Comparison of inhaled milrinone, nitric oxide and prostacyclin in acute respiratory distress syndrome.

AIM: To evaluate the safety and efficacy of inhaled milrinone in acute respiratory distress syndrome (ARDS). METHODS: Open-label prospective cross-over pilot study where fifteen adult patients with hypoxemic failure meeting standard ARDS criteria and monitored with a pulmonary artery catheter were recruited in an academic 24-bed medico-surgical intensive care unit. Random sequential administration of iNO (20 ppm) or nebulized epoprostenol (10 µg/mL) was done in all patients. Thereafter, inhaled milrinone (1 mg/mL) alone followed by inhaled milrinone in association with inhaled nitric oxide (iNO) was administered. A jet nebulization device synchronized with the mechanical ventilation was use to administrate the epoprostenol and the milrinone. Hemodynamic measurements and partial pressure of arterial oxygen (PaO2) were recorded before and after each inhaled therapy administration. RESULTS: The majority of ARDS were of pulmonary cause (n = 13) and pneumonia (n = 7) was the leading underlying initial disease. Other pulmonary causes of ARDS were: Post cardiopulmonary bypass (n = 2), smoke inhalation injury (n = 1), thoracic trauma and pulmonary contusions (n = 2) and aspiration (n = 1). Two patients had an extra pulmonary cause of ARDS: A polytrauma patient and an intra-abdominal abscess Inhaled nitric oxide, epoprostenol, inhaled milrinone and the combination of inhaled milrinone and iNO had no impact on systemic hemodynamics. No significant adverse events related to study medications were observed. The median increase of PaO2 from baseline was 8.8 mmHg [interquartile range (IQR) = 16.3], 6.0 mmHg (IQR = 18.4), 6 mmHg (IQR = 15.8) and 9.2 mmHg (IQR = 20.2) respectively with iNO, epoprostenol, inhaled milrinone, and iNO added to milrinone. Only iNO and the combination of inhaled milrinone and iNO had a statistically significant effect on PaO2. CONCLUSION: When comparing the effects of inhaled NO, milrinone and epoprostenol, only NO significantly improved oxygenation. Inhaled milrinone appeared safe but failed to improve oxygenation in ARDS.

A specific and sensitive HPLC-MS/MS micromethod for milrinone plasma levels determination after inhalation in cardiac patients.

BACKGROUND: Milrinone administered through inhalation is an emerging method aimed at specifically reducing pulmonary hypertension without affecting systemic pressures. Its administration has been shown to be useful both in patients undergoing cardiac surgery and for persistent pulmonary hypertension of the newborn. These populations are prone to receive many concomitant medications and/or blood sampling may require a low volume quantification method. To address these issues in view of pharmacokinetic studies, this article aims to develop and validate a specific and sensitive analytical assay using high performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS) detection for the quantification of milrinone plasma concentrations after inhalation in patients undergoing cardiac surgery. METHODS: Plasma samples (50 µL) were extracted using ethyl acetate. Milrinone was separated on a C18 analytical column at 50°C. The mobile phase consisted of methanol and 10 mM ammonium acetate (45:55 vol/vol). The electrospray was operated in the negative ionization mode and monitored the following mass transitions: m/z 212.1 → 140.0 at 36 eV for milrinone and m/z 252.1 → 156.1 at 32 eV for olprinone. RESULTS: Calibration curves followed a quadratic regression in the concentration range of 0.3125-640 ng/mL. The lower limit of quantification is 0.3125 ng/mL and is based on a low plasma volume of 50 µL. Mean drug recovery and accuracy were ≥72.3% and 96.0%, respectively. Intraday and interday precision coefficient of variation (%) was ≤7.4% and ≤11.5%, respectively. The specificity allowed milrinone quantification in the multidrug administration conditions of cardiopulmonary bypass. CONCLUSIONS: This validated micromethod proved to be highly sensitive and specific while using a low volume of plasma. Its low volume and its lower limit of quantification indicate that this approach is suitable for further characterization of milrinone pharmacokinetics in both adults (inhalation) and neonates.