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Looking beyond PPHN: the unmet challenge of chronic progressive pulmonary hypertension in the newborn.

ABSTRACT: Abstract Infants with forms of pulmonary hypertension (PH) that persist or develop beyond the first week of life are an understudied group of patients with up to 40%-60% mortality. The clinical management of the progressive PH that develops in these infants is challenging because of the nonspecific signs and symptoms of clinical presentation, the limited diagnostic sensitivity of standard echocardiographic techniques, and the lack of proven therapies. The signaling mechanisms that underlie the structural and functional abnormalities in the pulmonary circulation of these infants are not yet clear. The ability to improve outcomes for these patients awaits technological advances to improve diagnostic capabilities and therapeutic discoveries made in basic science laboratories that can be tested in randomized clinical trials.

SUBMITTER: Fike CD

PROVIDER: S-EPMC4070810 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Looking beyond PPHN: the unmet challenge of chronic progressive pulmonary hypertension in the newborn.

Fike Candice D CD Aschner Judy L JL

Pulmonary circulation 20130901 3

Abstract Infants with forms of pulmonary hypertension (PH) that persist or develop beyond the first week of life are an understudied group of patients with up to 40%-60% mortality. The clinical management of the progressive PH that develops in these infants is challenging because of the nonspecific signs and symptoms of clinical presentation, the limited diagnostic sensitivity of standard echocardiographic techniques, and the lack of proven therapies. The signaling mechanisms that underlie the s ...[more]

PMID: 24618533

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Project description:Key pointsPeak oxygen uptake, a primary determinant of prognosis, mortality and quality of life, is diminished in patients with chronic obstructive pulmonary disease (COPD), with mounting evidence supporting an important role for peripheral dysfunction, particularly within skeletal muscle. In patients with severe COPD and activity-matched controls, muscle oxygen transport and utilization were assessed at peak effort during single-leg knee-extensor exercise (KE), where ventilation is assumed to be submaximal. This strategy removes ventilation as the major constraint to exercise capacity in COPD, allowing maximal muscle function to be attained and evaluated. During maximal KE, both convective arterial oxygen delivery to the skeletal muscle microvasculature and subsequent diffusive oxygen delivery to the mitochondria were diminished in patients with COPD compared to control subjects. These findings emphasize the importance of factors, beyond the lungs, that influence exercise capacity in this patient population and may, ultimately, influence the prognosis, mortality and quality of life for patients with COPD.AbstractPeak oxygen uptake ( V?O2peak ), a primary determinant of prognosis, mortality and quality of life, is diminished in patients with chronic obstructive pulmonary disease (COPD). Mounting evidence supports an important role of the periphery, particularly skeletal muscle, in the diminished V?O2peak with COPD. However, the peripheral determinants of V?O2peak have not been comprehensively assessed in this cohort. Thus, the hypothesis was tested that both muscle convective and diffusive oxygen (O2 ) transport, and therefore skeletal muscle peak O2 uptake ( V?MO2peak ), are diminished in patients with COPD compared to matched healthy controls, even when ventilatory limitations (i.e. attainment of maximal ventilation) are minimized by using small muscle mass exercise. Muscle O2 transport and utilization were assessed at peak exercise from femoral arterial and venous blood samples and leg blood flow (by thermodilution) in eight patients with severe COPD (forced expiratory volume in 1s (FEV1 ) ± SEM = 0.9 ± 0.1 l, 30% of predicted) and eight controls during single-leg knee-extensor exercise. Both muscle convective O2 delivery (0.44 ± 0.06 vs. 0.69 ± 0.07 l min-1 , P < 0.05) and muscle diffusive O2 conductance (6.6 ± 0.8 vs. 10.4 ± 0.9 ml min-1 mmHg-1 , P < 0.05) were ?1/3 lower in patients with COPD than controls, resulting in an attenuated V?MO2peak in the patients (0.27 ± 0.04 vs. 0.42 ± 0.05 l min-1 , P < 0.05). When cardiopulmonary limitations to exercise are minimized, the convective and diffusive determinants of V?MO2peak , at the level of the skeletal muscle, are greatly attenuated in patients with COPD. These findings emphasize the importance of factors, beyond the lungs, that may ultimately influence this population's prognosis, mortality and quality of life.

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.

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Looking beyond PPHN: the unmet challenge of chronic progressive pulmonary hypertension in the newborn.

Publications

Looking beyond PPHN: the unmet challenge of chronic progressive pulmonary hypertension in the newborn.

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