Asynchrony events are frequent during noninvasive ventilation with pressure support in infants and in children despite adjusting the cycling-off criterion. Compared with pressure support, neurally adjusted ventilator assist allows improving patient-ventilator synchrony by reducing trigger delay and the number of asynchrony events. Further studies should determine the clinical impact of these findings.

The main cause of pulmonary hypertension in newborn babies results from the failure of the pulmonary circulation to dilate at birth, termed 'persistent pulmonary hypertension of the newborn' (PPHN). This syndrome is characterized by sustained elevation of pulmonary vascular resistance, causing extrapulmonary right-to-left shunting of blood across the ductus arteriosus and foramen ovale and severe hypoxaemia. It can also lead to life-threatening circulatory failure. There are many controversial and unresolved issues regarding the pathophysiology of PPHN, and these are discussed. PPHN is generally associated with factors such as congenital diaphragmatic hernia, birth asphyxia, sepsis, meconium aspiration and respiratory distress syndrome. However, the perinatal environment-exposure to nicotine and certain medications, maternal obesity and diabetes, epigenetics, painful stimuli and birth by Caesarean section-may also affect the maladaptation of the lung circulation at birth. In infants with PPHN, it is important to optimize circulatory function. Suggested management strategies for PPHN include: avoidance of environmental factors that worsen PPHN (e.g. noxious stimuli, lung overdistension); adequate lung recruitment and alveolar ventilation; inhaled nitric oxide (or sildenafil, if inhaled nitric oxide is not available); haemodynamic assessment; appropriate fluid and cardiovascular resuscitation and inotropic and vasoactive agents.

ClinicalTrials.gov Identifier: NCT01490580, EudraCT number: 2009-014885-25.

Although inhaled NO (iNO) therapy is often effective in treating infants with persistent pulmonary hypertension of the newborn (PPHN), up to 40% of patients fail to respond, which may be partly due to abnormal expression and function of soluble guanylate cyclase (sGC). To determine whether altered sGC expression or activity due to oxidized sGC contributes to high pulmonary vascular resistance (PVR) and poor NO responsiveness, we studied the effects of cinaciguat (BAY 58-2667), an sGC activator, on pulmonary artery smooth muscle cells (PASMC) from normal fetal sheep and sheep exposed to chronic intrauterine pulmonary hypertension (i.e., PPHN). We found increased sGC α(1)- and β(1)-subunit protein expression but lower basal cGMP levels in PPHN PASMC compared with normal PASMC. To determine the effects of cinaciguat and NO after sGC oxidation in vitro, we measured cGMP production by normal and PPHN PASMC treated with cinaciguat and the NO donor, sodium nitroprusside (SNP), before and after exposure to 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, an sGC oxidizer), hyperoxia (fraction of inspired oxygen 0.50), or hydrogen peroxide (H(2)O(2)). After treatment with ODQ, SNP-induced cGMP generation was markedly reduced but the effects of cinaciguat were increased by 14- and 64-fold in PPHN fetal PASMC, respectively (P < 0.01 vs. controls). Hyperoxia or H(2)O(2) enhanced cGMP production by cinaciguat but not SNP in PASMC. To determine the hemodynamic effects of cinaciguat in vivo, we compared serial responses to cinaciguat and ACh in fetal lambs after ductus arteriosus ligation. In contrast with the impaired vasodilator response to ACh, cinaciguat-induced pulmonary vasodilation was significantly increased. After birth, cinaciguat caused a significantly greater fall in PVR than either 100% oxygen, iNO, or ACh. We conclude that cinaciguat causes more potent pulmonary vasodilation than iNO in experimental PPHN. We speculate that increased NO-insensitive sGC may contribute to the pathogenesis of PPHN, and cinaciguat may provide a novel treatment of severe pulmonary hypertension.

No abstract

No abstract

No abstract

Tourneux P, Markham N, Seedorf G, Balasubramaniam V, Abman SH. Inhaled nitric oxide improves lung structure and pulmonary hypertension in a model of bleomycin-induced bronchopulmonary dysplasia in neonatal rats. Am J Physiol Lung Cell Mol Physiol 297: L1103-L1111, 2009. First published October 16, 2009 doi:10.1152/ajplung.00293.2009.-Whether inhaled nitric oxide (iNO) prevents the development of bronchopulmonary dysplasia (BPD) in premature infants is controversial. In adult rats, bleomycin (Bleo) induces lung fibrosis and pulmonary hypertension, but the effects of Bleo on the developing lung and iNO treatment on Bleoinduced neonatal lung injury are uncertain. Therefore, we sought to determine whether early and prolonged iNO therapy attenuates changes of pulmonary vascular and alveolar structure in a model of BPD induced by Bleo treatment of neonatal rats. Sprague-Dawley rat pups were treated with Bleo (1 mg/kg ip daily) or vehicle (controls) from day 2 to 10, followed by recovery from day 11 to 19. Treatment groups received early (days 2-10), late (days 11-19), or prolonged iNO therapy (10 ppm; days 2-19). We found that compared with controls, Bleo increased right ventricular hypertrophy (RVH), and pulmonary arterial wall thickness, and reduced vessel density alveolarization. In each iNO treatment group, iNO decreased RVH (P Ͻ 0.01) and wall thickness (P Ͻ 0.01) and restored vessel density after Bleo (P Ͻ 0.05). iNO therapy improved alveolarization for each treatment group after Bleo; however, the values remained abnormal compared with controls. Prolonged iNO treatment had greater effects on lung structure after bleomycin than late treatment alone. We conclude that Bleo induces lung structural changes that mimic BPD in neonatal rats, and that early and prolonged iNO therapy prevents right ventricle hypertrophy and pulmonary vascular remodeling and partially improves lung structure. lung development; nitric oxide; alveolarization BRONCHOPULMONARY DYSPLASIA (BPD) is the chronic lung disease of infancy that most commonly occurs in premature infants who require mechanical ventilation and oxygen therapy for acute respiratory distress, but it also occurs in immature infants with few signs of initial disease (25). BPD has a multifactorial etiology, including oxygen toxicity (40), preterm delivery (53), hypoxia or hyperoxia (32, 50), infection, and inflammation (25). Perinatal inflammation can result from diverse mechanisms, including chorioamnionitis, hyperoxia, infection, or ventilator-induced lung injury, and it is strongly related to the development of BPD in various animal models, as well as in the clinical setting (8,29,37,59).Histologically, BPD is characterized by disruption of alveolar and vascular growth after preterm birth. The saccular and alveolar periods of lung development are characterized by rapid increases in vessel growth and septation of the distal air space. These periods of lung development occur from the 24th wk of gestation through the first 3 yr of life in humans and during the first 3 wk of ...