Inhaled milrinone in cardiac surgical patients: pharmacokinetic and pharmacodynamic exploration

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 (R-0) and peak (R-max) ratios as well as magnitude of peak response (Delta(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 Delta(Rmax-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 R-0 and R-max (mean difference, 0.58: 95% CI 0.43-0.73; P<0.001). Individual AUEC correlated with AUC (r=0.3890, r(2)=0.1513; P=0.045); significance increased after exclusion of non-responders (r=4787, r(2)=0.2292; P=0.024). Individual AUEC correlated with Delta Rmax-R0 (r=5973, r(2)=0.3568; P=0.001). Both Delta 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.

Automated summary

This study investigated the PK/PD relationship of inhaled milrinone in patients with pulmonary hypertension undergoing cardiac surgery, using the mAP/mPAP ratio as a PD marker. The results showed that peak concentrations of milrinone were reached at the end of inhalation, and the magnitude of the peak response of the mAP/mPAP ratio was associated with difficult separation from bypass.