INHALED NITRIC OXIDE IS ASSOCIATED WITH INCREASED ENDOTHELIN-1 LEVELS: A POTENTIAL CAUSE OF THE REBOUND PULMONARY HYPERTENSION PHENOMENON

Background: Endothelin-1 has been implicated as a cause of acute pulmonary hypertension (PHTN). Inhaled nitric oxide (iNO) has emerged as frontline therapy for PHTN, including PHTN following repair of congenital heart disease. Proposed advantages of iNO include its lack of significant systemic hemodynamic effects, and its relative `safety'. However, `rebound' PHTN has been described when inhaled NO is weaned, suggesting either impaired endogenous NO production or elevated levels of vasoconstricting agents such as ET-1. ET-1 and NO are known to crosstalk, and it is possible that iNO may affect levels of ET-1. This clinical study was undertaken in order to determine the effects of inhaled NO on levels of ET-1. Methods: Group 1- Fifteen infants and children with congenital heart disease (age 3 d-23 mos) requiring iNO for post-CPB PHTN. Arterial blood was obtained prior to iNO, at several time points during, and 24 hours following cessation of inNO. Group 2 consisted of ten adult medical patients placed on iNO therapy, and Group 3 included six infants post-CPB who were at risk for PHTN but who did not require iNO. Results: In Group 1, the average increase in ET-1 levels was 48% by 12 hrs of iNO therapy (mean average values= 3.94 pg/ml vs. 2.83 pg/ml), and levels remained elevated at 48 hours. With cessation of iNO ET-1 levels decreased an average of .59 pg/ml, from 107% of baseline to 86% of baseline. In Group 2, ET-1 levels increased above baseline by an average of 44%, 61%, 51%, and 50% at 2, 12, 24, and 48 hours (mean average values= 3.25, 3.3, 3.1, and 3.0 pg/ml compared with baseline of 2.33pg/ml). Prior to cessation of iNO, ET-1 levels were 124% of baseline (2.89 pg/ml) and fell dramatically to 54% of baseline (1.26 pg/ml) within 24 hours of discontinuing iNO. In Group 3, ET-1 levels decreased by an average of 24% and 35% at 12 and 24 hours post-op. (2.29, 1.68, 1.21 pg/ml at baseline, 12, and 24 hours). Conclusion: ET-1 levels increase by as much as 61% following institution of inhaled NO therapy. The increase in ET-1 does not appear to be a result of CPB as levels did not increase in non-treated patients post-CPB, but did occur in non-surgical adult patients. These data suggest that iNO results in an increase in systemic ET-1 levels. Levels decrease back towards baseline after 48 hours, and decrease abruptly when iNO is stopped. This increase in ET-1 may explain part of the rebound phenomenon seen when attempting to wean iNO, and suggests that once iNO