It may be argued that withdrawal of iNO is not to blame. Instead, the hypoxemia may be caused by the progression of the underlying pathophysiology. However, the dose-dependent nature of the degree of hypoxemia and the failure to describe rebound hypoxemia in patients treated with placebo gas sug- gest that iNO is playing an active, not a passive, role. Looking to the future, much remains to be learned. Are we using the correct dose of iNO for the right duration? Are we selecting the best patients for treat- ment? Does iNO delay the initiation of ECMO? Is the delay associated with an increased risk for morbid- ity? In the era of surfactant, high-frequency ventila- tion, and iNO, understanding how to safely avoid ECMO takes on new importance. Only by discover- ing how, when, and in whom we should use iNO will we improve the health of critically ill neonates. Davidson et al are to be applauded for the collabo-
OBJECTIVES: To systematically review the evidence on the use of iNO in infants born at ⱕ 34 weeks’ gestation who receive respiratory support. METHODS: Medline, Embase, the Cochrane Central Register of Con- trolled Studies, PsycInfo, ClinicalTrials.gov, and proceedings of the 2009 and 2010 Pediatric Academic Societies meetings were searched in June 2010. Additional studies from reference lists of eligible articles, relevant reviews, and technical experts were considered. Two investi- gators independently screened search results and abstracted data from eligible articles. We focus here on mortality, bronchopulmonary dysplasia (BPD), the composite outcome of death or BPD, and neuro- developmental impairment.
We calculated ambient NO concentrations in typ- ical transport vehicles and tested the performance of 3 iNO delivery systems. For the calculation of ambi- ent NO concentrations, we assumed a “worst-case scenario” after a complete release of a “D” cylinder (Table 1). The Lear Jet 35 has a cabin volume of 322 cubic feet and complete air exchange of the cabin occurs in 1.25 minutes. Without air exchange (ie, instantaneous maximal concentration), the complete release of a “D” cylinder would yield a maximum concentration of 30.8 ppm NO. The King Air 90 has a cabin volume of 247 cubic feet and complete air exchange of the cabin occurs in 4.8 minutes. Again, in the absence of air exchange, the NO concentration after complete release of a “D” cylinder would yield a maximum concentration of 40.2 ppm within the cabin. The King Air 200 aircraft has a cabin volume of 393 cubic feet and complete air exchange occurs in 4.1 minutes. In this scenario, the maximum NO con- centration within the cabin would be 25.3 ppm. The Eurocopter A-Star has a cabin volume of 106 cubic feet. This helicopter is not pressurized and the air exchange rate is variable. Because of the small cabin volume, instantaneous maximum NO concentration after complete release of a “D” cylinder could reach
There is marked variation in response to iNO between patients  and in the same patient at different times. After prolonged use, there is a leftward shift in the dose-response curve such that, without regular titration against a therapeutic goal, there is a risk of excessive iNO administration that is associated with toxicity and loss of the therapeutic effect . Cardiac transplantation may be complicated by pulmonary hypertension and RVF that are improved with iNO . Early ischaemia-reperfusion injury after lung transplantation manifests clinically as pulmonary oedema and is a cause of significant morbidity and mortality [33,34]. Although iNO is a useful therapy in this circumstance , it did not prevent ischaemia-reperfusion injury in clinical lung transplantation .
RESULTS. Eleven randomized, controlled trials of inhalednitricoxide therapy for preterm infants were found. The trials were grouped into 3 categories according to the entry criteria, that is, entry in the first 3 days of life on the basis of oxygenation criteria (early rescue), enrollment after 3 days on the basis of elevated risk of bronchopulmonary dysplasia, and routine use for intubated preterm infants. Early rescue treatment based on oxygenation criteria did not seem to affect mortality or bronchopulmonary dysplasia rates. Routine use for intubated preterm infants showed a barely significant reduction in the incidence of the combined outcome of death or bronchopulmonary dysplasia (relative risk [RR]: 0.91 [95% confidence limits (CLs): 0.84, 0.99]). Later treatment based on the risk of bronchopulmonary dysplasia showed no significant effect on this outcome. Early rescue treatment showed a trend toward increased incidence of severe intracranial hemorrhage, whereas routine use for intubated preterm infants seemed to show a reduction in the incidence of either severe intracranial hemorrhage or periventricular leukoma- lacia (RR: 0.70 [95% CLs: 0.53, 0.91]).
Our study, the only multicentered epidemiologic investigation of a cohort of neonates with PPHN ever analyzed, suggests that the optimal treatment of ne- onates with PPHN before the use of inhalednitricoxide is unknown. It strongly suggests that infusion of alkali to induce metabolic alkalosis is not equiva- lent in its effects to hyperventilation. This investiga- tion highlights the difficulty of evaluating treatments introduced into practice without randomized clinical trials. We must examine untested therapies for evi- dence of efficacy and to question the use of therapies failing this examination. Our study suggests that in PPHN, a reevaluation of the roles of hyperventila- tion, alkali infusion, and paralysis is warranted.
limitations make it impractical to use these data to examine relationships be- tween INO therapy and subsequent mor- tality or need for ECMO for individual infants. However, cumulative hospital mortality rates are less subject to such confounding, as severity of CDH is likely to have varied less dramatically among pe- diatric referral hospitals with ECMO pro- grams over the 9-year study period. We attempted to correct for any residual confounding due to illness severity by repeating analyses on only those infants who underwent surgical repair, and by adjusting for rates of repair and ECMO use in regression analyses examining the relationship between hospital-speci ﬁ c INO use and mortality rates.
concluded that initial treatment with iNO at 2 ppm does not result in acute improvements in oxygen- ation and actually may attenuate the subsequent re- sponses to NO at 20 ppm. Our study, which is very similar in the number of patients per group, demon- strates that treatment at an initial concentration of 1 ppm does, in fact, significantly improve oxygenation almost as much as the high-dose group. Further- more, all of our patients who initially did not re- spond at 1 or 2 ppm responded to increased doses of NO in direct contrast to the observations of Cornfield et al, who reported that the subsequent use of 20 ppm in infants who had received earlier treatment with 2 ppm did not result in an improvement in oxygenation or a change in OI (42.6 – 42). Adult stud- ies in patients with acute RDS (ARDS) indicate that the ED 50 of iNO for adults is 0.1 to 1.0 ppm of NO. 12
In the current issue of the journal, Ellsworth 1 et al report a small but signiﬁcant increase (from 5.0% to 6.2%) in the off-label use of inhalednitricoxide (iNO) between 2009 and 2013 in preterm infants born earlier than 30 weeks. This increase occurred in spite of the publication of the iNO Consensus Statement 2 in 2011 and the 2014 report from the American Academy of Pediatrics. 3 Both reports conclude, on the basis of quality A evidence, with recommendations against using iNO to reduce mortality and morbidity in preterm infants with respiratory failure. The ﬁndings of Ellsworth et al are probably
We demonstrate that off-label prescription of iNO is not associated with improved survival in a large cohort of extremely premature neonates with RDS. Among subjects whose RDS was associated with PPHN, treatment with iNO did not affect survival beyond the first week of life. In the absence of PPHN, iNO was prescribed rarely (<1%), although its use was associated with increased mortality. The demographic characteristics and outcomes of our matched cohort were similar to those of the 2 largest US clinical trials of early iNO. 9, 12 Likewise, among nearly
Since the toxic effects of NO are partly dose-dependent, it is essential to use the lowest effective dose. The appropriate dose of iNO is, however, debated. Recommended start dose of iNO in infants with persistent pulmonary hypertension is 10 ppm and the maximal dose is 20 ppm. In peri-postoperative treatment associated with heart surgery in adults, the recom- mended start dose is 20 ppm and the maximal dose is 40 ppm. 42 In this study, doses of iNO were based on clinically relevant doses and on prior porcine studies of hypoxic pul- monary hypertension. 13,43 The current report indicates that doses above 5 ppm exert minimal additional pulmonary vaso- dilation and that iNO in a clinical maximal dose is not capable of completely reversing an acute rise in pulmonary arterial pressure. Similar ﬁ ndings have been presented by other authors. 43,44 However, it seems possible, based on the present data and the dose-dependent correlation of PDNO, that higher doses of PDNO may completely reverse an acute increase in pulmonary arterial pressure. A further dose elevation to con- ﬁ rm this was not performed in this study in order to sustain a clinically relevant MAP of minimum 60 mm Hg.
ous trials of iNO attempted to enroll infants at an OI ⱖ 25, the average OI at enrollment was nearly 40, compared with 19.5 in our study. OI was closely followed in our study infants, and standard iNO was initiated when the threshold of 25 was reached. Therefore, careful monitoring of infants in respira- tory failure may allow us to institute standard iNO expeditiously when the threshold of 25 is reached, decreasing the probability of ECMO/mortality. In addition, wider application of surfactant therapy and high-frequency ventilation ( ⱖ 80% before or in con- junction with standard iNO) may have contributed to decreased use of ECMO in our study infants, as previously reported. 10,16
ticle presents new and interesting observations on a treatment that has proved effective and seemingly safe in term infants with pulmonary hypertension, caution must be observed in extending these uncon- trolled observations to treatment of infants who are particularly vulnerable to adverse side effects. The results presented in this article must not be inter- preted as evidence to support the use of iNO for premature infants with chronic lung disease. Such expanded use of iNO awaits the results of the ran- domized, controlled trials that are proposed by Banks and associates in this issue of Pediatrics.
We conclude that the use of low-dose iNO may result in sustained improvement in oxygenation in some infants with severe BPD, allowing them to tolerate lower inspired oxygen concentrations and decreased ventilator support. It remains to be deter- mined whether therapy with low-dose iNO may be beneficial and safe for infants with less severe or developing BPD. In addition, because none of the infants studied had difficulty weaning to 10 ppm of nitricoxide, doses of iNO at #10 ppm may be effec- tive in this population. Randomized controlled trials of iNO in BPD are essential to verify these results.
constriction), selected as the worst and best performing devices, respectively, in the experimental study. For the injection and mixing element, simulations indicated enhanced mixing between the NO-containing gas stream and air stream resulting from separation and recombination of the gas mixture along different flow paths through the three angled fins positioned immediately downstream from the NO injection point. This is similar to the mixing process through traditional static mixing elements used in a variety of engineering fields, which contain multiple baffles in series, each similar to the three-fin design used at present. For use in breathing circuits, low resistance to flow is critical; therefore, a single (non-repeated) mixing element is preferred.
W hen it became clear in the late 1980s that the previously unidentified endothelium-de- rived relaxing factor was in fact nitricoxide (NO), it offered doctors the opportunity to use, for the first time, a selective pulmonary vasodilator in a variety of patient groups. In relation to the newborn (those with respiratory disease frequently have rela- tively high pulmonary artery pressure), this agent seemed to offer particular therapeutic opportunities. In preterm infants, increased use of surfactant and antenatal steroids during the early 1990s altered the pattern of preterm lung disease, with fewer infants developing severe acute respiratory failure. As a re- sult, trials of inhaled NO (iNO) were focused on those preterm infants who continued to have major respiratory problems despite antenatal steroids and surfactant, ie, the sickest and smallest infants. A Co- chrane review of iNO studies 1 includes 3 trials, 2–4 the
guideline compliance. Compliance was initially measured by searching for phy- sician documentation of iNO initiation and weaning in the physician progress notes in the electronic medical record. After the ﬁ rst quarter following imple- mentation, we found that physician documentation in the medical record was lacking with respect to justi ﬁ cation for weaning or not weaning. iNO weaning remained inconsistent and dif ﬁ cult to track. Therefore, we shared these ﬁ nd- ings with the CTICU staff and reeducated them on the importance of the guidelines and the SMART phrases developed for our electronic medical record system to facilitate usage of the guidelines. We also altered the way we tracked compliance. Instead of measuring documentation of iNO initiation and weaning justi ﬁ cation or plan in the physician progress notes, we elected to track the usage of the iNO initiation and weaning SMART phrases in our elec- tronic medical record. This method was a more consistent and easily obtainable plan of tracking compliance with initi- ation and weaning guidelines.
The survival of preterm and extremely low birthweight neonates has increased dramatically . There have been dramatic responses to exogenous surfactant treatment. However, a subset of these neonates with hyaline membrane disease may have suboptimal response because of severe pulmonary hypertension [3,4]. Inhalednitricoxide may be beneficial for them by dilating the pulmonary vasculature, improving ventilation/perfusion mismatch, and decreasing the pulmonary inflammatory response [5,6]. Inhalednitricoxide has an established role for the management of persistent pulmonary hypertension in term neonates . Its role in preterm neonates has been controversial and its safety and efficacy have been questioned [8,9]. Meta-analysis of randomised trials done up to 1999 did not give conclusive answers . Studies done in the past were underpowered and had methodological limitations such as entry criteria, drug concentration, and duration and definition of response. To resolve this controversy recent randomised trials have been conducted. I searched the MEDLINE (PubMed), CINAHL, EMBASE, Cochrane-controlled trials and did a hand-search of major paediatric and neonatology journals for randomised trials pertaining to the use of inhalednitricoxide in preterm neonates from 1996 onwards. This communication discusses three recently concluded large multi-centric trials and summarises the results of other randomised trials:
due to worsening of the ventilation perfusion distributions, caused by a greater increase in blood flow compared to the increase in airflow reaching the vasodilated areas. Taking into account these earlier studies, our patients received 30 µ g/kg IBW/hour doses, which obviously prevented excess vasodila- tion and lowering of ventilation/perfusion ratio (V/Q) ratio. This dose was chosen because it was the highest dose safely tested so far and the objective of this study was to observe with FRI the vascular effect induced by the strongest safe dose. Further studies are needed to determine the dose– response relationship.
on lung structure and function in chroni- cally ventilated preterm lambs. Am J Respir Crit Care Med. 2005;172(7):899 – 906 6. Tang JR, Markham NE, Lin YJ, et al. Inhalednitricoxide attenuates pulmonary hyper- tension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor. Am J Physiol Lung Cell Mol Physiol. 2004;287(2):L344 – L351 7. Clark RH, Ursprung RL, Walker MW, Ellsbury