Inhaled nitric oxide in persistent pulmonary hypertension of the newborn (original) (raw)
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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.
Inhaled NO in the experimental setting
Early Human Development, 2008
Nitric oxide, a gas molecule, is a unique pharmaceutical agent that can be inhaled and thus delivered directly to the lung. More than a decade of intensive laboratory and clinical investigation has culminated in the current role for inhaled NO as the only selective pulmonary vasodilator for the treatment of persistent pulmonary hypertension of the newborn (PPHN). Not surprisingly, this potent and successful therapy continues to be studied intensively to better define its mechanism of action and role in PPHN treatment. In addition, there remains intense interest in possible new applications for newborns, as well as strategies that may enhance its efficacy. This review describes several areas of current research on amplification of NO signaling in the neonatal pulmonary vasculature, and reviews our current knowledge about the role of iNO in other conditions such as congenital diaphragmatic hernia and congenital heart disease. In addition, laboratory and clinical studies addressing a potential role for iNO as a therapeutic modality for the preterm infant are reviewed.
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.
Clinical Therapeutics, 2010
Background: The use of inhaled nitric oxide (NO) has been studied for the treatment of hypoxic respiratory failure (HRF) in newborns who require mechanical ventilation. Although inhaled NO is typically used in patients with a greater severity of illness, the treatment response (eg, improvement in oxygenation) and the associated outcomes (eg, time on mechanical ventilation) may be affected by the timing of treatment and baseline severity of illness. Objectives: This analysis was conducted to assess the effects of inhaled NO on measures of oxygenation, efficacy of inhaled NO across a range of illness severity strata, and duration of mechanical ventilation. Methods: This was a retrospective pooled analysis of 3 pivotal clinical trials comparing inhaled NO (starting dose, 20 ppm) with control (100% oxygen or nitrogen gas) in term and late preterm (gestational age ≥34 weeks) infants with HRF who required mechanical ventilation. Data on partial pressure of arterial oxygen (PaO 2), inspired oxygen concentration, and mean airway pressure at 0 and 30 minutes after administration of inhaled NO were extracted from the case-report forms from the 3 clinical trials and used to calculate the oxygenation index (OI). The change in PaO 2 was assessed by baseline severity of illness, stratified based on the OI (≤15 = mild, >15 to ≤25 = moderate, >25 to ≤40 = severe, >40 = very severe). The duration of mechanical ventilation was compared between the inhaled NO and control groups. Results: Five hundred twenty-four patients were analyzed (260 inhaled NO, 264 control). The overall mean (SD) birth weight and gestational age of the patients were 3.4 (0.58) kg and 39.1 (1.96) weeks, respectively. After 30 minutes of treatment, there was a significant increase from baseline in PaO 2 with inhaled NO compared with control (54.91 vs 14.15 mm Hg, respectively; P < 0.001). The increases from baseline in PaO 2 at 30 minutes were statistically significant for inhaled NO compared with controls across all severity strata (mild: 62.39 vs-23.03 mm Hg, respectively [P = 0.003]; moderate: 52.93 vs 18.28 mm Hg [P = 0.004]; severe: 62.07 vs 13.95 mm Hg [P < 0.001]; very severe: 45.17 vs 18.66 mm Hg [P < 0.001]). On Kaplan-Meier analysis, the median duration of mechanical ventilation was 11 and 14 days in the inhaled NO and control groups, respectively (P = 0.003). Conclusions: This pooled analysis of data from 3 clinical trials in term and late preterm infants with HRF requiring mechanical ventilation found that inhaled NO at a starting dose of 20 ppm was associated with improved oxygenation acutely and a reduced median duration of mechanical ventilation. The improvements were significant across all severity-of-illness strata. (Clin Ther.
Improved Oxygenation in a Randomized Trial of Inhaled Nitric Oxide for PPHN.• 1498
Pediatric Research, 1996
Objective. To determine the effect of inhaled nitric oxide (NO) on clinical outcome in newborns with persistent pulmonary hypertension (PPHN). Design. A prospective, randomized trial of patients referred to a level 3 nursery in a single large center. Clinicians were not masked to group assignment. Crossover of patients from control to NO treatment was not permitted. Methods. We randomized 49 mechanically ventilated newborns, transferred to our center with clinical and echocardiographic evidence of severe PPHN (arterial oxygen tension [PaO 2 ] <100; fractional inspired oxygen ؍ 1) to treatment with or without NO. Patients with gestational age <34 weeks or with congenital heart disease or diaphragmatic hernia were excluded. High-frequency oscillatory ventilation was used but not allowed concomitantly with NO. Primary outcome variables were oxygenation, mortality, and use of extracorporeal membrane oxygenation (ECMO). Results. Meconium aspiration syndrome and isolated PPHN were the most common diagnoses (32/49) and were distributed equally between groups. The median age at the time of entry into the study was similar between groups, 25 hours for control patients and 18 hours for NO patients. Median baseline oxygenation index (OI) was similar in 23 control (OI ؍ 29) and 26 NO (OI ؍ 30) patients. Mortality (8%), use of ECMO (33%), median days on mechanical ventilation (9 days), and duration of supplemental oxygen (13 days) were not different between treatment groups. PaO 2 , oxygen saturation, and OI improved in the NO group compared with baseline and to control patients at 15 minutes. The median percent change in OI (؊31%) in the NO group was significantly different from baseline and from the control group. The difference in oxygenation between treatment groups was still apparent 12 hours after baseline. Before cannulation for ECMO, oxygenation was better in the NO group compared with control patients. Among patients who were placed on ECMO, the median time from baseline to ECMO cannulation was 2.4 hours (range, 1 to 12 hours) among control patients and 3.3 hours (range, 2 to 68 hours) for those randomized to receive NO. There was a tendency to observe fewer adverse neurologic events (seizure and intracranial hemorrhage) in the NO group (4/26 vs 8/23). One child with alveolar capillary dysplasia confirmed by postmortem examination could not be weaned from 80 parts per million of NO and transiently developed methemoglobinemia (peak methemoglobin level ؍ 17%). No other side effects were observed. Conclusions. Although mortality and ECMO use were similar for both treatment groups using this study size and design, sustained improvement in oxygenation with NO and better oxygenation at initiation of ECMO may have important clinical benefits. We speculate that modification of treatment to include specific lung expansion strategies with NO treatment and recognition that early improvement of oxygenation may be sustained with NO may lead to reduced use of ECMO in NO treated patients compared with controls. Pediatrics 1997; 100(5). URL: http://www.pediatrics.org/cgi/content/full/ 100/5/e7; persistent fetal circulation, extracorporeal membrane oxygenation, high-frequency oscillatory ventilation, alveolar capillary dysplasia, methemoglobin.
Journal of Perinatal Medicine, 2006
Aim: To determine whether inhaled nitric oxide might reduce the need for excessive respiratory alkalosis to maintain systemic oxygenation in infants with persistent pulmonary hypertension of the newborn (PPHN). Materials and methods: A retrospective historical cohort study of 34 infants with PPHN with oxygenation index (OI) of 25 or more, including 19 infants without inhaled nitric oxide (i-NO) therapy (control group) and 15 infants with inhaled nitric oxide therapy (i-NO group) was performed. The initial dose of 10 ppm of i-NO was administered and no responders received the maximum dose of 25 ppm. We evaluated the mortality rate and the change of OI index and PaCO 2 during the first 6 days. Results: There were no significant differences in characteristics between groups. Two of 15 in the i-NO group and 6 of 19 infants in the control group died during the first 48 h. Baseline OI, PaCO 2 and arterial pH were similar in the two groups. OI in the i-NO group was significantly higher than in the control group between 12 and 96 h. PaCO 2 in the i-NO group was higher than in the control group between 24 and 144 h. Conclusion: i-NO therapy for PPHN might improve systemic oxygenation without excessive hypocapnia. However there was no reduction in duration of ventilation support or oxygen supply.