferase Level Within 7 Postoperative Days | 152 IU/L |
Secondary
Number of Participants With Delayed Recovery of Liver Function
The incidence of delayed recovery of hepatic function (DRHF) were used as surrogate parameters indicating the possible benefits of RIPC. DRHF was defined based on a proposal by the International Study Group of Liver Surgery, as follows: an impaired ability of the liver to maintain its synthetic, excretory, and detoxifying functions, which are characterized by an increased PT INR and concomitant hyperbilirubinemia (considering the normal limits of the local laboratory) on or after postoperative day 5. The normal upper limits of PT and bilirubin in our institutional laboratory were 1.30 INR and 1.2 mg/dL, respectively. If either the PT INR or serum bilirubin concentration was preoperatively elevated, DRHF was defined by an increasing PT INR and increasing serum bilirubin concentration on or after postoperative day 5 (compared with the values of the previous day).
Time frame: postoperative 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RIPC | Number of Participants With Delayed Recovery of Liver Function | 5 Participants |
| Control | Number of Participants With Delayed Recovery of Liver Function | 0 Participants |
Secondary
Postoperative Liver Regeneration
The postoperative liver regeneration index (LRI) at postoperative 1 month ) was used as surrogate parameters indicating the possible benefits of RIPC. The LRI was defined as \[(VLR - VFLR)/VFLR)\] × 100, where VLR is the volume of the liver remnant and VFLR is the volume of the future liver remnant. Liver volume was calculated by CT volumetry using 3-mm-thick dynamic CT images. The graft weight was subtracted from the total liver volume to define the future liver remnant.
Time frame: 1 month
| Arm | Measure | Value (MEAN) |
|---|---|---|
| RIPC | Postoperative Liver Regeneration | 83.3 percentage of liver volume |
| Control | Postoperative Liver Regeneration | 94.9 percentage of liver volume |