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The use of milrinone in neonates with persistent pulmonary hypertension of the newborn - a randomised controlled trial pilot study (MINT 1): study protocol and review of literature.

ABSTRACT: Persistent pulmonary hypertension of the newborn (PPHN) is a relatively common condition which results in a mortality of up to 33%. Up to 40% of infants treated with nitric oxide (iNO) either have a transient response or fail to demonstrate an improvement in oxygenation. Milrinone, a selective phosphodiesterase 3 (PDE3) inhibitor with inotropic and lusitropic properties may have potential benefit in PPHN. This pilot study was developed to assess the impact of milrinone administration on time spent on iNO in infants with PPHN. This is a multicentre, randomized, double-blind, two arm pilot study, with a balanced (1:1) allocation of 20 infants. In this pilot study, we hypothesise that infants ?34 weeks gestation and???2000 g with a clinical and echocardiography diagnosis of PPHN, intravenous milrinone used in conjunction with iNO will result in a reduction in the time spent on iNO. In addition, we hypothesise that milrinone treatment will lead to an improvement in myocardial performance and global hemodynamics when compared to iNO alone. We will also compare the rate of adverse events associated with the milrinone, and the pre-discharge outcomes of both groups. The purpose of this pilot study is to assess the feasibility of performing the trial and to obtain preliminary data to calculate a sample size for a definitive multi-centre trial of milrinone therapy in PPHN. Trial registration: www.isrctn.com; ISRCTN:12949496; EudraCT Number:2014-002988-16.

SUBMITTER: El-Khuffash A

PROVIDER: S-EPMC6276183 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The use of milrinone in neonates with persistent pulmonary hypertension of the newborn - a randomised controlled trial pilot study (MINT 1): study protocol and review of literature.

El-Khuffash Afif A McNamara Patrick J PJ Breatnach Colm C Bussmann Neidin N Smith Aisling A Feeney Oliver O Tully Elizabeth E Griffin Joanna J de Boode Willem P WP Cleary Brian B Franklin Orla O Dempsey Eugene E

Maternal health, neonatology and perinatology 20181203

Persistent pulmonary hypertension of the newborn (PPHN) is a relatively common condition which results in a mortality of up to 33%. Up to 40% of infants treated with nitric oxide (iNO) either have a transient response or fail to demonstrate an improvement in oxygenation. Milrinone, a selective phosphodiesterase 3 (PDE3) inhibitor with inotropic and lusitropic properties may have potential benefit in PPHN. This pilot study was developed to assess the impact of milrinone administration on time spe ...[more]

PMID: 30524749

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Project description:BACKGROUND:Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome characterized by suboptimal oxygenation as a result of sustained elevation in pulmonary vascular resistance after birth. Currently, the therapeutic mainstay for PPHN is optimal lung inflation and selective vasodilatation with inhaled nitric oxide (iNO). However, iNO is not available in all countries and not all infants will respond to iNO. Milrinone is a phosphodiesterase III inhibitor which induces pulmonary vasodilatation by its actions through a cyclic adenylate monophosphate mediated signaling pathway. OBJECTIVES:To assess efficacy and safety in infants with PPHN either treated with: milrinone compared with placebo or no treatment; milrinone compared with iNO; milrinone as an adjunct to iNO compared with iNO alone; milrinone compared with potential treatments for PPHN other than iNO. SEARCH STRATEGY:We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2010), MEDLINE and EMBASE databases from their inception until January 2010. We searched the reference lists of potentially relevant studies without any language restriction. SELECTION CRITERIA:Fully published randomized controlled trials (RCTs) and quasi-RCTs comparing milrinone with placebo, iNO or potential treatments other than iNO in neonates with PPHN were included if trials reported any clinical outcome. DATA COLLECTION AND ANALYSIS:We found no studies meeting the criteria for inclusion in this review. MAIN RESULTS:We found no studies meeting the criteria for inclusion in this review. AUTHORS' CONCLUSIONS:The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs. Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or, in well resourced countries, should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone.

Project description:BACKGROUND:Substantial numbers of neonates with hypoxic respiratory failure (HRF) do not immediately respond to inhaled nitric oxide (iNO) and are often labeled as non-responders. This retrospective data analysis assessed time to treatment response in the iNO key registration trial. METHODS:Treatment response was defined as a??10% increase in partial pressure of arterial oxygen (PaO2) or a??10% decrease in oxygenation index (OI) after initiation of study gas without the need for extracorporeal membrane oxygenation (ECMO). The proportion of patients showing a response at 30?min, 1?h, 24?h, and?>24?h after iNO or placebo initiation was calculated and stratified by baseline PaO2 and OI. RESULTS:Data from 248 patients (iNO: n =?126; placebo: n =?122) were included; 66 patients receiving iNO showed improvement in oxygenation without needing ECMO versus 38 receiving placebo. Of the 66 iNO responders, 73% responded within ?30?min, 9% within ?1?h, 12% within ?24?h, and 6% after 24?h. Of the 38 patients with improvement in oxygenation without needing ECMO while receiving placebo, 53% showed improvement within ?30?min, 16% within ?1?h, 29% within ?24?h, and 3% after 24?h. Baseline disease severity was not predictive of time to response. Of the 48 patients in the iNO treatment group who were classified as non-responders due to eventual need for ECMO and not included in the analysis of responders, 40 (83%) had an initial improvement in oxygenation during iNO therapy. CONCLUSIONS:Changes in PaO2 and OI after iNO initiation appear to be imprecise biomarkers of response to therapy in neonates with HRF. In some patients treated with iNO, it took up to 24?h to achieve improvement in oxygenation without need for ECMO, and a majority of those who eventually required ECMO did show an initial improvement in oxygenation during iNO treatment. Thus, reliable, objective, early criteria for iNO response still need to be established, and initial PaO2/OI responses should be interpreted with caution, particularly when considering discontinuing iNO therapy.

Project description:Background:Congenital diaphragmatic hernia (CDH) is commonly associated with pulmonary hypoplasia and pulmonary hypertension (PH). PH associated with CDH (CDH-PH) is frequently resistant to conventional pulmonary vasodilator therapy including inhaled nitric oxide (iNO) possibly due to right and left ventricular dysfunction. Milrinone is an intravenous inotrope and lusitrope with pulmonary vasodilator properties and has been shown anecdotally to improve oxygenation in PH. We developed this pilot study to determine if milrinone infusion would improve oxygenation in neonates ?36 weeks postmenstrual age (PMA) with CDH. Methods/design:Data on pulmonary vasodilator management and outcome of CDH patients was collected from 18 university NICUs affiliated with the Neonatal Research Network (NRN) from 2011 to 2012. The proposed pilot will be a masked, placebo-controlled, multicenter, randomized trial of 66 infants with CDH with an oxygenation index (OI) ?10 or oxygen saturation index (OSI) ?5. The primary outcome is the oxygenation response, as determined by change in OI at 24 h after initiation of study drug. As secondary outcomes, we will determine oxygenation at 48 h and 72 h post-infusion, right ventricular pressures on echocardiogram and the incidence of systemic hypotension, arrhythmias, intracranial hemorrhage, survival without extracorporeal membrane oxygenation, and chronic lung disease (oxygen need at 28 days postnatal age). Finally, we will evaluate the pulmonary and nutritional status at 4, 8 and 12 months of age using a phone questionnaire. Results:Three hundred thirty-seven infants with CDH were admitted to NRN NICUs in 2011 and 2012 of which 275 were ?36 weeks PMA and were exposed to the following pulmonary vasodilators: iNO (39%), sildenafil (17%), milrinone (17%), inhaled epoprostenol (6%), intravenous epoprostenol (3%), and intravenous PGE1 (1%). ECMO was required in 36% of patients. Survival to discharge was 71%. Discussion:CDH is an orphan disease with high mortality with few randomized trials evaluating postnatal management. Intravenous milrinone is a commonly used medication in neonatal/pediatric intensive care units and is currently used in 17% of patients with CDH within the NRN. This pilot study will provide data and enable further studies evaluating pulmonary vasodilator therapy in CDH. Trial registration:ClinicalTrials.gov; NCT02951130; registered 14 October 2016.

Dataset Information

The use of milrinone in neonates with persistent pulmonary hypertension of the newborn - a randomised controlled trial pilot study (MINT 1): study protocol and review of literature.

Publications

The use of milrinone in neonates with persistent pulmonary hypertension of the newborn - a randomised controlled trial pilot study (MINT 1): study protocol and review of literature.

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