Inhaled nitric oxide in the management of preterm infants with severe respiratory failure. Inhaled nitric oxide in the treatment of moderate persistent pulmonary hypertension of the newborn: a randomized controlled, multicenter trial. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS. The safety and efficacy of nitric oxide therapy in premature infants. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. The European Study Group of Inhaled Nitric Oxide. Interactive effects of high-frequency oscillatory ventilation and inhaled nitric oxide in acute hypoxemic respiratory failure in pediatrics. Randomized, controlled trial of low-dose inhaled nitric oxide in the treatment of term and near-term infants with respiratory failure and pulmonary hypertension. Inhaled nitric oxide therapy in premature infants with mild to moderate respiratory distress syndrome. Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. The Neonatal Inhaled Nitric Oxide Study Group (NINOS).
Elevated pulmonary vascular resistance and poor ventilation-perfusion matching are commonly found in preterm infants with severe respiratory distress syndrome (RDS) and respiratory failure. Inhaled nitric oxide (iNO) can improve gas exchange and decrease pulmonary vascular resistance. This study was conducted to determine whether iNO therapy improves oxygenation in such infants.
                Between July 2000 and 2006, 65 preterm infants (birth weight, <1500 g; gestational age, <31 weeks) with severe RDS and respiratory failure requiring mechanical ventilation and an oxygenation index (OI)>or=25 were randomly divided into two groups. Group A infants (n=32) received iNO therapy. iNO was started at a dose of five parts per million (p.p.m.). The maximal dose of NO was 20 p.p.m. Group B infants (n=33) did not receive iNO therapy, receive inhaled oxygen placebo only, was served as control group. Mechanical ventilation and iNO therapy were managed by neonatologists who were not involved in safety monitoring, data analysis and interpretation, or manuscript preparation. This study was randomized but not blinded.
                The OI was significantly lower (P<0.01) in the iNO therapy group than in the control group at 30 min, 3, 12 and 24 h after initiating iNO therapy. Six infants in the iNO-treated group and 10 infants in the control group died. Post hoc analyses did not reveal any significant differences in the incidences of chronic lung disease (CLD), intracranial hemorrhage (ICH), patent ductus arteriosus (PDA), retinopathy of prematurity (ROP) or duration of intubation between the iNO-treated and the control groups.
                We conclude that iNO therapy leads to an improvement in oxygenation without short-term side effects (such as pulmonary hemorrhage, intracranial hemorrhage, pneumothorax or acute deterioration) in premature infants with severe RDS and respiratory failure. However, iNO therapy does not significantly reduce mortality rate or the incidences of CLD, ICH, PDA or ROP. Inhaled nitric oxide (iNO) improves oxygenation and reduces the need for extracorporeal membrane oxygenation in infants with severe persistent pulmonary hypertension of the newborn (PPHN). The effectiveness of iNO in the treatment of moderate PPHN has not been adequately defined. We therefore conducted a randomized, prospective multicenter study to assess whether iNO in patients with moderate PPHN would improve arterial p(a)O(2), prevent progression to severe PPHN, and improve outcomes.
                Infants > or = 34 weeks gestation with moderate pulmonary hypertension (alveolar-arterial oxygen gradient (AaDO(2)) 500-599 Torr) were randomly assigned to continue standard medical therapy (control group) or standard medical therapy plus iNO (iNO group). For each patient in the iNO group, iNO concentration was increased in steps of 10-20 ppm every 30 minutes until there was no further improvement in arterial p(a)O(2). This concentration of iNO was then maintained while all other ventilatory support, including inspired oxygen concentration, was weaned according to a predefined protocol.
                In all, 27 of 40 control patients (58%) compared to six of 40 infants (15%) in the iNO group failed assigned therapy and developed severe PPHN (p<0.0005). Arterial p(a)O(2) improved from 112+/-48 to 133+/-100 (p=0.132) in control infants compared to an increase from 101+/-29 to 208+/-118 (p<0.0005) in iNO-treated patients. For the first 36 hours after study, entry AaDO(2) levels and ventilatory support were significantly lower in iNO-treated infants compared to control patients.
                In patients with moderate PPHN, treatment with iNO improves arterial p(a)O(2), reduces the amount of ventilatory support needed, and prevents progression to severe PPHN. Inhaled nitric oxide (iNO) reduces the use of extracorporeal membrane oxygenation (ECMO)/incidence of death in term and near-term neonates with severe hypoxic respiratory failure. We conducted a randomized, double masked, multicenter trial to determine whether administration of iNO earlier in respiratory failure results in additional reduction in the incidence of these outcomes.
                Neonates who were born at > or =34 weeks' gestation were enrolled when they required assisted ventilation and had an oxygenation index (OI) > or =15 and <25 on any 2 measurements in a 12-hour interval. Infants were randomized to early iNO or to simulated initiation of iNO (control). Infants who had an increase in OI to 25 or more were given iNO as standard therapy.
                The trial enrollment was halted after 75% of target sample size was reached because of decreasing availability of eligible patients. The 150 infants who were given early iNO and 149 control infants had similar baseline characteristics. Arterial oxygen tension increased by >20 mm Hg in 73% of early iNO and 37% of control infants after study gas initiation. Control infants received standard iNO and deteriorated to OI >40 more often than infants who were given early iNO. The incidence of death (early iNO, 6.7% vs control, 9.4%), ECMO (10.7% vs 12.1%), and their combined incidence (16.7% vs 19.5%) were similar in both groups.
                iNO improves oxygenation but does not reduce the incidence of ECMO/mortality when initiated at an OI of 15 to 25 compared with initiation at >25 in term and near-term neonates with respiratory failure. A randomized, controlled clinical trial was performed with patients with acute respiratory distress syndrome (ARDS) to compare the effect of conventional therapy or inhaled nitric oxide (iNO) on oxygenation. Patients were randomized to either conventional therapy or conventional therapy plus iNO for 72 h. We tested the following hypotheses: (1) that iNO would improve oxygenation during the 72 h after randomization, as compared with conventional therapy; and (2) that iNO would increase the likelihood that patients would improve to the extent that the FI(O2) could be decreased by > or = 0.15 within 72 h after randomization. There were two major findings. First, That iNO as compared with conventional therapy increased Pa(O2)/FI(O2) at 1 h, 12 h, and possibly 24 h. Beyond 24 h, the two groups had an equivalent improvement in Pa(O2)/FI(O2). Second, that patients treated with iNO therapy were no more likely to improve so that they could be managed with a persistent decrease in FI(O2) > or = 0.15 during the 72 h following randomization (11 of 20 patients with iNO versus 9 of 20 patients with conventional therapy, p = 0.55). In patients with severe ARDS, our results indicate that iNO does not lead to a sustained improvement in oxygenation as compared with conventional therapy. To assess the safety-efficacy balance of low-dose inhaled nitric oxide (iNO) in hypoxemic premature infants because no sustained beneficial effect has been demonstrated clearly and there are concerns about side effects.
                Eight hundred and sixty infants <32 weeks were randomized at birth to receive 5 ppm iNO or placebo when they presented with hypoxemic respiratory failure (HRF) defined by a requirement for mechanical ventilation, fraction of inspired oxygen (FIO 2 ) >40%, and arterio-alveolar ratio in oxygen (aAO 2 ) <0.22. The primary end point was intact survival at 28 days of age.
                Sixty-one of 415 infants presented with HRF and were compared with 84 of 445 controls who presented with HRF. There was no difference in the primary end point (61.4% in infants [23% with HRF who were treated with iNO] vs 61.1% in controls [21.4% in controls with HRF]; P = .943). For the infants with HRF who were treated with iNO, there was no significant difference from controls for intraventricular hemorrhage (IVH) (6% vs 7%), necrotizing enterocolitis (8% vs 6 %), or patent ductus arteriosus (PDA) (34% vs 37%). Compared with nonhypoxemic infants, the risk of bronchopulmonary displasia (BPD) increased significantly in HRF controls (OR = 3.264 [CI 1.461-7.292]) but not in infants with HRF who were treated with iNO (OR = 1.626 [CI 0.633-4.178]).
                iNO appears to be safe in premature infants but did not lead to a significant improvement in intact survival on day 28. To determine whether inhalation of nitric oxide (INO) can increase the frequency of reversal of acute lung injury (ALI) in nitric oxide (NO) responders.
                Prospective, open, randomised, multicentre, parallel group phase III trial.
                General ICUs in 43 university and regional hospitals in Europe.
                Two hundred and sixty-eight adult patients with early ALI.
                NO responders were patients whose PaO(2) increased by more than 20 % when receiving 0, 2, 10 and 40 ppm of INO for 10 min within 96 h of study entry. Responders were randomly allocated to conventional treatment with or without INO. INO, 1-40 ppm, was given at the lowest effective dose for up to 30 days or until an end point was reached. The primary end point was reversal of ALI. Clinical outcome parameters and safety were assessed in all patients.
                Two hundred and sixty-eight patients were recruited, of which 180 were randomised NO responders. Frequency of reversal of ALI was no different in INO patients (61 %) and controls (54 %; p > 0.2). Development of severe respiratory failure was lower in the INO (2.2 % ) than controls (10.3 %; p < 0.05). The mortality at 30 days was 44 % for INO patients, 40 % for control patients (p > 0.2 vs INO) and 45 % in non-responders.
                Improvement of oxygenation by INO did not increase the frequency of reversal of ALI. Use of inhaled NO in early ALI did not alter mortality although it did reduce the frequency of severe respiratory failure in patients developing severe hypoxaemia. High-frequency oscillatory ventilation (HFOV) and inhaled nitric oxide (iNO) have been reported to improve oxygenation in children with acute hypoxemic respiratory failure (AHRF), but their roles in the treatment of AHRF remains unknown. The use of HFOV improves oxygenation by increasing lung recruitment. iNO can improve oxygenation in AHRF, but it may have limited efficacy in patients with poor lung inflation. Based on these findings, we hypothesized that the combined treatment of HFOV and inhalation of low-dose NO would improve oxygenation and survival in children with severe AHRF compared with children treated with conventional mechanical ventilation (CMV) or either treatment alone.
                Tertiary pediatric intensive care units at seven academic centers.
                Post hoc analysis of data from children enrolled in a multicenter, randomized, masked study of the use of iNO in the treatment of AHRF.
                A total of 108 pediatric patients with AHRF defined as an oxygenation index of >15 twice within 6 hrs. Mode of ventilation (HFOV or CMV) was determined by the patient's physician based on guidelines to maximize oxygenation. The patient was then randomized to treatment with or without iNO. Comparisons were made between patients who were treated with HFOV plus iNO (n = 14), HFOV alone (n = 12), CMV plus iNO (n = 35), and CMV alone (n = 38).
                Ventilation with CMV or HFOV with or without iNO.
                We found that the change in Pao /Fio ratio was greatest in the HFOV plus iNO group compared with the other treatment groups at 4 hrs (p =.02) and 12 hrs (p =.01). After 24 hrs of treatment, both HFOV plus iNO and HFOV alone resulted in greater improvement in Pao2/Fio2 ratio than either CMV alone or CMV plus iNO (p =.005). After 72 hrs, treatment with HFOV alone resulted in a greater improvement in Pao2/Fio2 ratio than either CMV alone or CMV plus iNO (p =.03). There was no difference in predefined treatment failures between treatment groups.
                We conclude that the combination of HFOV with iNO causes a greater improvement in oxygenation than either treatment strategy alone in children with severe AHRF. We speculate that the enhanced lung recruitment by HFOV enhances the effects of low dose iNO on gas exchange. Recent reports indicate that inhaled nitric oxide (iNO) causes selective pulmonary vasodilation, increases arterial oxygen tension, and may decrease the use of extracorporeal membrane oxygenation (ECMO) in infants with persistent pulmonary hypertension of the newborn (PPHN). Despite these reports, the optimal dose and timing of iNO administration in PPHN remains unclear.
                To test the hypotheses that in PPHN 1) iNO at 2 parts per million (ppm) is effective at acutely increasing oxygenation as measured by oxygenation index (OI); 2) early use of 2 ppm of iNO is more effective than control (0 ppm) in preventing clinical deterioration and need for iNO at 20 ppm; and 3) for those infants who fail the initial treatment protocol (0 or 2 ppm) iNO at 20 ppm is effective at acutely decreasing OI.
                A randomized, controlled trial of iNO in 3 nurseries in a single metropolitan area. Thirty-eight children, average gestational age of 37.3 weeks and average age <1 day were enrolled. Thirty-five of 38 infants had echocardiographic evidence of pulmonary hypertension. On enrollment, median OI in the control group, iNO at 0 ppm, (n = 23) was 33.1, compared with 36.9 in the 2-ppm iNO group (n = 15).
                Initial treatment with iNO at 2 ppm for an average of 1 hour was not associated with a significant decrease in OI. Twenty of 23 (87%) control patients and 14 of 15 (92%) of the low-dose iNO group demonstrated clinical deterioration and were treated with iNO at 20 ppm. In the control group, treatment with iNO at 20 ppm decreased the median OI from 42.6 to 23.8, whereas in the 2-ppm iNO group with a change in iNO from 2 to 20 ppm, the median OI did not change (42.6 to 42.0). Five of 15 patients in the low-dose nitric oxide group required ECMO and 2 died, compared with 7 of 23 requiring ECMO and 5 deaths in the control group.
                In infants with PPHN, iNO 1): at 2 ppm does not acutely improve oxygenation or prevent clinical deterioration, but does attenuate the rate of clinical deterioration; and 2) at 20 ppm acutely improves oxygenation in infants initially treated with 0 ppm, but not in infants previously treated with iNO at 2 ppm. Initial treatment with a subtherapeutic dose of iNO may diminish the clinical response to 20 ppm of iNO and have adverse clinical sequelae. Inhaled nitric oxide (iNO) therapy has been demonstrated to acutely improve oxygenation in preterm infants with severe pulmonary disease. Administration of iNO to the premature infants with less severe pulmonary illness has not yet been studied extensively. Therefore, the authors performed a pilot study enrolling thirty-four premature infants with respiratory distress syndrome (RDS) within 72 hours of age, birth weight between 500-2,000 g, whose oxygenation indexes exceeded our birthweight-specific criteria. Infants were randomly assigned to either treatment with (iNO group; n = 16) or without (control group; n = 18) iNO. Inhaled NO was started at 20 ppm and weaned to 5 ppm over 24-48 hours. Routine cranial ultrasonography was performed and the occurrence of intraventricular hemorrhage (IVH) was interpreted by an attending pediatric radiologist unaware of the treatment group assignment. The study showed that the two groups were of similar birth weight (mean+/-SEM): control 901+/-73 g vs iNO 874+/-70 g; and gestational age: control 27.2+/-0.5 wk vs iNO 26.8+/-0.5 wk. Other baseline parameters between the two groups were also similar. The mean ages of the infants at the time of entry were 11.7+/-2.2 and 8.3+/-0.9 hours in the controls and iNO group. The entry oxygenation index (OI) did not differ between the two groups: control 11.9+/-2.2 vs iNO 10.8+/-1.50. After 30 minutes of iNO therapy, there was a 50 per cent increase in partial pressure of oxygen tension (PaO2) and 15 per cent reduction in OI, (p = 0.02 and p = 0.04 vs baseline, respectively). No statistical difference in the incidence of significant IVH (Grade III and IV) was detected: control 27.8 per cent; iNO 25.0 per cent. The incidence of other acute complications as well as early neonatal death, were comparable between the groups. The mean methemoglobin concentration was 1.2+/-0.5 per cent. In conclusion, these preliminary data suggest that iNO, as used in this protocol, acutely improves oxygenation without increasing significant IVH in premature infants with mild to moderate RDS. These important findings serve to justify further study of the efficacy of iNO on long term pulmonary outcome and mortality in this group of infants. We designed and conducted a randomized, double-masked, controlled multicenter study to determine whether inhaled nitric oxide (INO) in term and near-term infants with congenital diaphragmatic hernia (CDH) would reduce the occurrence of death and/or the initiation of extracorporeal membrane oxygenation (ECMO).
                Infants of 34 weeks gestation or more, <14 days of age with CDH, without known structural heart disease, requiring assisted ventilation for hypoxemic respiratory failure with two oxygenation indices (OIs) of 25 or more at least 15 minutes apart, were eligible for this trial. Infants were centrally randomized and then received masked treatment with 20 ppm NO or 100% oxygen as control. Infants with less than a full response to 20 ppm NO (increase in PaO2 > 20 Torr) after 30 minutes were evaluated at 80 ppm NO/control study gas.
                The 28 control and 25 treated infants enrolled by the 13 participating centers were not significantly different at randomization for any of the measured variables including prerandomization therapies and initial OIs (45.8 +/- 16.3 for controls, 44.5 +/- 14.5 for INO). Death at <120 days of age or the need for ECMO occurred in 82% of control infants compared with 96% of INO infants (ns). Death occurred in 43% of controls and 48% of the INO group (ns), and ECMO treatment was used for 54% of control and 80% of INO-treated infants. There was no significant improvement in PaO2 (delta PaO2 7.8 +/- 19.8 vs 1.1 +/- 7.6 Torr, ns) nor significant reduction in OI (-2.7 +/- 23.4 vs 4.0 +/- 14.8, ns) associated with INO treatment. Mean peak nitrogen dioxide (NO2) concentration was 1.9 +/- 1.3 ppm and the mean peak methemoglobin was 1.6 +/- 0.8 mg/dL. No infant had study gas discontinued for toxicity. There were no differences between the control and INO groups for the occurrence of intracranial hemorrhage, specific grades of intracranial hemorrhage, periventricular leukomalacia, brain infarction, and pulmonary or gastrointestinal hemorrhages.
                Although the immediate short-term improvements in oxygenation seen in some treated infants may be of benefit in stabilizing responding infants for transport and initiation of ECMO, we conclude that for term and near-term infants with CDH and hypoxemic respiratory failure unresponsive to conventional therapy, inhaled NO therapy as used in this trial did not reduce the need for ECMO or death.
INO cannot be recommended for patients with AHRF. INO results in a transient improvement in oxygenation but does not reduce mortality and may be harmful.