Pulmonary toxicity associated with nitric oxide in term infants with severe respiratory failure (original) (raw)
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Inhaled nitric oxide in persistent pulmonary hypertension of the newborn
The Lancet, 1992
Background: This study was designed to evaluate the effect of nitric oxide (NO) on the management of neonates with severe persistent pulmonary hypertension refractory to high-frequency oscillatory ventilation. Methods: The birth weight and the gestational age of infants were 3125.5 ± 794 g (mean ± SD) and 39 ± 2.4 weeks, respectively. All neonates were ventilated for an average of 137.5 min (range 90-180 min) prior to NO therapy. The mean oxygenation index (OI) of all neonates prior to NO was 46.3 ± 5 (mean ± SEM). NO was initially administered at 20 parts per million (ppm) for at least 2 h and increased gradually by 2 ppm to a maximum of 80 ppm. Results: Eighteen infants (75%) responded and six (25%) did not respond to the treatment. Three neonates died in the responding group, while all the nonresponders died (P = 0.0001). The survival rate was 62.5% among all neonates. NO significantly decreased OI (P < 0.0001) and improved the arterial/alveolar (a/A) oxygen ratio (P < 0.0001) within the first 2 h of NO therapy in 61.1% of the responders. However, the OI and the a/A oxygen ratio remained almost the same throughout the treatment in the non-responders and the non-survivors. Conclusion: Inhaled NO at 20 ppm, following adequate ventilation for 2 h without significant response, could be used to identify the majority of the nonresponders in order to seek other alternatives.
Inhaled Nitric Oxide: The authors reply
Critical Care Medicine, 1999
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.
Low-dose inhaled nitric oxide for neonates with pulmonary hypertension
Journal of Paediatrics and Child Health, 1996
Objective: Inhaled nitric oxide (iNO) has been shown to cause selective pulmonary vasodilatation and improve ventilationperfusion matching and may be an important therapeutic option for the treatment of persistent pulmonary hypertension of the newborn (PPHN). We report our experience on the use of iNO in neonates with severe PPHN. Methodology: Inhaled NO was administered to 10 infants with PPHN and persistent hypoxaemia (meconium aspiration syndrome, n = 9; pneumonia, n = 1) after failure of conventional therapy to improve oxygenation. With the exception of one infant, iNO was commenced at 10 ppm. Results: After 30 min exposure to iNO, the arterial oxygen tension (PaO,) rose from a median of 49 mmHg (6.5 kPa) [range 12-82mmHg (1.6-10.9 kPa)] to 75mmHg (10 kPa) [range 17-450mmHg (2.3-60 kPa)] (P = 0.005), while the median oxygenation index fell (pre-iNO of 37 vs post-iN0 20) (P = 0.005) and median systemic arterial pressure rose (pre-iNO 46.5 mmHg (6.2 kPa) [range 32-63 mmHg (4.3 to 8.4 kPa vs post-iN0 54.5 mmHg (7.3 kPa) [range 36-74 kPa]) P = 0.005). All infants subsequently continued to receive iNO with the duration of exposure to iNO ranging from 12 to 168 h (median duration 100 h). Three infants died despite showing an initial beneficial response to iNO. The mean duration of intubation for survivors was 11.9k2.6 days. Methaemoglobinaemia and toxic levels of nitrogen dioxide were not seen during iNO administration. Of the seven survivors, 12 month follow up in two infants and 4 month follow up in four infants showed age-appropriate neurodevelopmental skills, with one infant having very mild hearing loss. Conclusions: Inhaled NO reduces the oxygenation index by improving the PaO, and decreasing ventilation pressures, and appears to be clinically useful in severely hypoxaemic infants with PPHN refractory to conventional treatment.
Inhaled Nitric Oxide and Persistent Pulmonary Hypertension of the Newborn
New England Journal of Medicine, 1997
Background Persistent pulmonary hypertension of the newborn causes systemic arterial hypoxemia because of increased pulmonary vascular resistance and right-to-left shunting of deoxygenated blood. Inhaled nitric oxide decreases pulmonary vascular resistance in newborns. We studied whether inhaled nitric oxide decreases severe hypoxemia in infants with persistent pulmonary hypertension. Methods In a prospective, multicenter study, 58 full-term infants with severe hypoxemia and persistent pulmonary hypertension were randomly assigned to breathe either a control gas (nitrogen) or nitric oxide (80 parts per million), mixed with oxygen from a ventilator. If oxygenation increased after 20 minutes and systemic blood pressure did not decrease, the treatment was considered successful and was continued at lower concentrations. Otherwise, it was discontinued and alternative therapies, including extracorporeal membrane oxygenation, were used. Results Inhaled nitric oxide successfully doubled systemic oxygenation in 16 of 30 infants (53 percent), whereas conventional therapy without inhaled nitric oxide increased oxygenation in only 2 of 28 infants (7 percent). Long-term therapy with inhaled nitric oxide sustained systemic oxygenation in 75 percent of the infants who had initial improvement. Extracorporeal membrane oxygenation was required in 71 percent of the control group and 40 percent of the nitric oxide group (P ϭ 0.02). The number of deaths was similar in the two groups. Inhaled nitric oxide did not cause systemic hypotension or increase methemoglobin levels. Conclusions Inhaled nitric oxide improves systemic oxygenation in infants with persistent pulmonary hypertension and may reduce the need for more invasive treatments.
Current status of inhaled nitric oxide therapy in the perinatal period
Early Human Development, 1997
The recent discovery of nitric oxide (NO) and the elucidation of its biological roles has been accompanied by significant advances in our understanding of several physiological and pathological processes. Impaired NO synthesis and / or release may underlie the pathophysiology of several cardiopulmonary disorders characterised by hypoxemia and pulmonary hypertension. Inhaled NO produces selective pulmonary vasodilation and appears to be an effective new therapy for infants with pulmonary vasospasm or hypoxemia associated with ventilation-perfusion imbalance. Although formal reports from current randomised and controlled clinical trials of inhaled NO therapy are awaited, preliminary results suggest an improved outcome. NO is, however, still an investigational drug. The limitations of this therapy and its toxicology are reviewed.
Inhaled nitric oxide in infants referred for extracorporeal membrane oxygenation: Dose response
Journal of Pediatrics, 1994
To determine the role of inhaled nitric oxide (NO) in a population of critically ill hypoxic near-term infants and to determine the close response to inhaled NO, we examined a consecutive group of 23 infants referred for neonatal extracorporeal membrane oxygenation (ECMO) who had an oxygen index of 20 or greater after treatment with bovine surfactant. Inhaled NO was administered in concentrations from 5 to 80 ppm in random order to 23 infants. Overall, 13 infants had a significant response (an improvement in arterial oxygen pressure >10 mm Hg or arterial oxygen saturation >10%) to the first administration of inhaled NO, and one infant had a late response. There was no significant difference in the response to inhaled NO as measured by changes in arterial oxygen pressure or in the alveolar-arterial difference in partial pressure of oxygen, for any of the doses from 5 to 80 ppm. Thirteen infants had echocardiographic evidence of persistent pulmonary hypertension; 11 of these infants responded, compared with 3 responders among the 10 infants without persistent pulmonary hypertension of the newborn (p <0.01). Overall, 11 infants required ECMO; there were two deaths in this group. Seven infants had congenital diaphragmatic hernia; five of those had a response to NO inhalation and four required ECMO. Our study demonstrates that there is no significant difference in response between low and high doses of inhaled NO and that this treatment may prevent the need for ECMO in some infants referred for this therapy, especially in infants with pulmonary hypertension. Prospective, controlled, randomized, and blinded trials of low doses of inhaled NO are needed to determine the clinical role of this potentially useful therapy. (J PEDIATR 1994;124:302-8) A majority of infants referred for neonatal extracorporeal membrane oxygenation have evidence of pulmonary hypertension with associated right-to-left or bidirectional shunting at the foramen ovale, patent ductus, or both. 1, 2 A1though ECMO therapy has proved beneficial, 3 this therapy is highly invasive and is associated with significant risks. Numerous agents used in the past to treat neonatal pulmonary hypertension have failed because they simultaneously
Inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn
Acta paediatrica Japonica; Overseas edition, 1995
Increasing evidence suggests that the pulmonary vascular endothelium is an important mediator of resting pulmonary vascular tone through the synthesis and release of a variety of vasoactive substances including nitric oxide (NO). In addition, pulmonary endothelial dysfunction (such as impairment of NO synthesis) is present in lung injury and may contribute to the pathophysiology of pulmonary hypertensive disorders. Recently, exogenously administered NO gas has been utilized to treat infants with persistent pulmonary hypertension of the newborn (PPHN). These preliminary studies suggest that inhaled NO is a promising new therapy for the treatment of infants with PPHN. Controlled clinical trials must now be performed to determine if the use of inhaled NO improves the long-term outcome of patients with PPHN. Long-term exposure must be monitored closely for potential toxicity which includes methemoglobinemia and lung injury secondary to peroxynitrite and nitrogen dioxide production.
Therapeutic advances in cardiovascular disease, 2016
Nitric oxide (NO) has a significant role in modulating the respiratory system and is being exploited therapeutically. Neonatal respiratory failure can affect around 2% of all live births and is responsible for over one third of all neonatal mortality. Current treatment method with inhaled NO (iNO) has demonstrated great benefits to patients with persistent pulmonary hypertension, bronchopulmonary dysplasia and neonatal respiratory distress syndrome. However, it is not without its drawbacks, which include the need for patients to be attached to mechanical ventilators. Notably, there is also a lack of identification of subgroups amongst abovementioned patients, and homogeneity in powered studies associated with iNO, which is one of the limitations. There are significant developments in drug delivery methods and there is a need to look at alternative or supplementary methods of NO delivery that could reduce current concerns. The addition of NO-independent activators and stimulators, or...