Ischaemia Reperfusion Injury, Liver Transplantation, Perioperative Complications
Conditions
Keywords
liver transplantation, ischemia-reperfusion injury, liver graft function, anesthesia, inflamatory response, perioperative complications, hemodynamics
Brief summary
Hepatic reperfusion during liver transplantation remains a critical phase associated with significant hemodynamic and systemic disturbances, despite advances in surgical and anesthetic management. This phase is characterized by the release of acidotic, hypothermic, and hyperkalemic blood containing metabolic byproducts and inflammatory mediators resulting from ischemia-reperfusion injury. Clinically, reperfusion is associated with hemodynamic instability, including reductions in cardiac output and arterial pressure, as well as cardiac dysfunction and arrhythmias, often requiring pharmacologic support. These alterations may affect not only immediate intraoperative stability but also short- and long-term outcomes for both the patient and the graft. The abrupt restoration of blood flow to the transplanted liver leads to the systemic release of accumulated metabolites, reactive oxygen species, and inflammatory mediators, contributing to a systemic inflammatory response that may impact distant organs, including the kidneys and heart. Several revascularization strategies have been investigated to mitigate reperfusion-related injury: initial reperfusion via the portal vein, initial reperfusion through the hepatic artery, and simultaneous reperfusion through the portal vein and hepatic artery. A less frequently used and insufficiently studied strategy, not routinely or systematically implemented, involves diverting the initial reperfusion blood from the graft to the surgical field, followed by the restoration of hepatic blood outflow to the systemic circulation. This study hypothesizes that discarding the initial reperfusion blood via the infrahepatic vena cava will attenuate early hemodynamic, metabolic, and inflammatory changes and reduce postoperative complications compared to conventional reperfusion techniques.
Detailed description
Hepatic reperfusion during liver transplantation remains a critical phase associated with significant hemodynamic and systemic disturbances, despite advances in surgical and anesthetic management. This phase is characterized by the release of acidotic, hypothermic, and hyperkalemic blood containing metabolic byproducts and inflammatory mediators resulting from ischemia-reperfusion injury. Clinically, reperfusion is associated with hemodynamic instability, including reductions in cardiac output and arterial pressure, as well as cardiac dysfunction and arrhythmias, often requiring pharmacologic support. These alterations may compromise immediate intraoperative stability and have been associated with adverse short- and long-term outcomes for both the recipient and the graft. The abrupt restoration of blood flow to the transplanted liver results in the systemic release of accumulated metabolites, reactive oxygen species, and inflammatory mediators, triggering a systemic inflammatory response that may extend beyond the liver and affect distant organs, including the kidneys and heart. Several revascularization strategies have been investigated to mitigate reperfusion-related injury, including portal vein, hepatic artery, and simultaneous reperfusion approaches. However, none have consistently demonstrated a clear benefit in reducing ischemia-reperfusion injury or improving clinical outcomes. An alternative and less explored strategy involves diverting and discarding the initial reperfusion blood from the graft before restoring venous outflow to the systemic circulation. Patients listed for liver transplantation at the study center will be systematically screened for eligibility. Written informed consent will be obtained from all eligible participants prior to enrollment, in accordance with institutional ethical standards. This study is a prospective randomized clinical trial designed to evaluate whether discarding the initial reperfusion blood via the infrahepatic vena cava attenuates early hemodynamic, metabolic, and inflammatory disturbances and improves postoperative outcomes compared with conventional reperfusion techniques.
Interventions
Discarding of the initial 180 mL of reperfusion blood from the graft via the infrahepatic vena cava during liver transplantation prior to restoration of hepatic venous outflow to systemic circulation.
Conventional liver transplantation without discarding the initial reperfusion blood.
Sponsors
Study design
Masking description
This is an open-label study. Due to the nature of the surgical intervention, blinding is not feasible. Outcomes will be assessed using objective clinical and laboratory measures.
Intervention model description
Participants will be randomized in a 1:1 ratio to one of two groups: liver transplantation with discarding of the initial reperfusion blood or conventional liver transplantation without discard. The study follows a parallel-group design to compare the effects of the intervention on early graft function, hemodynamic stability, and postoperative outcomes.
Eligibility
Inclusion criteria
* Adults aged 18 years or older * Candidates for liver transplantation at Hospital das Clínicas, University of São Paulo Medical School (HCFMUSP) * Able to provide written informed consent
Exclusion criteria
* Inability to provide informed consent * Previous liver surgery * Fulminant hepatitis * Specific liver diseases associated with severe electrolyte disturbances * End-stage renal disease requiring dialysis * Combined organ transplantation * Living donor liver transplantation * Liver retransplantation * Highly sensitized patients with limited availability of blood products * Hematologic diseases * Portal vein thrombosis involving more than 50% of the lumen * Portopulmonary hypertension (mean pulmonary artery pressure \> 20 mmHg), diagnosed preoperatively or intraoperatively
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak alanine aminotransferase (ALT) | Within 72 hours after transplantation | Peak serum ALT level (U/L) as a biomarker of early graft injury following liver transplantation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Arterial Pressure | Intraoperative, during reperfussion, 30 minutes after reperfusion, and postoperative day 1. | Monitoring arterial pressure (systolic, diastolic e medium) Unit of Measure: mmHg. |
| Cardiac Rhythm | Intraoperative, during reperfussion, 30 minutes after reperfusion, and postoperative day 1 | Cardiac rhythm monitoring with electrocardiography in ECG lead 2 and V5 |
| Cardiac Output | Intraoperative, during reperfussion, 30 minutes after reperfusion, and postoperative day 1. | Monitoring continuous cardiac output. Unit of Measure: L/min. |
| Arterial serum potassium levels | Intraoperative and daily from postoperative day 1 up to day 7. | Perioperative changes in arterial potassium levels (Unit of measure: mEq/L). |
| Blood coagulation thromboelastometry | Intraoperative (at the start of surgery, 5 minutes after reperfusion, and at the end of surgery). | Assessment of intraoperative coagulation changes using rotational thromboelastometry (ROTEM), including EXTEM and FIBTEM parameters, and activated clotting time (ACT). |
| International normalized ratio (INR) | Daily up to 72 hours after transplantation. | Assessment of graft function using international normalized ratio (INR). |
| Aspartate aminotransferase levels (AST) | Daily up to 7 days and weekly up to 30 days after transplantation. | Assessment of graft injury using serum levels of AST (Unit of measure: U/L). |
| Serum Tumor Necrosis Factor-alpha (TNF-α) | At the start of surgery, end of surgery, postoperative day 1, and postoperative day 3. | Serum levels of inflammatory mediator TNF-α (Unit of measure: pg/mL). |
| Serum B-type natriuretic peptide (BNP) | At the start of surgery, 30 minutes after reperfusion and postoperative day 1. | Assessment of BNP levels as a marker of cardiac hemodynamic stress. Unit of Measure: pg/mL. |
| Serum creatinine levels | Up to 30 days after transplantation. | Assessment of serum creatinine levels to evaluate renal function (Unit of measure: mg/dL), |
| Postoperative complications | Within 30 days after transplantation. | Complications graded according to the Clavien-Dindo classification. |
| ICU length of stay | Up to 30 days after transplantation. | Days of length of stay in the intensive care unit. |
| Hospital length of stay | Up to 30 days after transplantation. | Total hospital length of stay in days. |
| Arterial serum sodium levels | Intraoperative and daily from postoperative day 1 up to day 7. | Perioperative changes in arterial serum sodium levels (Unit of measure: mEq/L). |
| Arterial serum lactate levels | Intraoperative and daily from postoperative day 1 up to day 7. | Perioperative changes in arterial serum lactate levels (Unit of measure mg/dL), |
| Arterial serum calcium levels | Intraoperative and daily from postoperative day 1 up to day 7. | Perioperative changes in arterial serum calcium levels (Unit of measure mg/dL), |
| Serum glucose levels | Intraoperative and daily from postoperative day 1 up to day 7. | Perioperative changes in serum glucose levels (Unit of measure: mg/dL). |
| Arterial serum pH | Intraoperative and daily from postoperative day 1 up to day 7. | Perioperative changes in arterial pH units. |
| Arterial serum bicarbonate | Intraoperative and daily from postoperative day 1 up to day 7. | Perioperative changes in arterial serum bicarbonate (Unit of measure mmol/L) |
| Factor V activity levels | Daily up to 72 hours after transplantation . | Assessment of graft function using Factor V activity levels measure as percentage. |
| Alkaline phosphatase levels | Daily up to 7 days and weekly up to 30 days after transplantation. | Assessement of graft function using alkaline phosphatase levels (Unit of measure: U/L), |
| Gamma-glutamyl transferase levels | Daily up to 7 days and weekly up to 30 days after transplantation. | Assessment of liver function using serum levels of gamma-glutamyl transferase up to 7 days and weekly up to 30 days after transplantation (Unit of measure: U/L). |
| Serum ammonia levels | Daily up to 7 days and weekly up to 30 days after transplantation. | Assessment of serum ammonia levels to evaluate liver function.(Unit of measure: mcmol/L). |
| Serum urea levels | Up to 30 days after transplantation. | Assessment of serum urea levels to evaluate renal function (Unit of measure: mg/dl), |
| Urine output | Up to 30 days after transplantation. | Assessment of renal function measured by daily urine output. |
| Need for renal replacement therapy | Up to 30 days after transplantation. | Need for renal replacement therapy (hemodialysis or continuous renal replacement therapy). |
| Serum Interleukin-6 (IL-6) levels | At the start of surgery, end of surgery, postoperative day 1, and postoperative day 3. | Serum levels of inflammatory mediator IL-6 (Unit of measure: pg/mL), |
| Serum Tumor Necrosis Factor-alpha (TNF-α) levels | At the start of surgery, end of surgery, postoperative day 1, and postoperative day 3. | Serum levels of inflammatory mediator TNF-α levels. (Unit of measure: pg/mL) |
| Serum Interleukin-17 (IL-17) levels | At the start of surgery, end of surgery, postoperative day 1, and postoperative day 3. | Serum levels of inflammatory mediator IL-17 (Unit of measure: pg/mL). |
Contacts
Hospital das Clínicas, University of São Paulo Medical School
Hospital das Clínicas, University of São Paulo Medical School
Hospital das Clínicas, University of São Paulo Medical School
Hospital das Clínicas, University of São Paulo Medical School
Hospital das Clínicas, University of São Paulo Medical School
Hospital das Clínicas, University of São Paulo Medical School