Iloprost in persistent pulmonary hypertension of the newborn

Ehlen, Michael; Wiebe, Beatrix

doi:10.1017/s1047951103000726

Cited by 51 publications

(63 citation statements)

References 7 publications

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“…during cardiac surgery, iloprost had a beneficial effect both in adult and pediatric patients. Because it has a different site of action than NO and prevents lung damage in a model of neutrophil-induced lung injury (29), it would theoretically be a suitable treatment in the newborn infant (10). In adult patients with PH, inhaled iloprost is recommended as a third or fourth-line agent or as an adjunct to i.v.…”

Section: Discussionmentioning

confidence: 99%

Circulatory Effects of Inhaled Iloprost in the Newborn Preterm Lamb

et al. 2009

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Inhaled NO (iNO) has an established role in the treatment of pulmonary hypertension (PH) in the newborn. However, costs and potential toxicity associated with iNO have generated interest in alternative inhaled selective pulmonary vasodilators such as iloprost. In a preterm lamb model of respiratory distress syndrome, we studied effects of increasing doses of iloprost followed by iNO on right ventricular pressure (RVP) and circulation including cerebral oxygenation. Fetal sheep were randomized to three doses (0.2-4 mg/kg) of iloprost (n ϭ 9) or saline (n ϭ 10), administered as 15-min inhalations with 15-min intervals after a 60-min postnatal stabilization. No differences were found in RVP, arterial PO 2 , or cardiac index according to treatment. The cerebral oxygenation, measured with near-infrared spectroscopy, deteriorated in control lambs, but not in iloprost lambs. Iloprost treatment followed by iNO resulted in a larger decrease (p ϭ 0.007) in RVP than saline treatment followed by iNO. In conclusion, iloprost stabilized cerebral oxygenation and when followed by iNO had a larger effect on RVP than iNO alone. Although species differences may be relevant, these results suggest that iloprost should be studied in newborn infants for the treatment of PH. circulation, the pulmonary vascular resistance decreases rapidly. The vascular tone in pulmonary arteries is regulated by a balance of vasoconstrictors and vasodilators. Endothelin, hypoxemia, and acidemia have strong constrictor effects on pulmonary arterioles (1). The main endogenous vasodilators are the endothelial-derived substances NO and prostacyclin, which increase endothelial cell production of cGMP and cAMP, respectively (1). When the transition is disturbed, the pulmonary arterial resistance remains elevated resulting in considerable hypoxemia and low-oxygen delivery to tissue. As arterial O 2 tension does not necessarily reflect the oxygen delivery to tissue because of low perfusion or extraction, near-infrared spectroscopy (NIRS) has been applied to monitoring tissue oxygenation (2).Inhaled NO (iNO) exerts a rapid pulmonary vasodilatation and is an established treatment of pulmonary hypertension (PH) in newborn infants (3). iNO has, however, several disadvantages, such as unpredictable and nonsustained effect, and rebound PH after withdrawal (4). The toxic NO product peroxynitrite inhibits prostacyclin synthase (5), the key enzyme of prostacyclin synthesis. Further, NO causes an increased endothelin-1 release (6). Thus, other effective agents with fewer side effects are sought for the treatment of PH in the newborn.Prostanoids have been administered in the clinical setting mainly in adults as i.v. infusions of prostacyclin, s.c. infusion of treprostinil, and inhalations of iloprost (7). I.v. prostacyclin causes severe systemic hypotension in newborns (8). Inhaled prostacyclin decreases pulmonary vascular resistance without decreasing systemic blood pressure. The prostacyclin analogue iloprost has a longer half-life (almost 30 min) than prostac...

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Section: Discussionmentioning

confidence: 99%

Circulatory Effects of Inhaled Iloprost in the Newborn Preterm Lamb

et al. 2009

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“…Several case reports have similarly shown that inhaled prostacyclin (iPGI 2 ) is effective through pulmonary vasodilation in full-term and preterm infants with PPHN. [1][2][3][4][5] Hypoxemia in our patient was refractory to iNO but improved with iPGI 2 . We propose that this response may be due to a physiological mechanism different from pulmonary vasodilatation.…”

Section: Introductionmentioning

confidence: 56%

“…Previous reports of neonates treated with iPGI 2 have shown significant improvement in oxygenation without demonstrating an improvement in RVSP. [1][2][3][4][5] Hence, it is likely that increased surfactant production resulting from stimulation of ATII by iPGI 2 was in part responsible for improvement in oxygenation in this ELBW infant with significant lung disease. We acknowledge that several of our interventions are known to improve hypoxemia.…”

Section: Discussionmentioning

confidence: 95%

“…12 iPGI 2 acts locally, avoiding the systemic effects of hypotension and rebound hypertension seen with intravenous use, and has been successfully used in infants to treat PPHN. [1][2][3][4][5] Inhaled PGI 2 has been shown in rat alveolar type II cells (ATII) to enhance surfactant formation when lungs are stretched. Under normal conditions, surfactant production increases when ATII undergo stretch.…”

Section: Discussionmentioning

confidence: 99%

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Can inhaled prostacyclin stimulate surfactant in ELBW infants?

et al. 2007

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Respiratory distress syndrome (RDS) causes significant hypoxia in extremely low birth weight (ELBW) infants. We report an ELBW infant with RDS and pulmonary hypertension whose hypoxia did not respond to inhaled nitric oxide but improved with inhaled prostacyclin. We propose that inhaled prostacyclin alleviated the hypoxia by stimulating surfactant secretion. (2007) 27, 724-726; doi:10.1038/sj.jp.7211811 Journal of PerinatologyKeywords: persistent pulmonary hypertension; hypoxia; respiratory distress syndrome; prostacyclin; surfactant; extremely-low-birth-weight infant Background Hypoxemia is a feature of respiratory distress syndrome. Patent ductus arteriosus (PDA) and persistent pulmonary hypertension of the newborn (PPHN) can exacerbate hypoxemia. Inhaled nitric oxide (iNO) is effective for treatment of PPHN in full-term infants by decreasing pulmonary vascular resistance, thereby decreasing right-to-left shunting and alleviating hypoxemia. Several case reports have similarly shown that inhaled prostacyclin (iPGI 2 ) is effective through pulmonary vasodilation in full-term and preterm infants with PPHN. 1-5 Hypoxemia in our patient was refractory to iNO but improved with iPGI 2 . We propose that this response may be due to a physiological mechanism different from pulmonary vasodilatation.

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“…The advantages of an inhaled agent include improved selectivity for the pulmonary vascular bed, which is superior for patients with acute pulmonary hypertensive crisis with hemodynamic compromise and low cardiac output. This approach may improve ventilation/perfusion mismatch and oxygenation, and successful use has been reported in pediatric populations, including those with persistent pulmonary hypertension of the newborn and post cardiopulmonary bypass [85][86][87][88][89][90][91][92], and those refractory to inhaled nitric oxide or sildenafil [93,94]. Acute bronchoconstriction is a potential adverse event and compliance can be poor due to the need for frequent aerosol administrations, up to 8-12 times daily [11].…”

Section: Prostanoidsmentioning

confidence: 99%

Pharmacotherapy of Pulmonary Hypertension

2013

Handbook of Experimental Pharmacology

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Pulmonary arterial hypertension is a serious disease with significant morbidity and mortality. While it can occur idiopathically, it is more commonly associated with other cardiac or lung diseases. While most of the available therapies were tested in adult populations, and most therapies in children remain off-label, new reports and randomized trials are emerging that inform the treatment of pediatric populations. This review discusses currently available therapies for pediatric pulmonary hypertension, their biologic rationales, and evidence for their clinical effectiveness. KeywordsPulmonary hypertension; Pulmonary vasculature; Vasodilator; Nitric Oxide; Phosphodiesterase; Prostacyclin; Endothelin NORMAL PULMONARY VASCULAR TRANSITIONDuring fetal life, the placenta serves as the organ of gas exchange, and the fetal circulation uses a series of adaptive mechanisms to maximize delivery of oxygen to metabolically active organs such as the brain, gut and kidney. The most highly oxygenated blood enters the fetus via the umbilical vein. To efficiently direct oxygenated blood to the systemic circulation and minimize oxygen loss, almost 90% of fetal blood flow is diverted past the lungs through anatomic shunts through the foramen ovale and the ductus arteriosus. While the lung rapidly grows its network of small pulmonary arteries during the second half of gestation [1], blood flow in the pulmonary circulation remains highly restricted by hypoxic pulmonary vasoconstriction of small pulmonary arteries, which is reversed at birth by the sudden increase in lung oxygenation when the newborn takes his or her first breath. After birth, the first few breaths induce a rapid decrease in pulmonary vascular resistance and increase in pulmonary vascular flow in response to lung expansion, increased oxygen tension, and increased pH. Pulmonary artery pressure and vascular resistance decrease more slowly, with pulmonary arterial pressure reaching its nadir ~2-3 weeks after birth. However, the responsiveness to hypoxia is retained into adulthood, and pulmonary hypertension can be easily triggered in the newborn period by hypoxic lung disease, apnea, or other causes.© 2012 Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptPediatr Clin North Am. Author manuscript; available in PMC 2013 October 01. DEFINITION AND CLASSIFICATION OF PEDIATRIC PULMONARY HYPERTENSIONPulmonary hypertension is necessary to support gas exchange in the fetus, but if pulmonary arterial pressure is elevated after birth or during infancy or childhood,...

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Iloprost in persistent pulmonary hypertension of the newborn

Cited by 51 publications

References 7 publications

Circulatory Effects of Inhaled Iloprost in the Newborn Preterm Lamb

Circulatory Effects of Inhaled Iloprost in the Newborn Preterm Lamb

Can inhaled prostacyclin stimulate surfactant in ELBW infants?

Pharmacotherapy of Pulmonary Hypertension

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