Inhaled Pulmonary Vasodilator Therapy in Adult Lung Transplant

Abstract

IMPORTANCE Inhaled nitric oxide (iNO) is commonly administered for selectively inhaled pulmonary vasodilation and prevention of oxidative injury after lung transplant (LT). Inhaled epoprostenol (iEPO) has been introduced worldwide as a cost-saving alternative to iNO without high-grade evidence for this indication.OBJECTIVE To investigate whether the use of iEPO will lead to similar rates of severe/grade 3 primary graft dysfunction (PGD-3) after adult LT when compared with use of iNO.DESIGN, SETTING, AND PARTICIPANTS This health system-funded, randomized, blinded (to participants, clinicians, data managers, and the statistician), parallel-designed, equivalence clinical trial included 201 adult patients who underwent single or bilateral LT between May 30, 2017, and March 21, 2020. Patients were grouped into 5 strata according to key prognostic clinical features and randomized per stratum to receive either iNO or iEPO at the time of LT via 1:1 treatment allocation.INTERVENTIONS Treatment with iNO or iEPO initiated in the operating room before lung allograft reperfusion and administered continously until cessation criteria met in the intensive care unit (ICU). MAIN OUTCOMES AND MEASURESThe primary outcome was PGD-3 development at 24, 48, or 72 hours after LT. The primary analysis was for equivalence using a two one-sided test (TOST) procedure (90% CI) with a margin of 19% for between-group PGD-3 risk difference. Secondary outcomes included duration of mechanical ventilation, hospital and ICU lengths of stay, incidence and severity of acute kidney injury, postoperative tracheostomy placement, and in-hospital, 30-day, and 90-day mortality rates. An intention-to-treat analysis was performed for the primary and secondary outcomes, supplemented by per-protocol analysis for the primary outcome.RESULTS A total of 201 randomized patients met eligibility criteria at the time of LT (129 men [64.2%]). In the intention-to-treat population, 103 patients received iEPO and 98 received iNO. The primary outcome occurred in 46 of 103 patients (44.7%) in the iEPO group and 39 of 98 (39.8%) in the iNO group, leading to a risk difference of 4.9% (TOST 90% CI, -6.4% to 16.2%; P = .02 for equivalence). There were no significant between-group differences for secondary outcomes.CONCLUSIONS AND RELEVANCE Among patients undergoing LT, use of iEPO was associated with similar risks for PGD-3 development and other postoperative outcomes compared with the use of iNO.

Intraoperative Circulatory Support in Lung Transplantation: Current Trend and Its Evidence

“…Inhaled NO can improve oxygenation by reducing the alveolar shunt volume and shows a pronounced reduction in right ventricular afterload without affecting systemic afterload [ 73 ]. Studies on the effects during transplantation demonstrated an improvement in oxygenation and a decrease in pulmonary arterial pressure [ 74 ]. However, randomised clinical data demonstrating an improvement in outcome are lacking.…”

“…A more recent study compared iNO with inhaled epoprostenol, which is significantly less expensive. There were no differences in outcome [ 74 ]. Side effects of iNO include renal failure, methaemoglobinaemia, and in the experimental setting, platelet dysfunction.…”

Critical Care Management Following Lung Transplantation

“…Therefore, the routine use of inhaled NO in lung transplantation is not recommended, but its selective use is recommended for patients with severe graft dysfunction showing severe hypoxemia and elevated pulmonary artery pressure [ 37 ]. Inhaled epoprostenol was recently reported to be equivalent to inhaled NO for preventing severe graft dysfunction [ 38 ]. However, it remains unclear whether either inhaled NO or epoprostenol conferred any benefit and whether their routine use to prevent graft dysfunction should be supported.…”

Role of Pulmonary Vasodilators in Ameliorating Primary Graft Dysfunction Following Lung Transplant

“…International registries have reported an incidence of PGD-3 at 72 hours approaching 15%, but it is unusual to observe rates exceeding 5% to 10% in experienced centers . The nonrandomized trial by Moreno et al, cited in the study by Ghadimi et al, did show a high incidence (45%) of PGD-3 at 72 hours, which was reduced to 17.2% with iNO . However, that report presented insufficient patient information, methods for patient selection or treatment allocation, and potentially has considerable selection bias.…”

“…In the blinded randomized clinical trial by Ghadimi et al, inhaled epoprostenol was reported to be equivalent to inhaled nitric oxide (iNO) in preventing severe grade 3 primary graft dysfunction (PGD-3). While institution-specific contracts greatly influence the cost of iNO, it is generally an expensive therapy.…”