Dexmedetomidine to Prevent Hepatic Ischemia-reperfusion Injury-induced Glycocalyx Degradation and Early Allograft Dysfunction in Liver Transplantation

Assiut University

Status and phase: Active, not recruiting; Phase 4

Conditions: Liver Transplant; Complications

Treatments: Drug: Normal Saline; Drug: Dexmedetomidine

Study type: Interventional

Funder types: Other

Identifiers

NCT05031026

AYA1

Details and patient eligibility

About

the aim of the study is to approve the hypothesis that dexmedetomidine can protect against glycocalyx degradation induced by hepatic ischemia-reperfusion injury and hence can reduce the subsequent complications as early allograft dysfunction, other organ dysfunction and hemodynamic instability

Full description

The endothelial glycocalyx (EGCX) is a carbohydrate conjugate. It forms the vascular endothelial surface layer and is an important mediator of vascular permeability, coagulation, and inflammation. Inflammation, ischemia reperfusion, diabetes, and hypervolemia can cause EGCX damage.

When the EGCX is damaged by different mechanisms, glycocalyx-shedding products can be measured in the plasma. Syndecan-1 and heparan sulfate are two of components of the endothelial glycocalyx that have increased plasma concentrations after glycocalyx injury. The amount of glycocalyx-shedding correlates with the severity of the underlying pathological condition as different studies have shown.

The EGCX is an important target in the pathophysiological process of ischemia-reperfusin injury (IRI). Its destruction appears to play a central pathophysiological role in the development of IRI in conditions like shock, myocardial infarction, stroke, traumatic blood loss and during solid organ transplantation.

That damage to the endothelial glycocalyx significantly contributes to the development of IRI as recent studies have suggested. Schiefer et al. reported significantly higher plasma levels of syndecan-1 in liver graft recipients after transplantation than before transplantation, indicating destruction of the endothelial glycocalyx.

In animal studies, various drugs that may protect and/or restore the endothelial glycocalyx have been tested, while human trials are still lacking. Glycocalyx-protective strategies have been investigated during major surgery and the results indicated that preventive measures may be effective against glycocalyx destruction.

Dexmedetomidine is a potent and highly selective α2 adrenoreceptor agonist. It is widely used for sedation in ICU and also offers a good perioperative hemodynamic stability and an intraoperative anesthetic- sparing effect. So, it is used as an anesthetic adjuvant during surgery. Some studies have applied it for postoperative sedation in the setting of liver transplantation. Experimentally, it has a favorable effect on liver tissues in case of sepsis. It is also reported to have protective effects against IRI of the heart, kidney, brain, testis and recently against IRI of the liver.

The protective effects of dexmedetomidine against liver injury induced by ischemia and reperfusion during adult Liver transplantation, are indicated by suppression of the serum Intercellular adhesion molecule-1 (ICAM-1) levels, better scores of histopathological assessment, and augmented postoperative liver function tests.

The activation of α2 adrenoreceptors might be attributable to anti-inflammatory, anti-oxidant, and other cellular protective properties.

The protection might be also attributable to the enhancement of Nuclear factor, erythroid 2 like 2 (Nrf2) pathway and the suppression of mitogen-activated protein kinase (MAPK), Caspase-3/Poly (ADP-Ribose) polymerase (PARP), and Toll-like receptor 4 (TLR4)/NF-κB pathways.

In the clinical setting, a randomized controlled trial by Wang et al. of 44 patients undergoing hepatectomy found that intraoperative treatment with dexmedetomidine resulted in lower serum ALT and AST levels in the first 72 hours postoperatively.

Another study conducted in rats found that dexmedetomidine inhibited the decrease of EGCX thickness and the increase of the blood level of syndecan-1 which induced by heat stroke, which suggests that dexmedetomidine may have a protective action for EGCX.

To the investigators knowledge and till 2021, no previous human studies had discussed the protective effect of dexmedetomidine against glycocalyx degradation induced by hepatic ischemia-reperfusion injury and its impact on early allograft dysfunction in the sitting of adult living donor liver transplantation.

Enrollment: 60 estimated patients

Sex: All

Ages: 18 to 60 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Patients aged 18-60 years.
2. Model for end-stage liver disease (MELD) score 12-20.
3. No severe hemodynamic instability.
4. The liver donors aged 18-50 years and the sum of macro- and microvesicular hepatic steatosis has to be less than 30%.

Exclusion criteria

1. History of psychiatric/neurological illness.
2. Cardiovascular disease.
3. Hypertensive patients.
4. Morbid obese patients (body mass index (BMI) > 35).
5. Chronic obstructive pulmonary disease; pulmonary dysfunction (PaO2 less than 60 mmHg).
6. Known allergic reaction to any of the study medications.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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60 participants in 3 patient groups, including a placebo group

donor group

Active Comparator group

Description:

where donors only will receive dexmedetomidine

Treatment:

Drug: Dexmedetomidine

recpient group

Active Comparator group

Description:

where recepients only will receive dexmedetomidine

Treatment:

Drug: Dexmedetomidine

control group

Placebo Comparator group

Description:

both donors and recipients will receive a placebo

Treatment:

Drug: Normal Saline