Pulmonary toxicity associated with nitric oxide in term infants with severe respiratory failure

doi:10.1016/S0022-3476(98)70312-9

The Journal of Pediatrics

Volume 132, Issue 5, May 1998, Pages 827-829

Presented in part at the Sixty-fifth Annual Meeting of the Society for Pediatric Research in Washington D.C., May 6-10, 1996.

https://doi.org/10.1016/S0022-3476(98)70312-9 Get rights and content

Abstract

We prospectively analyzed airway specimens from 24 newborn infants. Inhaled nitric oxide (≤20 ppm for 1 to 4 days to 12 infants) did not affect the concentrations of the lipid peroxidation product, the surface activity, or the cytokines (interleukin-1, granulocyte-macrophage colony-stimulating factor, interleukin-1 receptor antagonist). Nitrotyrosine was detected after 10 days of life in the two infants requiring prolonged ventilation, suggesting toxicity of endogenous nitric oxide. (J Pediatr 1998;132:827-9)

Section snippets

Patients and Methods

Term infants with PPHN (n = 24) were treated at the University of California, Irvine Medical Center. Half of the infants received inhaled NO as part of the prospective study.⁹ The indications of NO therapy were (1) echocardiographic evidence of PPHN, (2) oxygen index >35 cm H₂O/torr or alveolar-arterial difference in partial pressure of oxygen (torr) >610 torr despite conventional treatment (mechanical ventilation and intravenous vasodilators), and (3) informed consent by parent(s). NO was

Results

The two groups had similar birthweight (3649 ± 219 gm, mean ± SD) versus control 3360 ± 179 gm), gestation at birth (39.2 ± 0.8 weeks vs control 38.8 ± 0.7 weeks), and male/female ratio (5:7 vs control 7:5). Three pairs had meconium aspiration, two severe asphyxia, three severe asphyxia and meconium aspiration, one meconium aspiration and sepsis, one respiratory distress syndrome, and one idiopathic PPHN. One infant treated with NO had pulmonary hemorrhage and severe asphyxia; the infant in the

Discussion

Persistent pulmonary hypertension of the newborn is frequently associated with inflammatory lung disease or severe asphyxia and resuscitation at birth. Excess of superoxide radicals generated in these conditions may react with inhaled NO, resulting in formation of peroxynitrite, which exacerbates the potential toxicity of NO. In this study inhaled NO caused no detectable pulmonary toxicity.

Formation of nitrotyrosine in situ is the result of oxidation of NO to peroxynitrite that subsequently

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Inhaled nitric oxide attenuates hyperoxic and inflammatory injury without alteration of phosphatidylcholine synthesis in rat lungs
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Other reports revealed that iNO above 80 ppm in hyperoxia may be associated with impaired surfactant function in young animals [19,20], supposedly caused by inactivation of surfactant protein, peroxidation of surfactant lipid, and decrease of surface activity [46]. In contrast, iNO at 20 ppm or less can prevent surfactant dysfunction caused by hyperoxia in animal [18] and clinical studies [47]. Johnson-Varghese et al. [22] recently reported that hyperoxia (95% oxygen) significantly increased apoptotic cell death and inflammatory cytokine release in cultured fetal and adult rat AEC II, and NO did not potentiate apoptosis or production of proinflammatory cytokines.
We hypothesized that inhaled nitric oxide (iNO), a selective vasodilator for pulmonary hypertension, may exacerbate hyperoxia-related lung inflammatory injury by alteration of phosphatidylcholine (PC) synthesis in mature lungs. Healthy adult rats were allocated to 4 groups and exposed to: 95% oxygen, or 20 ppm iNO, or both (ONO), or room air, all for 48 h. ³H-choline chloride was injected i.v. at 10 min, 8, 16, and 24 h prior to the end of 48 h exposure and the animal lungs were processed. In oxygen group, oxidative damage and inflammation were significantly induced compared to the room air group. In ONO group there were significantly elevated glutathione, attenuated malondialdehyde, myeloperoxidase, and wet-to-dry lung weight ratio in lung parenchyma, decreased white cell counts and vascular-to-alveolar leakage of albumin in bronchoalveolar lavage fluid. In both oxygen and ONO groups both total phospholipids and surfactant protein-A were significantly increased compared with the room air group. Newly synthesized ³H-PC was low in the lungs of NO group but high over time in both oxygen and ONO groups. Morphologically, lung injury was mild in ONO, but moderate in both oxygen and NO groups. We conclude that iNO alleviated oxidative damage and inflammation, and reduced alveolar leakage in hyperoxic injury of the mature lungs. Hyperoxia enhanced production of surfactant, whereas iNO did not attenuate this effect.
Inhaled Nitric Oxide
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Citation Excerpt :
Concentrations of more than 20 parts per million (ppm) provide little additional hemodynamic benefit in most patients; therefore, 20 ppm is generally the recommended starting dose, and even lower doses are often sufficient. Prolonged treatment (longer than 10 days) has been associated with pulmonary toxicity.18 Finally, inhalation of NO has been shown by some investigators to inhibit platelet function and lengthen bleeding time,19,20 although most of the controlled neonatal trials have not shown a significant increase in bleeding complications in infants receiving NO.
Inhaled nitric oxide (NO) plays an important role in treating persistent pulmonary hypertension of the newborn (PPHN), which is marked by a pathologic elevation of pulmonary vascular resistance. There is good evidence that the use of inhaled NO reduces the need for extracorporeal membrane oxygenation for term babies with severe PPHN of any cause, except in those infants with congenital diaphragmatic hernia, for which a benefit has not been shown. Although reducing the need for extracorporeal membrane oxygenation is beneficial in terms of cost and morbidity, inhaled NO has not been shown to decrease mortality in any neonatal population. Inhaled NO has also been shown to improve oxygenation in premature infants, although longer-term benefits have not been consistently demonstrated. This article will review the physiology of NO, its mechanisms of action in PPHN, and examine the evidence that supports its use in term and preterm infants with pulmonary hypertension.
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^☆: From the Department of Pediatrics, Division of Neonatal Medicine, University of California, Irvine Medical Center, Orange, California; the Department of Pediatrics, University of Oulu, Oulu, Finland; the Department of Pediatrics, Division of Neonatal Medicine, Vanderbilt University, Nashville, Tennessee; and Sierra Vista Regional Medical Center, San Luis Obispo, California

^☆☆: Supported in part by the Foundation for Maternal and Infant Care.

^★: Reprint requests: Mikko Hallman, MD, Department of Pediatrics, University of Oulu, Kajaanintie 52 A, 90220 Oulu, Finland.

^★★: 0022-3476/98/$5.00 + 0 9/21/86319

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Pulmonary toxicity associated with nitric oxide in term infants with severe respiratory failure☆,☆☆,★,★★

Abstract

Section snippets

Patients and Methods

Results

Discussion

J Pediatr

Arch Biochem Biophys

Suppression of arthritis by an inhibitor of nitric acid synthetase

J Exp Med

Endogenous nitric oxide inhibits the synthesis of cyclooxygenase products and interleukin-6 by rat Kuppfer cells

J Leukoc Biol

The biology of nitrogen oxides in the airways

Am J Resp Crit Care Med

The role of peroxynitrite in nitric oxide-mediated toxicity

Curr Topics Microbiol Immunol

Mechanisms of peroxynitrite-induced injury to pulmonary surfactants

Am J Physiol (Lung Cell Mol Physiol 9)