A Specific and Sensitive HPLC–MS/MS Micromethod for Milrinone Plasma Levels Determination After Inhalation in Cardiac Patients

Gavra, Paul; Nguyen, Anne Quynh-Nhu; Théôret, Yves; Litalien, Catherine; Denault, André

doi:10.1097/ftd.0000000000000072

Cited by 12 publications

(5 citation statements)

References 21 publications

(18 reference statements)

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“…This is most likely related to the systemic vasodilatory effect of the drug and the elevated peak plasma concentrations (over 200 ng•ml −1 ) 32,33 . However, when milrinone is administered by inhalation, plasma levels are lower and no systemic hypotension is reported (as demonstrated in this study) [34][35][36] . In a recent multicenter randomized controlled trial, we did not observe any difference in terms of arterial pressure change in the group receiving inhaled milrinone vs. placebo 17 .…”

Section: Discussionmentioning

confidence: 75%

Inhaled milrinone in cardiac surgical patients: a pilot randomized controlled trial of jet vs. mesh nebulization

Nguyen

Denault

Théôret

et al. 2020

Sci Rep

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inhaled milrinone administered before cardiopulmonary bypass (cpB) reduces the severity of pulmonary hypertension during cardiac surgery. However, milrinone pharmacokinetics has not been determined for this route of administration. the objective of this study was to investigate inhaled milrinone dosing in vitro and early plasma concentrations in vivo after jet and mesh nebulization. twelve pulmonary hypertensive patients scheduled for cardiac surgery were randomized to receive milrinone (5 mg) by inhalation before CPB using a jet or mesh nebulizer. In vitro experiments were conducted to determine the inhaled dose delivered with either jet or mesh nebulization. In vivo experiments involved hemodynamic monitoring and blood samples drawn from patients for the first 15 min after the end of inhalation to determine early plasma concentrations. After mesh nebulization, the mean in vitro inhaled dose was almost 3-fold higher compared to jet nebulization (46.4% vs 16.6% for mesh and jet, respectively; mean difference, 29.8%; 95% CI, 14.1 to 45.5; P = 0.006). Consistent with this, the early plasma concentrations in vivo were also 2-3 fold higher after mesh nebulization (P = 0.002-0.005). After inhalation (jet or mesh nebulization), milrinone early plasma concentrations remained within the therapeutic range. no systemic hypotension was reported in our patients. Intravenous milrinone, a phosphodiesterase inhibitor and inodilator, has been extensively used in cardiac surgery for the treatment of pulmonary hypertension (PH), particularly during difficult separation from cardiopulmonary bypass (CPB) 1-4. An important drawback of intravenous milrinone is its association with systemic hypotension 5-7. To avoid this side effect, inhalation has been proposed as an alternative therapeutic route of administration for milrinone 8-10. Pulmonary drug delivery presents advantages such as rapid absorption, high bioavailability, and high local concentrations 11. Consequently, a hypothesis was put forward in the past decade that inhaled milrinone administered prior to CPB would have a protective effect against the exacerbation of PH in cardiac surgical patients 12,13 by minimizing CPB-related inflammation 14 , preventing pulmonary endothelial dysfunction 15 , and facilitating separation from CPB 16. More recently, a multicenter randomized controlled trial demonstrated the clinical efficacy of inhaled milrinone in reducing the degree of PH; however, it was not associated with a reduction in difficulty separating from CPB 17. Several factors could explain those results, including suboptimal drug delivery 18. Nebulizers are commonly used drug delivery devices in aerosol therapy for patients with pulmonary diseases. These devices operate by converting liquid formulations into fine breathable droplets. There are three types of nebulizers: jet, ultrasonic and mesh 19. Apart from four clinical studies using ultrasonic 9,14 or mesh nebulizers 17,20 , jet nebulizers have been the standard drug delivery devices for inhaled milrinone in adult cardiac ...

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Section: Discussionmentioning

confidence: 75%

Inhaled milrinone in cardiac surgical patients: a pilot randomized controlled trial of jet vs. mesh nebulization

Nguyen

Denault

Théôret

et al. 2020

Sci Rep

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“…First, the optimal dosage and concentration of iMil are based on limited data. 22,29,30 Jaski et al studied intravenous iMil concentrations in patients with congestive heart failure and reported a concentration-related positive inotropic action. 5 The concentration at the lowest iMil dosage was\156 ngÁmL -1 , and as the dose was increased, the concentration rose to [ 400 ngÁmL -1 .…”

Section: Discussionmentioning

confidence: 99%

“…51 As we were able to confirm, iMil levels \ 100 ngÁmL -1 are unlikely to induce significant systemic hypotension in cardiac patients. 50 Nguyen, 22 Gavra, 29,30 and Haglund 19 have measured iMil concentrations following nebulization in patients with an LV assist device. It is possible that the limited effect of iMil on PH could be secondary to a lower and ineffective concentration in some patients.…”

Section: Discussionmentioning

confidence: 99%

“…The 5-mg dose selected (resulting in a range of 50-80 lgÁkg -1 ) was based on previous studies, our experience in using iMil, 10,11,14,17 and various pharmacokinetic (PK) studies. 22,29,30 Concomitant medications were permitted according to local standards of care, with the exception of iMil. during the surgery and titrated according to blood pressure and central venous pressure (CVP).…”

Section: Pharmacological Treatmentmentioning

confidence: 99%

“…The plasma supernatant was frozen at -70°C until high-performance liquid chromatography-tandem mass spectrometry analysis. 29,30 Hemodynamic parameters (MAP and MPAP) were recorded at times corresponding to blood collection, and the MAP/MPAP ratio was calculated as a pharmacodynamic marker. 37,38 Noncompartmental analysis was subsequently performed on PK and PD data using Phoenix TM software (Certara, St. Louis, MO, USA).…”

Section: Pharmacokinetic and Pharmacodynamic (Pd) Substudymentioning

confidence: 99%

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

Denault

Bussières

Arellano

et al. 2016

Can J Anesth/J Can Anesth

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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. RésuméObjectif 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 transoesophagienne. Les groupes ont été comparés selon notre critère d'évaluation principal, soit le niveau de difficulté du sevrage de la CEC. Parmi les critères...

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Developmental Pharmacokinetics and Age-Appropriate Dosing Design of Milrinone in Neonates and Infants with Acute Kidney Injury Following Cardiac Surgery

et al. 2019

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A Specific and Sensitive HPLC–MS/MS Micromethod for Milrinone Plasma Levels Determination After Inhalation in Cardiac Patients

Cited by 12 publications

References 21 publications

Inhaled milrinone in cardiac surgical patients: a pilot randomized controlled trial of jet vs. mesh nebulization

Inhaled milrinone in cardiac surgical patients: a pilot randomized controlled trial of jet vs. mesh nebulization

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

Developmental Pharmacokinetics and Age-Appropriate Dosing Design of Milrinone in Neonates and Infants with Acute Kidney Injury Following Cardiac Surgery

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