Inhaled milrinone attenuates experimental acute lung injury

Bueltmann, Moritz; Kong, Xiangyang; Mertens, Michael; Yin, Ning; Yin, Jun; Liu, Zhongmin; Koster, Andreas; Kuppe, Hermann; Kuebler, Wolfgang M.

doi:10.1007/s00134-008-1344-9

Cited by 25 publications

(23 citation statements)

References 41 publications

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“…Recent studies [12][13][14][15][16] evaluated the effect of different drugs, but they used invasive procedures like post-mortem histology and regional evaluation of lung inflammation through analysis of bronchoalveolar lavage (BAL) fluid.…”

Section: Introductionmentioning

confidence: 99%

Time course of metabolic activity and cellular infiltration in a murine model of acid-induced lung injury

et al. 2012

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Section: Introductionmentioning

confidence: 99%

Time course of metabolic activity and cellular infiltration in a murine model of acid-induced lung injury

et al. 2012

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“…19 In brief, 5 weeks after MCT treatment, rats were anesthetized, tracheotomized, and mechanically ventilated with a tidal volume of 6 mL/kg bw and a positive end-expiratory pressure of 3 mmHg at 80 breaths/min, as described elsewhere. 20 …”

Section: Assessment Of Pulmonary Hemodynamics and Right Ventricular Hmentioning

confidence: 99%

Dose‐Dependent, Therapeutic Potential of Angiotensin‐(1–7) for the Treatment of Pulmonary Arterial Hypertension

et al. 2015

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The effects of the heptapeptide angiotensin-(1-7) (Ang-(1-7)), via its receptor Mas, oppose many of the effects of the classic angiotensin II signaling pathway, and pharmacological exploitation of this effect is currently actively pursued for a wide range of cardiovascular, neoplastic, or immunological disorders. On the basis of its vasodilatory and antiproliferative properties, Ang-(1-7) has consequentially also been proposed as a novel therapeutic strategy for the treatment of pulmonary arterial hypertension (PAH). In this study, we tested the effectiveness of Ang-(1-7) and its stable, cyclic analog cAng-(1-7) over a range of doses for their therapeutic potential in experimental PAH. In the monocrotaline (MCT) rat model of PAH, Ang-(1-7) or cAng-(1-7) were injected in doses of 30, 100, 300, or 900 μg kg, and effects on pulmonary hemodynamics and vascular remodeling were assessed. Five weeks after MCT injection, right ventricular systolic pressure (RVSP) was significantly reduced for 3 dose groups treated with Ang-(1-7) (100, 300, and 900 μg kg) and for all dose groups treated with cAng-(1-7), as compared to untreated controls, yet the total reduction of RVSP was <50% at best and thus markedly lower than that with a positive treatment control with ambrisentan. Medial-wall thickness in pulmonary arterioles was only slightly reduced, without reaching significance, for any of the tested Ang-(1-7) compounds and doses. The reported moderate attenuation of PAH does not confirm the previously postulated high promise of this strategy, and the therapeutic usefulness of Ang-(1-7) may be limited in PAH relative to that in other cardiovascular diseases.Keywords: pulmonary hypertension, vascular remodeling, renin-angiotensin system. Pulmonary arterial hypertension (PAH) is a rare but ultimately fatal disease defined by an increase in mean pulmonary arterial pressure to >25 mmHg at rest or >30 mmHg during exercise.1 The pathogenesis of PAH is very diverse, in that PAH may be heritable or idiopathic or develop in association with a number of diseases, such as systemic sclerosis or HIV infection. The pathology of PAH is characterized by endothelial dysfunction, which becomes apparent as an imbalance in the release of vasoconstrictive and vasodilatory factors, such as endothelin and nitric oxide (NO), leading to pulmonary vasoconstriction and ultimately promoting structural remodeling of the pulmonary vasculature, resulting in a persistent elevation in pulmonary vascular resistance. 2,3 A series of therapeutic drugs have been approved for the treatment of PAH that target three different pathways: prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. 4 While these drugs have helped to improve life expectancy and quality of life in PAH patients in the past 2 decades, mortality remains high, as one-third of PAH patients die within 3 years of diagnosis; this emphasizes the need for further research and improved therapeutic options.

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“…In addition, iMil administered before cardiopulmonary bypass (CPB) has been shown to be superior to its intravenous form in reducing pulmonary reperfusion syndrome that has been associated with endothelial dysfunction. 9,27 Although iMil has been proposed as a treatment for PH and right ventricular (RV) failure, 20,25 at present, there is a lack of large studies comparing it with placebo in a doubleblind fashion. Accordingly, the primary purpose of this study was to compare iMil administered before CPB with placebo to determine its impact on facilitating separation from CPB.…”

Section: Résumémentioning

confidence: 99%

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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Inhaled milrinone attenuates experimental acute lung injury

Abstract: Inhalation of aerosolized milrinone may present a novel therapeutic strategy for the treatment of ALI.

Cited by 25 publications

References 41 publications

Time course of metabolic activity and cellular infiltration in a murine model of acid-induced lung injury

Time course of metabolic activity and cellular infiltration in a murine model of acid-induced lung injury

Dose‐Dependent, Therapeutic Potential of Angiotensin‐(1–7) for the Treatment of Pulmonary Arterial Hypertension

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

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