Inhaled milrinone in cardiac surgical patients: pharmacokinetic and pharmacodynamic exploration

Abstract

Mean arterial pressure to mean pulmonary arterial pressure ratio (mAP/mPAP) has been identified as a strong predictor of perioperative complications in cardiac surgery. We therefore investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationship of inhaled milrinone in these patients using this ratio (R) as a PD marker. Following approval by the ethics and research committee and informed consent, we performed the following experiment. Before initiation of cardiopulmonary bypass in 28 pulmonary hypertensive patients scheduled for cardiac surgery, milrinone (5 mg) was nebulized, plasma concentrations measured (up to 10 h) and compartmental PK analysis carried out. Baseline (R0) and peak (Rmax) ratios as well as magnitude of peak response (∆Rmax-R0) were measured. During inhalation, individual area under effect-time (AUEC) and plasma concentration–time (AUC) curves were correlated. Potential relationships between PD markers and difficult separation from bypass (DSB) were explored. In this study, we observed that milrinone peak concentrations (41–189 ng ml−1) and ΔRmax-R0 (− 0.12–1.5) were obtained at the end of inhalation (10–30 min). Mean PK parameters agreed with intravenous milrinone published data after correction for the estimated inhaled dose. Paired comparisons yielded a statistically significant increase between R0 and Rmax (mean difference, 0.58: 95% CI 0.43–0.73; P < 0.001). Individual AUEC correlated with AUC (r = 0.3890, r2 = 0.1513; P = 0.045); significance increased after exclusion of non-responders (r = 4787, r2 = 0.2292; P = 0.024). Individual AUEC correlated with ∆Rmax-R0 (r = 5973, r2 = 0.3568; P = 0.001). Both ∆Rmax-R0 (P = 0.009) and CPB duration (P < 0.001) were identified as predictors of DSB. In conclusion, both magnitude of peak response of the mAP/mPAP ratio and CPB duration were associated with DSB.