A multicentre randomized-controlled trial of inhaled milrinone in high-risk cardiac surgical patients.

PURPOSE: Inhaled milrinone (iMil) has been used for the treatment of pulmonary hypertension (PH) but its efficacy, safety, and prophylactic effects in facilitating separation from cardiopulmonary bypass (CPB) and preventing right ventricular (RV) dysfunction have not yet been evaluated in a clinical trial. The purpose of this study was to investigate if iMil administered before CPB would be superior to placebo in facilitating separation from CPB. METHODS: High-risk cardiac surgical patients with PH were randomized to receive iMil or placebo after the induction of anesthesia and before CPB. Hemodynamic parameters and RV function were evaluated by means of pulmonary artery catheterization and transesophageal echocardiography. The groups were compared for the primary outcome of the level of difficulty in weaning from CPB. Among the secondary outcomes examined were the reduction in the severity of PH, the incidence of RV failure, and mortality. RESULTS: Of the 124 patients randomized, the mean (standard deviation [SD]) EuroSCORE II was 8.0 (2.6), and the baseline mean (SD) systolic pulmonary artery pressure (SPAP) was 53 (9) mmHg. The use of iMil was associated with increases in cardiac output (P = 0.03) and a reduction in SPAP (P = 0.04) with no systemic hypotension. Nevertheless, there was no difference in the combined incidence of difficult or complex separation from CPB between the iMil and control groups (30% vs 28%, respectively; absolute difference, 2%; 95% confidence interval [CI], -14 to 18; P = 0.78). There was also no difference in RV failure between the iMil and control groups (15% vs 14%, respectively; difference, 1%; 95% CI, -13 to 12; P = 0.94). Mortality was increased in patients with RV failure vs those without (22% vs 2%, respectively; P < 0.001). CONCLUSION: In high-risk cardiac surgery patients with PH, the prophylactic use of iMil was associated with favourable hemodynamic effects that did not translate into improvement of clinically relevant endpoints. This trial was registered at ClinicalTrials.gov; identifier: NCT00819377.

RéSUMé: OBJECTIF: La milrinone inhalée est utilisée pour traiter l'hypertension pulmonaire (HP) mais son efficacité, son innocuité et ses effets prophylactiques pour faciliter le sevrage de la circulation extracorporelle (CEC) et prévenir la dysfonction ventriculaire droite (VD) n'ont pas encore été évalués dans le cadre d'une étude clinique. L'objectif de cette étude était d'examiner si la milrinone inhalée avant la CEC serait supérieure à un placebo pour faciliter le sevrage de la CEC. MéTHODE: Des patients de chirurgie cardiaque à risque élevé et souffrant d'HP ont été randomisés à recevoir de la milrinone inhalée ou un placebo après l'induction de l'anesthésie et avant la CEC. Les paramètres hémodynamiques et la fonction VD ont été évalués à l'aide d'un cathéter de l'artère pulmonaire et d'une échocardiographie transœsophagienne. Les groupes ont été comparés selon notre critère d'évaluation principal, soit le niveau de difficulté du sevrage de la CEC. Parmi les critères d'évaluation secondaires examinés figuraient la réduction de la gravité de l'HP, l'incidence d'insuffisance cardiaque droite et la mortalité. RéSULTATS: Au total, 124 patients ont été randomisés. Le score EuroSCORE II moyen (écart type [ÉT]) était de 8,0 (2,6), et la pression systolique de l'artère pulmonaire moyenne de base (ÉT) était de 53 (9) mmHg. L'utilisation de milrinone inhalée a été associée à des augmentations du débit cardiaque (P = 0,03) et à une réduction de la pression systolique de l'artère pulmonaire (P = 0,04) sans hypotension systémique. Toutefois, aucune différence n'a été observée dans l'incidence combinée de sevrage difficile ou complexe de la CEC entre le groupe milrinone inhalée et le groupe témoin (30 % vs 28 %, respectivement; différence absolue, 2 %; intervalle de confiance [IC] 95 %, −14 à 18; P = 0,78). Aucune différence n'a été observée non plus en matière d'insuffisance cardiaque droite entre le groupe milrinone inhalée et le groupe témoin (15 % vs 14 %, respectivement; différence, 1 %; IC 95 %, −13 à 12; P = 0,94). La mortalité était augmentée chez les patients avec insuffisance cardiaque droite (22 % vs 2 %, respectivement; P < 0.001). CONCLUSION: Chez les patients de chirurgie cardiaque à risque élevé atteints de HP, l'utilisation prophylactique de milrinone inhalée a été associée à des effets hémodynamiques favorables qui ne se sont pas traduits en améliorations des critères pertinents d'un point de vue clinique. Cette étude a été enregistrée au ClinicalTrials.gov; identifiant : NCT00819377.

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.

High-performance liquid chromatography assay using ultraviolet detection for urinary quantification of milrinone concentrations in cardiac surgery patients undergoing cardiopulmonary bypass.

An analytical assay using liquid-liquid extraction and high-performance liquid chromatography with ultraviolet detection was developed for the quantification of total (conjugated and unconjugated) urinary concentrations of milrinone after the inhalation of a 5 mg dose in 15 cardiac patients undergoing cardiopulmonary bypass. Urine samples (700 µL) were extracted with ethyl-acetate and subsequently underwent acid back-extraction before and after deconjugation by mild acid hydrolysis. Milrinone was separated on a strong cation exchange analytical column. The mobile phase consisted of a constant mixture of acetonitrile:tetrahydrofurane-NaH2 PO4 buffer (40:60 v/v, pH 3.0). Thirteen calibration curves were linear in the concentration range of 31.25-4000 ng/mL, using olprinone as the internal standard (r(2) range 0.9911-0.9999, n = 13). Mean milrinone recovery and accuracy were respectively 85.2 ± 3.1% and ≥93%. Intra- and inter-day precisions (coefficients of variation) were ≤5% and ≤8%, respectively. Over a 24 h collection period, the cumulative urinary milrinone recovered from 15 patients was 26.1 ± 7.7% of the nominal 5 mg dose administered. The relative amount of milrinone glucuronic acid conjugate was negligible in the urine of patients undergoing cardiopulmonary bypass This method proved to be reliable, specific and accurate to determine the cumulative amount of total milrinone recovered in urine after inhalation.

High performance liquid chromatography using UV detection for the quantification of milrinone in plasma: improved sensitivity for inhalation.

An improved analytical assay was developed and validated for the quantification of milrinone concentrations in patients undergoing cardiac surgery. A solid-phase extraction was optimized to isolate milrinone from a plasma matrix followed by HPLC using UV detection. Plasma samples (1 ml) were extracted using a C(18) solid-phase cartridge. Milrinone was separated on a strong cation exchange analytical column maintained at 23.4 degrees C. The mobile phase consisted of a gradient (10:90 to 45:55), 0.05 M phosphate buffer (pH 3):acetonitrile. Calibration curves were linear in the concentration range of 1.25-320 ng/ml. Mean drug recovery and accuracy were respectively > or =96% and > or =92%. Intra- and inter-day precisions (CV%) were < or =6.7% and < or =7.9%, respectively. This method proved to be reliable, specific and accurate. Using different types of column for extraction and separation of milrinone proved to be necessary to achieve the sensitivity and specificity required when milrinone is given by inhalation.