Effect Inhaled Nitric Oxide in Adult Liver Transplant

Orthotopic liver transplantation remains the only curative option for patients with end-stage liver disease. Despite continuous advances in surgical techniques and perioperative management, ischemia-reperfusion injury (IRI) remains a major contributor to early graft dysfunction, with clinical consequences including prolonged intensive care stay, increased morbidity, and higher resource utilization. Reperfusion of the donor liver, particularly after portal and arterial unclamping, frequently triggers a hemodynamic instability known as post-reperfusion syndrome. This syndrome is characterized by profound vasodilation, hypotension, and a significant increase in vasopressor requirements. In some patients, it progresses into post-reperfusion vasoplegia, a state of sustained low systemic vascular resistance and poor end-organ perfusion. This condition is often accompanied by renal dysfunction, coagulopathy, and impaired early graft function, which significantly affect patient outcomes.

The pathophysiology of hepatic IRI is complex, involving endothelial activation, neutrophil recruitment, oxidative stress, mitochondrial dysfunction, and cytokine release. A key mechanistic factor contributing to reperfusion injury is the reduced bioavailability of nitric oxide (NO), due either to decreased production by endothelial nitric oxide synthase (eNOS) or its rapid inactivation by reactive oxygen species and heme-containing proteins. NO plays an essential role in maintaining microvascular tone, limiting leukocyte adhesion, and protecting against mitochondrial and endothelial injury. Restoration of NO signaling has been shown to protect against IRI in preclinical models. Inhaled nitric oxide (iNO) is approved for pulmonary hypertension and neonatal hypoxemia, but accumulating evidence suggests that it may also exert extrapulmonary effects. Studies in both animals and humans have demonstrated that iNO can attenuate IRI in the liver, heart, and skeletal muscle by increasing circulating nitrite and other bioactive NO metabolites that act as reservoirs and mediators of NO activity during ischemic stress.

In the context of liver transplantation, two retrospective clinical studies have shown that intraoperative iNO administration (at 80 ppm (parts per million)) is safe and may accelerate the recovery of liver function, reduce hepatocellular apoptosis, and decrease postoperative complications. These findings suggest that iNO could modulate the hemodynamic response to reperfusion and improve graft performance. However, despite these promising results, no prospective controlled trials or before-after studies have yet evaluated the real-time impact of intraoperative iNO on reperfusion syndrome and vasoplegia in liver transplantation.

The investigators hypothesize that the intraoperative administration of inhaled nitric oxide reduces the severity of reperfusion syndrome and the incidence of post-reperfusion vasoplegia in adult patients undergoing liver transplantation. Furthermore, the investigators propose that this intervention contributes to improved early graft function, particularly with regard to excretory performance. The present study aims to prospectively assess these outcomes using a before-after design, comparing matched cohorts of patients undergoing liver transplantation with and without intraoperative iNO. By addressing this existing gap in the literature, the investigators hope to generate clinically relevant data that may support the integration of iNO into standard perioperative protocols for liver transplant recipients.

This study involves 2 patient groups:

1. Retrospective "before" group (control arm): Adult liver transplant recipients identified retrospectively from the institutional transplant database, including all patients who underwent orthotopic liver transplantation since the implementation of the OneChart electronic medical record (EMR) system at London Health Sciences Centre between the time period of January 1, 2020 - May 31, 2025. 2. Prospective "after" group (intervention arm): 60 consecutive adult patients undergoing liver transplantation after the implementation of the iNO protocol, with prospective intervention involving intraoperative administration of iNO and prospective data collection.

For the prospective, "after" study group, the participant's liver transplant procedure will proceed according to plan. Informed, written consent will be obtained prior to the start of surgery.

Inhaled nitric oxide will be administered via the anesthesia machine, under the supervision of the attending Anesthesiologist, at a concentration of 20 parts per million (ppm) starting at induction of anesthesia. At the onset of the anhepatic phase (i.e., after explantation of the native liver), the concentration will be increased to 80 ppm. Administration will be continued until the end of the surgical procedure, at which point iNO will be discontinued. Standard anesthesia and transplant protocols will be followed in both groups, with no additional changes aside from the administration of iNO.

Participation in the "before" group will only involve retrospective data collection from the patients' electronic medical record that will gather data collected during the period of January 1, 2020 - May 31, 2025.

Data that will be collected include demographic data, medical history, intraoperative surgical details, details of iNO administration (where applicable), and post-operative outcomes. The timeline for collecting postoperative outcomes will be between 0-72 hours following surgery.

• Impact of intraoperative administration of inhaled nitric oxide (iNO) on patient hospital stay. [Time frame: 0-72 hours following liver transplant]
• Impact of intraoperative administration of inhaled nitric oxide (iNO) on in-hospital mortality [Time frame: 0-72 hours following liver transplant]
• Impact of intraoperative administration of inhaled nitric oxide (iNO) on liver function [Time frame: 0-72 hours following liver transplant]
• Impact of intraoperative administration of inhaled nitric oxide (iNO) on blood clotting [Time frame: 0-72 hours following liver transplant]
• Impact of intraoperative administration of inhaled nitric oxide (iNO) on early graft dysfunction [Time frame: 0-72 hours following liver transplant]
• Impact of intraoperative administration of inhaled nitric oxide (iNO) on the requirements for post-operative therapies and medications. [Time frame: 0-72 hours following liver transplant]