Disease-related response to inhaled nitric oxide in newborns with severe hypoxaemic respiratory failure

Jc, Mercier; Lacaze, T; Storme, Laurent; Rozé, Jean‐Christophe; Dinh-Xuan, Anh Tuan; Dehan, M

doi:10.1007/s004310050928

Cited by 43 publications

(37 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…iNO is the first-line pulmonary vasodilator in many centers for the treatment of neonatal hypoxemic respiratory failure, but the response can be variable. For example, in meconium aspiration syndrome, it has been suggested that the effective alveolar distribution of iNO may be limited by meconium in the airways and that this may in part account for the variable response that has been described in this group (13). Nitric oxide alone is not always sufficient to break the vicious cycle of hypoxemia and pulmonary hypertension; thus, a percentage of infants continue to require extracorporeal life support, and a minority still die.…”

Section: Discussionmentioning

confidence: 99%

Interaction between Inhaled Nitric Oxide and Intravenous Sildenafil in a Porcine Model of Meconium Aspiration Syndrome

2004

View full text Add to dashboard Cite

There has been recent interest in the use of the phosphodiesterase-5 inhibitor sildenafil for treating pulmonary hypertension. We examined the interaction between inhaled nitric oxide (iNO) and i.v. sildenafil in 12 piglets with acute pulmonary hypertension and lung injury secondary to meconium aspiration. Six animals (controls) received no intervention after meconium instillation, and six received iNO (20 ppm) from 120 min, with the addition at 240 min of an i.v. sildenafil infusion (2 mg/kg over 2 h). Meconium instillation increased mean pulmonary artery (PA) pressure from 16.0 Ϯ 3.1 to 24.8 Ϯ 4.6 mm Hg (p Ͻ 0.01) and pulmonary vascular resistance (PVR) from 0.047 Ϯ 0.008 to 0.089 Ϯ 0.027 mm Hg · ml Ϫ1 · min Ϫ1· kg Ϫ1 (p Ͻ 0.01). Oxygenation index increased from 3 Ϯ 0.8 to 8.3 Ϯ 3.0 (p Ͻ 0.01). There were no further changes beyond 120 min in controls. iNO reduced PA pressure and PVR to baseline values, without influencing oxygenation. The addition of sildenafil further reduced PA pressure, tended to increase the cardiac output, and reduced PVR from 0.049 Ϯ 0.02 to 0.028 Ϯ 0.01 mm Hg · ml Ϫ1 · min Ϫ1 · kg Ϫ1 (p Ͻ 0.05). Sildenafil lowered the systemic blood pressure and systemic vascular resistance and produced profound arterial hypoxemia, reducing arterial PO 2 from 69 Ϯ 23 mm Hg to 49 Ϯ 15 mm Hg, despite substantial increases first in inspired oxygen fraction and subsequently in mean airway pressures. Consequently, the oxygenation index increased by 13.9 Ϯ 4.8 (p ϭ 0.01). When given in addition to iNO, sildenafil at a dose of Ͼ0.5 mg/kg produced profound pulmonary vasodilation, but this was coupled with an unacceptable deterioration in oxygenation and systemic vasodilation in this model of pulmonary hypertension with acute parenchymal lung disease. The discovery of the nitric oxide pathway has revolutionized the treatment of acute pulmonary hypertension. Inhaled nitric oxide (iNO) produces pulmonary vasodilation in ventilated lung regions by increasing cGMP levels within vascular smooth muscle (1) and is used to treat pulmonary hypertension in a variety of conditions, including persistent pulmonary hypertension of the newborn (2), primary pulmonary hypertension (3), and pulmonary hypertension early after pediatric cardiac surgery (4).Agents that inhibit the endogenous breakdown of cGMP by phosphodiesterase-5 in the lungs could theoretically have a role as adjuncts or alternatives to iNO in the treatment of acute pulmonary hypertension. E4021, a selective phosphodiesterase-5 inhibitor, was recently shown to produce highly selective pulmonary vasodilation in a model of neonatal pulmonary hypertension without parenchymal lung disease, and the authors concluded that this class of drugs may have a role in the clinical setting (5).There are increasing numbers of reports of the use of sildenafil, another phosphodiesterase-5 inhibitor, in the treatment of pulmonary hypertension. Oral sildenafil inhibits hypoxia-induced chronic pulmonary hypertension in an animal model (6), and there are anecdotal reports of its use i...

show abstract

Section: Discussionmentioning

confidence: 99%

Interaction between Inhaled Nitric Oxide and Intravenous Sildenafil in a Porcine Model of Meconium Aspiration Syndrome

2004

View full text Add to dashboard Cite

show abstract

“…8,9 In both primary and secondary persistent pulmonary hypertension of the newborn, INO improves oxygenation, reduces the need for ECMO, or improves neurodevelopmental outcomes when other therapies fail. [10][11][12][13] Clinicians have hoped that pulmonary hypertension in patients with CDH would respond similarly; however, no randomized trial has demonstrated that INO improves outcomes in these patients. Two well-designed, methodologically sound trials found that early INO treatment fails to improve survival or reduce need for ECMO in newborns with CDH.…”

mentioning

confidence: 99%

Inhaled Nitric Oxide Use in Neonates With Congenital Diaphragmatic Hernia

Campbell¹,

Herbst

Briden³

et al. 2014

Pediatrics

View full text Add to dashboard Cite

show abstract

“…In recent years, treatments for PPHN have been aimed at controlling or reversing the pulmonary endothelial dysfunction, which otherwise rapidly initiates the unrelenting cascade of pulmonary hypertension, right-toleft shunting, and hypoxemia. iNO has an important role in the acute management of pulmonary hypertension (14). However, the limited response in some patient groups, the potential for rebound upon iNO withdrawal, and more recent financial implications of long-term iNO therapy, coupled with our increasing understanding of other important molecular pathways in the pathophysiology of pulmonary hypertension, remain compelling stimuli for research into other agents (23,24).…”

Section: Discussionmentioning

confidence: 99%

“…iNO improves oxygenation and reduces the need for extracorporeal life support in some of the most severe cases (13). However, the individual response to iNO is disease specific (13,14). In infants with meconium aspiration syndrome, the distribution of iNO, and its subsequent efficacy, can be limited by the presence of meconium in the airways, reduced surfactant activity, and widespread ventilation-perfusion mismatch (14).…”

mentioning

confidence: 99%

“…However, the individual response to iNO is disease specific (13,14). In infants with meconium aspiration syndrome, the distribution of iNO, and its subsequent efficacy, can be limited by the presence of meconium in the airways, reduced surfactant activity, and widespread ventilation-perfusion mismatch (14). There is a need for continued investigation of adjuncts, or even alternatives to iNO, and in particular exploration of the role of systemic agents for the treatment of acute pulmonary hypertension.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Endothelin-A Receptor Blockade and Inhaled Nitric Oxide in a Porcine Model of Meconium Aspiration Syndrome

et al. 2004

View full text Add to dashboard Cite

Acute neonatal pulmonary hypertension is associated with increased activation of the endogenous endothelin pathway. We investigated the role of selective endothelin-A receptor blockade using i.v. BQ-123 in a piglet model of meconium aspiration syndrome. Meconium aspiration was induced in 18 anesthetized piglets. Six controls received no further intervention. Six piglets received 1 mg/kg BQ-123 at 120 min, with the addition of 20 ppm inhaled nitric oxide at 240 min. Six commenced nitric oxide therapy at 120 min, and were given i.v. BQ-123 at 240 min. The total study duration was 360 min. Meconium aspiration resulted in acute pulmonary hypertension and elevated endothelin-1 levels in all animals. There were no changes in pulmonary hemodynamics or endothelin-1 levels beyond 120 min in controls. In the group receiving BQ-123 first, this agent alone reduced the pulmonary artery pressure and pulmonary vascular resistance, and the subsequent addition of inhaled nitric oxide further reduced pulmonary artery pressure. In the group first receiving nitric oxide alone, this reduced the pulmonary artery pressure, and the addition of BQ-123 resulted in a fall in pulmonary vascular resistance. Endothelin-1 levels increased with both agents. BQ-123 was found to be a highly effective pulmonary vasodilator and augmented the effects of nitric oxide in this model of acute pulmonary hypertension. Abbreviations PPHN, persistent pulmonary hypertension of the newborn PVR, pulmonary vascular resistance ET, endothelin iNO, inhaled nitric oxide PPHN occurs when there is a failure of the normal rapid fall in PVR and increase in pulmonary blood flow with the onset of respiration at birth (1). Meconium aspiration syndrome is the single most common cause of PPHN, and can result in significant morbidity and mortality in term and near-term infants (2).The normal transition from the high-resistance fetal circulation to the low-resistance postnatal pulmonary circulation is associated with activation of the endogenous vasodilator nitric oxide-cyclic guanosine 5'-monophosphate pathway, and reduced release of the potent pulmonary vasoconstrictor, ET (3). The ET-1 isopeptide is a 21-amino acid polypeptide (4) that is produced within the pulmonary endothelium by the cleavage of its precursor, pro-ET (big ET), by ET converting enzyme. ET-1 is released by the vascular endothelium, and produces its effects through its interaction with at least two receptor subtypes-the A and B receptors, located on the vascular smooth muscle and endothelium. The pulmonary vasoconstrictor effects of ET-1 result mainly from activation of the G-proteincoupled smooth muscle A receptor, whereas stimulation of the endothelial ET-B receptor has been shown to result in vasodilatation (5). ET-1 is present in high levels at birth, with a gradual fall during the early neonatal period in healthy individuals (6). Elevated ET-1 levels have been demonstrated in animal models of meconium aspiration (7), in neonates with PPHN (3,8,9), and in older children (10) and adults (11) with pulmo...

show abstract

Disease-related response to inhaled nitric oxide in newborns with severe hypoxaemic respiratory failure

Cited by 43 publications

References 32 publications

Interaction between Inhaled Nitric Oxide and Intravenous Sildenafil in a Porcine Model of Meconium Aspiration Syndrome

Interaction between Inhaled Nitric Oxide and Intravenous Sildenafil in a Porcine Model of Meconium Aspiration Syndrome

Inhaled Nitric Oxide Use in Neonates With Congenital Diaphragmatic Hernia

Endothelin-A Receptor Blockade and Inhaled Nitric Oxide in a Porcine Model of Meconium Aspiration Syndrome

Contact Info

Product

Resources

About