Nitric oxide for respiratory failure in infants born at or
near term
Finer NN, Barrington KJ
Dates
Date edited: 23/08/2006
Date of last substantive update: 31/05/2006
Date of last minor update: 17/12/2000
Date next stage expected / /
Protocol first published: Issue 4, 1996
Review first published: Issue 1, 1998
Contact reviewer
Dr Neil Finer
Director of Neonatology
Pediatrics
University of California, San Diego
200 W Arbor Dr
San Diego
California USA
92103-8774
Telephone 1: 1 619 543 3759
Facsimile: 1 619 543 3812
E-mail: nfiner@ucsd.edu
Contribution of reviewers
Internal sources of support
NoneExternal sources of support
NoneWhat's new
This updates the review "Nitric oxide for respiratory failure in infants born at or near term", published in The Cochrane Library, Issue 2, 2001 (Finer 2001).This update includes two additional trials (Konduri and Sadiq). Both of these trials were of intervention at moderate severity, compared to waiting until severe disease occured.
Dates
Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /
Text of review
Synopsis
Inhaled nitric oxide is safe and can help some full term babies suffering respiratory failure who have not responded to the usual methods of support.
Inhaled nitric oxide can help some full term babies suffering respiratory failure who have not responded to the usual methods of support. Trials have shown that inhaled nitric oxide can increase the levels of oxygen in babies' blood and reduce the need for extracorporeal membrane oxygenation (ECMO), a highly technical and invasive therapy. Unfortunately, these benefits of inhaled nitric oxide care not seen in babies whose respiratory failure is due to a diaphragmatic hernia. Inhaled nitric oxide has not shown any short or longer term adverse effects.
Abstract
Background
Nitric oxide is a major endogenous regulator of vascular tone. Inhaled nitric oxide gas has been investigated as a treatment for persistent pulmonary hypertension of the newborn.
Objectives
To determine whether treatment of hypoxaemic term and near-term newborn infants with inhaled nitric oxide (iNO) improves oxygenation and reduces the rates of death, the requirement for extracorporeal membrane oxygenation (ECMO), or affects long term neurodevelopmental outcomes.
Search strategy
Electronic and hand searching of pediatric/neonatal literature and personal data files. In addition we contacted the principal investigators of articles which have been published as abstracts to ascertain the necessary information.
Selection criteria
Randomized and quasi-randomized studies of inhaled nitric oxide in term and near term infants with hypoxic respiratory failure. Clinically relevant outcomes, including death, requirement for ECMO, and oxygenation.
Data collection & analysis
Trial reports were analysed for methodologic quality using the criteria of the Cochrane Neonatal Review Group. Results of mortality, oxygenation, short term clinical outcomes (particularly need for ECMO), and long term developmental outcomes were tabulated.
Statistics: For categorical outcomes, typical estimates for relative risk and risk difference were calculated. For continuous variables, typical estimates for weighted mean difference were calculated. 95% confidence intervals were used. A fixed effect model was assumed for meta-analysis.
Main results
Fourteen eligible randomized controlled studies were found in term and near term infants with hypoxia.
Seven of the trials compared iNO to control (placebo or standard care without iNO) in infants with moderate or severe severity of illness scores.
Four of the trials compared iNO to control, but allowed back up treatment with iNO if the infants continued to satisfy the same criteria for severity of illness after a defined period of time.
Two trials enrolled infants with moderate severity of illness score (OI or AaDO2) and randomized to immediate iNO treatment or iNO treatment only if they deteriorated to more severe criteria.
One trial studied only infants with congenital diaphragmatic hernia (Ninos 1997), and one trial enrolled both preterm and term infants (Mercier 1998), but reported the majority of the results separately for the two groups.
Inhaled nitric oxide appears to improve outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO. The reduction seems to be entirely a reduction in need for ECMO; mortality is not reduced. Oxygenation improves in approximately 50% of infants receiving nitric oxide. The Oxygenation Index decreases by a (weighted) mean of 15.1 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg. Whether infants have clear echocardiographic evidence of persistent pulmonary hypertension of the newborn (PPHN) or not does not appear to affect outcome.
The outcome of infants with diaphragmatic hernia was not improved; indeed there is a suggestion that outcome was slightly worsened.
The incidence of disability, incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not.
Reviewers' conclusions
On the evidence presently available, it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia.
Background
Persistent pulmonary hypertension of the newborn (PPHN) is an important cause of cardiorespiratory failure in the near-term neonate (> 34 weeks), either as a primary condition of neonatal maladaptation or secondary to other diseases such as hyaline membrane disease (HMD), meconium aspiration, infection, and congenital diaphragmatic hernia. A review performed in 1996 of the Oxford Database of Perinatal Trials, which included PPHN as an outcome, showed that at that time, there was not a single randomized controlled trial that demonstrated that PPHN can be prevented by any perinatal interventions. PPHN is now the commonest underlying factor in infants who qualify for treatment with extracorporeal membrane oxygenation (ECMO).
Before inhaled nitric oxide (iNO) was available, conventional therapy involved paralysis, sedation, and the induction of alkalosis by hyperventilation and bicarbonate. None of these therapies have been proven to reduce mortality or the need for ECMO by prospective randomized trials. In addition, there was no clinically evaluated selective pulmonary vasodilator (other than iNO) that is free of systemic side effects.
There is now considerable evidence that the regulation of vascular muscle tone at the cellular level occurs via nitric oxide (NO). Nitric oxide is generated enzymatically by one of several NO synthases from L-arginine. NO activates guanyl cyclase by binding to its heme component leading to the production of cyclic GMP. The mechanism by which cyclic GMP relaxes vascular smooth muscle is not clear, but probably involves inhibition of activation-induced elevation in cytosolic calcium concentration.
Abman et al (Abman 1990) studied the late gestation ovine fetus and showed that inhibition of NO production caused fetal pulmonary and systemic hypertension with attenuation of the rise in pulmonary blood flow at delivery. They also demonstrated that inhibition of NO formation attenuated the pulmonary vasodilation produced by ventilation, increasing oxygen tension and shear stress (Cornfield 1992), and that inhalation of NO by the ovine fetus caused sustained and selective pulmonary vasodilation of a magnitude equal to that produced by 100% oxygen ventilation (Kinsella 1992a).
In the newborn lamb several models of pulmonary hypertension are reversed by 40 to 80 ppm of inhaled nitric oxide (iNO) (Frostell 1991; Fratacci 1991). Similar results using pulmonary vasoconstriction, produced by hypoxia with or without respiratory acidosis, were obtained by Roberts et al (Roberts 1993) who also demonstrated elevated plasma cyclic GMP levels following NO inhalation. In none of these studies was there an effect on the systemic circulation, specifically on systemic vascular resistance; in two studies, an increase in left to right shunting across the ductus arteriosus occurred during NO inhalation, demonstrating that iNO is a potent selective pulmonary vasodilator.
In adults with pulmonary hypertension, the initial observation by Higenbottam (Higenbottam 1988) that iNO decreases pulmonary vascular resistance was confirmed by Pepke-Zaba 1991 who showed that iNO (40 ppm) had a beneficial effect in reducing pulmonary hypertension with no change in systemic vascular resistance. In adults with ARDS, Rossaint et al showed that a reduction in pulmonary arterial pressure and a decrease in intrapulmonary shunting occurred within 40 minutes of inhalation of NO (Rossaint 1993). In these patients, the major benefit was likely due to an improvement in ventilation perfusion matching, rather than pure pulmonary vasodilatation.
Two uncontrolled reports in neonates with PPHN from separate groups working in Denver (Kinsella 1992b) and Boston (Roberts 1992) demonstrated that iNO rapidly produced a significant improvement in pre-ductal oxygen saturation, without the production of any detectable toxic effect such as methaemoglobinaemia. The Boston group (Roberts 1992) indicated that concentrations of 80 ppm of NO were required to achieve a response, whereas the Denver group (Kinsella 1992b) were able to produce beneficial effects with only 10-20 ppm. This latter group reported on nine further infants treated with iNO, eight of whom showed a sustained beneficial response (Kinsella 1993). A prospective evaluation of the dose response to iNO has been conducted in 23 infants referred for possible ECMO therapy by Finer et al (Finer 1994). These infants received multiple randomized doses of iNO from 5 to 80 ppm. Inhalation of NO was associated with significant improvements in PaO2, and decreases in A-aDO2 and oxygenation index (OI) for 14 out of 21 studied infants. There was no difference in response between 5 ppm and higher concentrations.
This preliminary evidence led to the performance of prospective randomized controlled clinical trials evaluating the role of inhaled nitric oxide in infants with respiratory failure.
Objectives
To determine whether treatment of hypoxaemic newborn infants with inhaled nitric oxide improves oxygenation and reduces the rates of death, the requirement for ECMO and, additionally, whether there are any effects on long term neurodevelopmental outcomes.
Criteria for considering studies for this review
Types of studies
Only randomized prospective clinical trials were included.
Types of participants
Newborn infants (< 1 month of age) with hypoxemia suspected to be due to either lung disease, pulmonary hypertension with right to left shunting, or both.
Only studies in term and near-term infants (> 34 weeks gestation) were included.
Efforts were made in all studies to exclude infants with intracardiac shunting due to structural congenital heart disease.
Infants with diaphragmatic hernia may respond differently to other near term infants (from preliminary data), and as far as possible results from infants with diaphragmatic hernias have been evaluated separately.
Types of interventions
Administration of inhaled nitric oxide gas in either masked or unmasked fashion; the comparison group received no nitric oxide initially and was receiving standard or maximal neonatal intensive care.
Types of outcome measures
1. Death or requirement for ECMO
2. Death prior to hospital discharge.
3. Requirement for ECMO (either actually receiving ECMO or meeting ECMO criteria) prior to hospital discharge.
4. Improvement in oxygenation (as a dichotomous variable) within 30 to 60 minutes.
5. Effects on oxygenation index after 30 to 60 minutes of therapy (both absolute values and change from baseline).
6. Effects on arterial PO2 after 30 to 60 minutes of therapy (both absolute values and change from baseline).
7. Neurodevelopmental disability at 18 to 24 months
8. Cerebral palsy
9. Cognitive impairment at 18 to 24 months
10. Deafness
Search strategy for identification of studies
Standard methods of the Neonatal Collaborative Review Group were used. Initially a MEDLINE search was performed in March 1997 using the search engine 'Melvyl medline plus' and the following search terms 'key word=nitric', and 'subject heading = infant, newborn'.
Society for Pediatric Research meeting abstracts on diskette for 1995, 1996, and 1997 were also searched using the terms 'control, controls or controlled' and 'nitric or NO'.
The search was last updated in November 2005 using the same search terms, but using PubMed as the search engine to include articles published from 1990 to November 2005. A search of the Society for Pediatric Research abstracts for 1998 - 2005 was also added.
Methods of
the review
Standard methods of the neonatal review group were used.
Each identified trial was assessed for methodological quality with respect to
a) masking of randomization
b) masking of intervention
c) completeness of follow up
d) masking of outcome assessment. Trials without a simultaneous control group (e.g. those with historical controls) were rejected.
Data on inclusion criteria, therapeutic interventions and outcomes were extracted for each included trial.
Selection of the studies, rating of quality, extraction of data and analysis and interpretation of the results were performed by both authors. Disagreements were settled by consensus.
Statistics: For categorical outcomes, typical estimates for relative risk and risk difference were calculated. For outcomes measured on a continuous scale, typical estimates for weighted mean difference were calculated. 95% confidence intervals were used. A fixed effect model was assumed.
Hetrogeneity was explored using the I2 statistic.
Description of studies
There were 14 trials identified in near term infants with hypoxaemic respiratory failure,; all used random allocation. (Barefield 1996; Clark 2000; Davidson 1997; Day 1996; Kinsella, hfo/iNO; Ninos 1996; Ninos 1997; Roberts 1996; Wessel 1996; Mercier 1998; Cornfield 1999; Christou 2000; Sadiq 1998; Konduri 2004)
Six of the trials compared iNO to control (placebo or standard care without iNO in infants with moderate or severe severity of illness scores.
One trial randomized infants to either iNO or high frequency ventilation.
Four of the trials compared iNO to control, but allowed back up treatment with iNO if the infants continued to satisfy the same criteria after a defined period of time.
Two trials enrolled infants with moderate severity of illness score (OI or AaDO2) and randomized to immediate iNO or iNO only if they deteriorated to more severe criteria (Konduri 2004; Sadiq 1998).
One trial enrolled only infants with diaphragmatic hernia, and compared iNO to placebo, open label iNO was not allowed. Ninos 1997
One study was excluded as some of the controls were historical and assignment to iNO or control was dependent upon availability of equipment (Hoffman 1997).
One of the above studies enrolled infants of any gestational age, but reported the majority of the descriptive and outcome data separately for their preterm (< 33 weeks gestation) and near term (> or = 33 weeks) babies (Mercier 1998). The studies vary in size from n = 17 (Barefield 1996) to n = 235 (Ninos 1996). Eligibility criteria have been reasonably homogeneous; some studies have excluded infants with either pulmonary hypoplasia of any cause or diaphragmatic hernias (Roberts 1996; Wessel 1996; Barefield 1996; Davidson 1997; Mercier 1998; Christou 2000; Konduri 2004), whereas the remaining studies included infants with these conditions (Kinsella, hfo/iNO; Day 1996; Clark 2000; Cornfield 1999; Sadiq 1998) or randomized them in a separate study (Ninos 1997). Most of the studies have been limited to near term infants (> = 34 weeks Clark 2000; Ninos 1996; Kinsella, hfo/iNO; Wessel 1996; Cornfield 1999; Christou 2000; > = 35 weeks Barefield 1996; 'full term' Roberts 1996; Davidson 1997), but Day 1996 included preterm infants.;
Hypoxaemic respiratory failure was required for entry into each of the studies, the criteria being an OI of 25 to 40 (Day 1996), PaO2 < 100 during ventilation with 100% oxygen (Barefield 1996; Wessel 1996; Christou 2000), PaO2 < 80 during ventilation with 100% oxygen (Kinsella, hfo/iNO), PaO2 < 55 during ventilation with 100% oxygen (Roberts 1996), OI > 25 on two occasions (Ninos 1996; Cornfield 1999), OI > 25 but PaO2 > 30 (Clark 2000). Mercier 1998 had the least stringent entry criteria, that is an OI of between 15 and 40 on two blood gases one hour apart.
Konduri 2004, and Sadiq 1998 enrolled infants with less severe respiratory failure, (Konduri 2004, OI 15 to 25, Sadiq 1998, AaDO2 500-599) and randomized to immediate iNO, compared to iNO only if the upper limit was later exceeded.
Most of the studies (Kinsella, hfo/iNO; Wessel 1996; Day 1996; Davidson 1997; Roberts 1996; Cornfield 1999; Christou 2000; Sadiq 1998) also required echocardiographic evidence of PPHN. Clark 2000 required clinical or echocardiographic evidence of PPHN.
All of the studies recorded data regarding short term effects on oxygenation. This was reported as either percentage or absolute change in PaO2 and Oxygenation index. Data for all of percentage and absolute changes and absolute values were available to us only for the Mercier 1998 study. Other studies gave the results in one way or the other.
The majority of these studies (Ninos 1996; Ninos 1997; Davidson 1997; Wessel 1996; Clark 2000; Roberts 1996; Christou 2000 and probably Wessel 1996) have not allowed backup use of iNO in controls who failed treatment. Barefield 1996 and Cornfield 1999, however, did allow such treatment and thus are relatively uninformative for the endpoint of the effect of iNO on survival or ultimate need for ECMO. It appears that Mercier 1998 allowed nitric oxide treatment of controls after the two hour outcome point, and in fact 8 of the term control infants received iNO even before this point. The data on these two important end points rely largely on the Ninos, Clark, and Christou studies in which they were the primary outcome; in the Roberts study these were secondary outcomes.
Barefield 1996 compared iNO with 'conventional treatment'. The infants had been treated with induction of alkalosis, both metabolic and respiratory, to obtain a pH of 7.65 or greater with a PCO2 of 25 to 35 torr and all infants were paralyzed with vecuronium and sedated. Infants were not allowed to receive other vasodilators during the trial. The infants were initially randomized to receive iNO at a dose of 20 ppm for a PaO2 of between 40 and 99 torr and 40 ppm for a PaO2 of less than 40 torr; increases were allowed up to 80 ppm. Treatment failure occurred if the PaO2 was less than 80 torr for one hour, less than 40 torr for greater than one hour regardless of pH, or less than 30 torr for 30 minutes regardless of pH. When infants met treatment failure criteria, they were crossed over and treated with iNO if they had not previously received iNO. The primary outcome of this trial was the need for ECMO or treatment failure. Seventeen of 19 eligible infants were enrolled in the trial. Of interest, only two of the 17 randomized infants had right to left extrapulmonary shunt at the time of study entry.
Davidson 1997 performed a multicenter study which compared three different doses of iNO (5 ppm, 20 ppm, 80 ppm) to a nitrogen placebo. They hypothesized that iNO would reduce the incidence of a PPHN Major Sequelae Index (MSI) which was constructed. This index included death, ECMO, neurologic sequelae or chronic lung disease. They enrolled 155 infants with echocardiographic evidence of PPHN and a PaO2 between 40 and 100 torr in 100% oxygen, with a wide range of illness severity at enrolment. They excluded infants who received surfactant therapy, and did not allow concurrent high frequency ventilation. Failure was defined as a PaO2 of less than 40 mmHg for greater than 30 minutes. Their study was terminated early due to poor enrolment. 155 infants were enrolled, 41 were entered into the control group and 114 into one of the three NO groups, with 41 receiving 5 ppm, 36 receiving 20 ppm and 37 receiving 80 ppm.
Day 1996 was a single centre study. They randomized infants with OI's between 25 and 40 to receive conventional therapy or 20 ppm of iNO, and all infants who presented with OI's over 40 or whose OI's increased to greater than 40 were then treated with open label iNO. As a result, there were 22 infants treated in the randomized portion of the trial who presented with OI's between 25 and 40 of whom 11 received iNO and 11 received conventional therapy. Much of their report combines the infants randomized to NO and the non-randomized infants who received NO and the control infants who crossed over to NO. We have only included data where it is clearly derived from the initially randomized comparison.
Kinsella, hfo/iNO compared nitric oxide to high frequency oscillatory ventilation (HFOV), rather than to 'standard therapy' and if infants failed the first therapy they were crossed over to the alternate therapy and then to combined treatment. The data from this study used in this review, therefore, relate only to the first comparison between the initially randomized groups. Kinsella, hfo/iNO was a multicenter study which excluded infants with lethal abnormalities and proscribed the use of surfactant after enrolment. The definition of success in this trial was the achievement of a PaO2 of greater than 60 torr with the assigned therapy. The initial randomization was to either iNO at 20-40 ppm or HFOV using the Sensormedics Oscillator. There were 205 infants enrolled in the trial when it was terminated as a result of an interim analysis which demonstrated a lack of efficacy. Thirty-one percent of the infants in this trial had received surfactant prior to enrolment.
The Ninos 1996 study was a multicenter trial. Subjects were 14 days of age or less without congenital structural heart disease. While all infants in the trial had an echocardiogram prior to randomization, an echocardiographic diagnosis of PPHN was not an inclusion criterion for this trial, as it was for all of the other trials herein reported. Infants were randomly assigned to receive either 20 ppm of iNO or placebo; in this study the placebo gas was 100% oxygen. The primary hypothesis was that the administration of iNO to such infants would reduce the risk of death or the need for ECMO by 120 days from 50% in control infants to 30% in infants receiving iNO. This study encouraged full aggressive conventional therapy including HFOV by centres experienced in its use, the use of a bovine surfactant as well as the maintenance of arterial blood pressure above 45 mmHg, induction of alkalosis (target pH 7.45 to 7.6) with encouragement for the use of sedation and/or paralysis and vasopressors and volume expansion as necessary to maintain blood pressure. The External Data Safety Monitoring Committee recommended termination of the trial after the second planned review of the data showed that the trial had reached the predetermined boundary of statistical significance at which time 235 infants (121 controls and 114 infants in the iNO group) had been enrolled. These two groups were well matched for their clinical characteristics and blood gas values and were nearly identical in the use of support treatments at the time of randomization. Approximately 55% of infants were receiving HFOV at the time of randomization and approximately 72% of infants had received surfactant prior to randomization. Over 90% of all infants had received volume and vasopressor support, neuromuscular blockade and sedation prior to randomization.
The Ninos 2000 publication represents the follow-up of the survivors of the two Ninos studies who underwent comprehensive neurodevelopmental assessment at 18 to 24 months of age. A secondary postulate of the original study was that the administration of iNO would lead to no increase in neurodevelopmental disability at 18 to 24 months. Of the 235 infants enrolled, 36 died, and 176 of the 199 survivors were assessed at follow-up, 88 control infants and 85 iNO infants. In addition, this study included the survivors of the parallel trial of infants with CDH (Ninos 1997). There were 29 survivors of the original 53 enrolled infants, and follow-up was available for 8 of the 13 iNO survivors and 14 of the 16 control infants. The survivors were well matched for their neonatal characteristics. Structured neurological examinations and hearing tests were performed, and Bayley scores of infant development were assigned, mostly by blinded assessors.
Roberts 1996 conducted a multicenter trial in infants who were on an FiO2 of 1.0 and had a post-ductal PaO2 of 55 torr or less on two consecutive determinations 30 minutes apart. Infants were excluded if they had polycythaemia (hematocrit of at least 70%), or uncorrected hypotension and aortic blood pressure of below 40 mm or an un-evacuated pneumothorax. Infants were also excluded from the trial if they had received treatment with HFOV or jet ventilation. Infants were included if they had previously received surfactant without sustained improvements in oxygenation. All infants had the FiO2 reduced to .9 and were enrolled if they maintained their PaO2 greater than 85% of their previous baseline. An interim analysis after 50 patients were enrolled demonstrated that iNO increased systemic oxygenation significantly compared to the control gas. There were 28 control group infants and 30 iNO infants who appeared well matched both for diagnoses, blood gases, oxygen indices, and ventilator settings.
Wessel 1996 was a single centre, open label trial. Management of these patients included sedation and neuromuscular blockade. The infants in this trial were permitted to have previously received surfactant therapy or HFOV. iNO therapy was initiated, after reduction of FiO2 to .97, at 80 ppm with a protocol which lowered the iNO dose to 40 ppm after one hour with continued weaning if tolerated. iNO was discontinued when a patient was cannulated for ECMO or when the clinician chose to initiate HFOV. The effectiveness of iNO was evaluated by alterations in oxygenation, mortality, and the use of ECMO. Fifty-one patients were enrolled of whom two were excluded. Of the infants in the study, 23 were randomized to receive conventional treatment compared to 26 who received iNO. Only four patients in this study were actually treated with surfactant and, as with the previous studies, the most common diagnosis was meconium aspiration (45% of enrolled patients). This group has now published follow up data, including neurodevelopmental outcomes, which were obtained by telephone interview of 60 of the 83 survivors of the original trial. The interview was conducted between one and four years of age.
Clark 2000 randomized 248 near term infants who were less than or equal to 4 days of age and had an oxygenation index of greater than 25 to either 20 ppm of nitric oxide or nitrogen placebo. Infants were not eligible if the PaO2 was less than 30 and the infants were considered to be in urgent need of ECMO for refractory hypotension (a mean blood pressure lower than 35 mmHg). Infants with congenital diaphragmatic hernia were not excluded, and data are available as a separate stratum allowing comparison of the results to those of Ninos 1997. Infants were stratified by one of five diagnostic categories and then randomized within that stratum. These strata were meconium aspiration, pneumonia, respiratory distress syndrome, lung hypoplasia syndromes including diaphragmatic hernia, and idiopathic persistent pulmonary hypertension. Echocardiographic or clinical confirmation of pulmonary hypertension was required. The primary outcome variable was the need for ECMO. After 24 hours of treatment with 20 ppm the dose was reduced to 5 ppm for up to a further 96 hours. Secondary outcome variables of oxygen dependence at 30 days and clinical or ultrasound defined neurological abnormality were evaluated.
All of the above described studies, with the exception of Kinsella, hfo/iNO, Day 1996 and Clark 2000, have excluded infants with congenital diaphragmatic hernia. This patient population is unique in their presentation and pathophysiology. As a result, a parallel study of infants with CDH was performed by the NINOS investigators using an identical study protocol to the main NINOS study; Ninos 1997. They enrolled 53 infants (28 control, 25 iNO treated) in their study whose primary hypothesis was that iNO would reduce the occurrence of death or the need for ECMO at 120 days. Their treated and control groups were well matched with baseline OI's of 45.8 + 16.3 in controls and 44.5 + 14.5 in the iNO treated infants.
Mercier 1998 was a randomized multi-centre trial in 33 French and Belgian neonatal units. 204 infants were entered into the trial of which 107 were near term infants. Randomization was by sealed envelopes kept at the study centre and was therefore adequately masked. The intervention was not blinded. The near-term infants were entered at an OI between 15 and 40, confirmed on two gases one hour apart, and treated either with iNO at 10 ppm or no iNO. Infants with pulmonary hypoplasia, including diaphragmatic herniae, were excluded. The primary outcome measure was oxygenation index at two hours. If an infant exceeded an OI of 40 during the two hour period, iNO therapy was allowed. After the two hour assessment, further therapy was at the discretion of the physician, and it is not reported how many infants received iNO at this time.
The randomization procedure stratified the infants according to gestation, mode of ventilation, and pulmonary diagnosis. Two thirds of the infants had received surfactant and just over half (57%) were on high frequency oscillatory ventilation. Thirty per cent of the infants had meconium aspiration syndrome, 25% idiopathic PPHN, and 45% had RDS. Enrolment into the study was terminated because of slowing recruitment after 204 of the originally planned 360 infants had been entered. ECMO was not available as a backup therapy, therefore the number of infants dying is the same as the number of infants dying or requiring ECMO.
Cornfield 1999 was a randomized study in three centres, that compared 2 ppm of inhaled NO to control. The hypothesis of the study was that low dose nitric oxide would acutely improve oxygenation. The study was unblinded. Thirty-eight full term infants were enrolled, nine of whom had a diaphragmatic hernia. After the initial one hour period, if the infants continued to have an OI of greater than 35, they were considered treatment failures and received 20 ppm of nitric oxide.
Christou 2000 randomized 42 infants, one of whom proved to have congenital heart disease and was removed from study, leaving 41 study infants. Inhaled NO at 40 ppm was compared to standard therapy, without placebo gas. After one hour, the dose was decreased to 20 ppm if tolerated, and daily attempts at weaning NO were made. Randomization is not clearly described other than the use of envelopes which were randomly drawn.
Sadiq 1998 randomized infants with a birth weight > 2 kg on assisted ventilation with 100% oxygen and an A-aDO2 between 500 and 599 torr on two blood gases at least one hour apart to inhaled NO (10 to 80 ppm) or standard medical management. Infants required echocardiographic evidence of pulmonary hypertension, and at least one dose of surfactant prior to enrolment. The primary outcome criterion was "severe pulmonary hypertension" that was defined as an A-aDO2 of greater than 600. If the infants satisfied this definition then iNO and other therapies including ECMO were allowed. Infants with diaphragmatic hernia were enrolled, only "lethal anomalies" being excluded.
Konduri 2004 randomized infants > or = 34 weeks gestation on assisted ventilation with an OI between 15 and 25 on FIO2 0.80 on any two arterial blood gases at least 15 minutes and not > 12 hours apart to iNO at 5 to 20 ppm or placebo (nitrogen gas). iNO was started at 5 ppm and increased if there was a partial response to a maximum of 20 ppm, (adjustments made by a single unmasked therapist, the remainder of the team were masked). Infants with diaphragmatic hernias, or cardiac malformations or more than 14 days old were excluded. The primary outcome was death or the need for ECMO. The control group received iNO if the OI exceeded 25.
Methodological quality of included studies
The overall quality of these studies is quite variable. The highest quality studies were fully blinded, adequately powered, multi-centre randomized controlled trials with external data monitoring groups that examined clinically important outcomes, such as Ninos 1996 and Clark 2000. There are a group of studies that were of intermediate quality, that had variable degrees of blinding, and examined primarily oxygenation outcomes: Mercier 1998; Roberts 1996; Davidson 1997. A third group of studies were single (or few) centre studies that were unblinded, had very small sample sizes and as a result investigated short term oxygenation responses: Barefield 1996; Cornfield 1999; Day 1996; Wessel 1996.
Kinsella, hfo/iNO is a unique study which was of high quality but had a rather complex protocol and cannot be directly compared to the remaining studies as it was comparing iNO and high frequency ventilation.
Several of the studies were terminated early. In the case of Ninos 1996, this was because pre-determined stopping rules were satisfied. In the case of Davidson 1997; Sadiq 1998; Mercier 1998; Konduri 2004 it was because of slowing enrolment.
Barefield 1996
Although this was a randomized study, the small sample size gives little protection against type two errors. There are also somewhat unbalanced groups with a mean OI at entry of 26 in the control group and 38 in the treatment group. Infants receiving iNO also appeared to have a lower pH (7.46 + .06 compared to 7.61 + .07), a higher PaCO2 (40 + 7 vs 28 + 4 torr), and a lower PaO2 (49 + 7 vs 63 + 7 torr). The study hypothesis is not clearly described. The sample size calculation required 24 patients per group, but the basis for this calculated sample size is not clear. Why the study was discontinued before enrolment of the calculated sample size is not described.
Wessel 1996
This small single centre study had unmasked intervention, and the allocation is not adequately described to ascertain if it was masked.
Clark 2000
This multi-centre trial had masked allocation and intervention, and complete follow-up. The published manuscript does not mention a prespecified sample size.
Cornfield 1999
Backup treatment with iNO was planned if the response to initial randomized treatment was inadequate. The randomization procedure is not described beyond a statement that "Patients were randomized through a computer generated random-number table", therefore masking of allocation is rated as unclear. The study was planned to enrol 60 patients. An interim analysis was preplanned at 2/3 of full enrolment, and performed blinded. The study was terminated after this interim analysis (n=38 patients) because a secondary analysis, i.e. response to 20 ppm after failure of initial therapy, differed between the groups. Early termination of this trial because of an unexpected finding with limited clinical significance, and no difference in clinically important outcomes has seriously limited the power of this study.
Davidson 1997
Had a 3 to 1 randomization scheme, which enabled the provision of dose response oxygenation information, but limited the number of controls. The study was terminated early and was therefore underpowered to detect clinical benefits.
Day 1996
This paper does not state how the sample size was arrived at. No study hypothesis is reported. Method of randomization is unclear, described as a 'blind draw'. The study objective is recorded as to "review the acute effects" of iNO.
Roberts 1996
The sample size determination leaves the study design open to the criticism of little protection against type one error, in that the authors reported that they planned to stop after 50 patients if the results showed a significant improvement in oxygenation, and there was no adjustment to the critical p-value for multiple looks at the data. Study hypothesis was not reported.
Ninos 1996
This was a masked multi-centre trial. Allocation, intervention and outcome assessment were all masked. Preplanned interim analyses were performed with standard stopping rules used. Significance of the primary outcome variable was noted after the second analysis.
Ninos 1997
This trial was designed in an unusual and pragmatic fashion to run simultaneously at the same centres as the main Ninos 1996 study, with a sample size which was planned by terminating enrolment when the main Ninos study was complete. Allocation, intervention and outcome analysis were all performed masked. Long term neurodevelopmental follow up of the infants in the Ninos 1996 trial and in Ninos 1997 was reported for 87% of survivors of Ninos 1996 (n = 173), and 76% of the survivors of Ninos 1997 (n = 53). All but 7 of the assessments were blinded as to the infants original treatment. One control and six iNO treated infants were assessed by non-blinded Bayley administrators
Mercier 1998
This multicentre trial had masked allocation and complete follow up, but the intervention was not masked. There were many protocol violations, (44 of the 54 assigned control therapy received it, and 55 of 62 assigned iNO received it).
Christou 2000 had a limited sample size as the study was terminated after appearance of the Ninos 1996 and Roberts 1996 results. The hypothesis is not explicitly stated; the objectives are listed as determining whether inhaled NO improves oxygenation in infants ventilated with high frequency, but not all of the infants were receiving this mode of therapy.
Sadiq 1998 was a multi-centre study with a relatively small sample. Study was terminated due to slowing enrolment. The intervention was not masked. Data with regard to death and ECMO were sought and provided by the principal investigator.
Konduri 2004 was a multicenter study with central randomization allocation and intervention were masked. (Thresholds compared were OI 15 to 25 compared to OI of > 25). Unfortunately, slow enrolment led to early termination of the study, but this was done without knowledge of the results, and should not affect the validity of the conclusions.
Results
COMPARISON 01: INHALED NO VERSUS CONTROL IN INFANTS WITH HYPOXIC RESPIRATORY FAILURE
Outcome 01-01: Death or requirement for ECMO
This outcome was reported by 9 trials. Six of these studies (Clark 2000; Davidson 1997; Ninos 1996; Roberts 1996; Wessel 1996; Christou 2000) did not allow backup use of iNO in controls who did not respond to initial treatment, whereas 3 studies (Barefield 1996, Mercier 1998; Cornfield 1999), did allow such backup use in iNO in controls. The results have been analysed in subgroups according to this distinction, and overall.
Among the subgroup of six studies that did not allow backup use of iNO in controls, three (Clark 2000; Ninos 1996; Roberts 1996) found a statistically significant reduction in the combined outcome, death or requirement for ECMO. The meta-analyses of all six trials in this subgroup found that iNO treatment resulted in a reduction in the incidence of death or requirement for ECMO (typical relative risk 0.65, 95% CI 0.55, 0.76; risk difference -0.20, 95% CI -0.27, -0.13).
Among the subgroup of studies which allowed backup use of iNO in controls, there was no significant effect on this outcome. Typical RR for death or need for ECMO 1.15 (95% CI 0.67, 1.97).
Among all eight studies which reported effect of iNO on death or requirement for ECMO, the typical effect remained significant: typical relative risk 0.68, 95% CI 0.59, 0.79; typical risk difference -0.16, 95% CI -0.22, -0.10.
Outcome 01-02: Death
Nine studies reported this outcome. Those not allowing backup use of iNO in controls included Clark 2000; Davidson 1997; Ninos 1996; Roberts 1996; Wessel 1996; Christou 2000. None of the individual studies found a significant effect. Likewise, in the meta-analysis, there was no evidence of effect (typical relative risk 0.92, 95% CI 0.58, 1.48). Studies that did allow backup use of iNO in controls included Barefield 1996; Cornfield 1999 and Mercier 1998. Again, none of these individual trials found a significant effect, nor did the meta-analysis (typical relative risk 0.86, 95% CI 0.37, 1.98). Overall, for all nine trials, there was no evidence of effect on death (typical relative risk 0.91, 95% CI 0.60, 1.37).
Outcome 01-03: Requirement for ECMO
Eight studies reported this outcome. Those not allowing backup use of iNO in controls included Clark 2000; Davidson 1997; Ninos 1996; Roberts 1996; Wessel 1996; Christou 2000. Four of these studies found that iNO treatment resulted in a significant reduction in requirement for ECMO (Clark 2000; Ninos 1996; Roberts 1996; Christou 2000). The meta-analysis of the results of the six studies in this subgroup supports a significant effect (typical relative risk 0.61, 95% CI 0.51, 0.72; typical risk difference -0.21, 95% CI -0.28, -0.14).
Among the two studies which did allow backup use of iNO in controls and had ECMO available for participants, (Barefield 1996; Cornfield 1999) neither found a significant effect, nor did the meta-analysis in this subgroup, typical relative risk 1.14 (95% CI 0.64, 2.02).
However, overall, for all eight trials, the meta-analysis shows a significant reduction in requirement for ECMO (typical relative risk 0.63, 95% CI 0.54, 0.75; typical risk difference -0.19, 95% CI -0.26, -0.12). Thus, the number needed to treat (NNT) with iNO to prevent one infant requiring ECMO is 5.3 (95% CI 3.8, 8.3).
Outcome 01-04: Failure to improve oxygenation (PaO2)
Three studies reported this outcome. Both Ninos 1996 and Roberts 1996 found a statistically significant benefit of iNO, whereas Kinsella, hfo/iNO found no evidence of effect. There is significant statistical heterogeneity of effect across studies; thus, no typical effect is calculated.
Outcome 01-05: Oxygenation index 30 to 60 minutes after treatment
Six studies reported this outcome (Barefield 1996; Clark 2000; Davidson 1997; Day 1996; Ninos 1996; Roberts 1996). All except Barefield found a statistically significant benefit of iNO. The results are remarkably homogeneous across studies. The meta-analysis shows that oxygenation index 30 to 60 minutes after commencing therapy is significantly lower in the iNO group (weighted mean difference -9.59, 95% CI -12.50, -6.68). Christou 2000 reported median changes in oxygenation index after 60 minutes which were -18 in the inhaled NO group and 0 in the controls.
Mercier 1998 reported OI results at 2 hours after starting treatment as median and interquartile ranges. Therefore, these data cannot currently be added to our analysis. However, the direction and magnitude of the effect of iNO was very similar: among controls median OI at baseline was 21.7 with little change at 2 hours (median 19.4) whereas in the iNO group the median OI at baseline was 25.9 and fell to 15.8 at two hours. The two hour OI was significantly different between groups, as was the absolute change in OI, median -2.7 in controls vs -7.8 in the iNO group.
Outcome 01-06: PaO2 30 to 60 minutes after treatment
This outcome was assessed in six studies: Barefield 1996; Clark 2000; Davidson 1997; Day 1996; Ninos 1996; Roberts 1996. All except Barefield found a statistically significant benefit of iNO. The results are remarkably homogeneous. The meta-analysis shows that PaO2 30 to 60 minutes after treatment is statistically significantly higher in the iNO group (weighted mean difference 45.5 mmHg, 95% CI 34.7, 56.3). Christou 2000 reported median changes in PaO2, which were 53 mmHg in the inhaled NO group and 2 mmHg in the controls.
INHALED NO VERSUS HIGH FREQUENCY VENTILATION IN INFANTS WITH HYPOXIC RESPIRATORY FAILURE
Only one study compared iNO to high frequency ventilation. Kinsella, hfo/iNO found that 23% of infants treated with HFOV compared to 28% of infants treated with iNO had a successful response, defined as PaO2 greater than 60 mmHg. Following crossover, 21% of the 75 HFOV failures responded to iNO whereas 14% of 77 iNO failures responded to HFOV (not significant). The study demonstrated that response to iNO was equivalent to that to HFOV in near-term infants with hypoxic respiratory failure. The authors evaluated infants who failed to respond to either therapy singly (n = 125) and showed that 32% responded to the combination. The authors concluded that the combination of HFOV and iNO was the most effective therapy for infants who failed to respond to either one. This study suggests that the use HFOV may be valuable in establishing adequate lung volumes such that iNO therapy may then be efficacious.
COMPARISON 02: INHALED NO VERSUS CONTROL IN INFANTS WITH DIAPHRAGMATIC HERNIA
Infants with diaphragmatic hernia do not appear to share the benefit of iNO; indeed there are suggestions that outcomes may be worse in infants with CDH who received inhaled NO compared to controls. We have combined the results of Ninos 1997 and the diaphragmatic hernia stratum of Clark 2000, the only other study for which such information can be extrapolated. The incidence of death or requiring ECMO was 40/46 controls and 36/38 with nitric oxide (relative risk 1.09, 95% CI 0.95, 1.26). Mortality rate was not changed (18/46 controls compared with 18/38 with nitric oxide, relative risk of death 1.20; 95% CI 0.74, 1.96) but there was a just significant increase in the requirement for ECMO (31/46 controls compared with 32/38 with nitric oxide, relative risk 1.27; 95% CI 1.00 to 1.62). This occurred despite the fact that infants with diaphragmatic hernia who received nitric oxide were more likely to improve their oxygenation (data from Ninos 1997 only, all control infants failed to improve oxygenation compared to 20/24 nitric oxide subjects, relative risk of failure to improve oxygenation was 0.83; 95% CI, 0.70, 1.00). The improvement overall, however, was small and not statistically significant. PaO2 30 minutes after treatment increased by 7.8 mmHg compared to 1.1 for the controls (mean difference 6.7; 95% CI 15.7 to -2.3) and oxygenation index decreased by 2.7 compared to an increase of 4.0 in controls (mean difference -6.70; 95%CI -18.39, +4.99).
NEURODEVELOPMENTAL AND OTHER LATE OUTCOMES
Two studies have reported long term neurological and developmental outcomes. The Ninos 2000 publication reported the neurodevelopmental outcomes from both the Ninos 1996 and Ninos 1997 studies, and Lipkin 2002 has reported the outcomes of Davidson 1997.
Wessel 1996 has reported neurodevelopmental outcomes obtained by telephone interview.
For survivors of the Ninos 1996 study, Bayley II testing (n = 154), a neurological examination (n = 172) and hearing tests (n = 157) were performed. There was no significant difference in the occurrence of neurodevelopmental sequelae between the iNO and control infants: 18/87 controls compared with 19/85 iNO infants did not have a normal neurologic examination, and 9/87 controls compared with 10/85 iNO infants had cerebral palsy. There were no differences in the occurrence of hearing impairment (defined as a threshold of more than 40 db, 23/82 evaluated controls compared with 24/75 evaluated iNO infants), or in scores on the Bayley Scales of Infant Development (MDI 87+18.7 for control infants vs 85+21.7 for iNO infants; PDI 93.6+17.5 for control infants vs with 85.7+21.2 for iNO infants). One or more neurodevelopmental disabilities occurred in 26/87 control infants compared with 29/85 iNO infants, (Ninos 1996). The occurrence of seizures was less in the iNO infants (13/87 controls compared with 4/85 iNO infants, p = 0.046). In addition there were no differences in the requirements for later hospital readmission, the use of home medications, apnea monitors, home oxygen, the use of gastrostomy tubes, or the requirement for speech therapy.
Survivors with CDH (from the Ninos 1997 study) had comparable neurodevelopmental outcomes at follow-up. The mean Bayley MDI among controls was 73.6 (SD 18) and PDI was 77.2 (SD 14.4); among the iNO treated infants the mean MDI was 69.1 (SD 17) and PDI was 75.8 (SD 25.8). Both controls and iNO infants had a high rate of sensorineural hearing loss (4/14 control compared with 3/8 iNO infants).
35 controls and 94 iNO treated infants from Davidson 1997 were examined at an average of 13 months of age, with a neurological examination, Bayley Scales of Infant Development and audiologic assessment. The prevalence of cerebral palsy, developmental delay (BSID scores more than 2SD below the mean) and hearing impairment(defined as mild 25 to 50 db threshold, or severe, > 50 db) were not different between groups. The general health of the infants in terms of hospitalizations and growth, was not different between groups.
The outcome data of Wessel 1996 used different scales due to the reliance on a telephone interview. They showed no difference in the developmental quotient calculated from the Motor and Social development scale of the 1981 Child Health Supplement to the National Health Interview Survey. The reliability, reproducibility and validity of this scale has received little attention. The number of infants with a quotient less than 70 was greater in the controls (4/25) than in the nitric oxide group (0/35). Although cerebral palsy, visual disability and hearing and speech disabilities are reported it is unclear how these were defined, and the incidence of overall neurological disability includes seizures. It is not, therefore, possible to add any of these data to the meta-analysis, but they do appear to show no evidence of neurodevelopmental impairment due to inhaled nitric oxide therapy. The study included an assessment of general and pulmonary health; 31% of the nitric oxide (n = 35) and 20% (n = 20) of the control patients had required hospital readmission, 14% of the nitric oxide and 24% of the control infants had reactive airways disease, neither of which were statistically significant.
The definitions used by the Ninos group, and Lipkin et al for the overall incidence of neurodevelopmental disability were dissimilar. The Ninos group report that one or more disabilities (CP, BSID MDI or PDI < 2SD, blind or hearing impaired) was not different between groups. Lipkin 2002 report the incidence of mild (1 to 2 mild impairments, including mild neurologic abnormalities and mild reduction in scores on the BSID, between 1 and 2 SD below the mean) and severe (cerebral palsy, > 2 mild, or at least 1 severe impairment). If we proceed on the assumption that the definition of severe impairment in Lipkin is similar enough to the Ninos definition of one or more neurodevelopmental disabilities for a combined analysis, this shows no effect of inhaled NO, typical RR of adverse outcome is 0.97 (95% CI 0.66 to 1.44)
COMPARISON 03: INHALED NO STARTED FOR MODERATE COMPARED TO SERIOUS DISEASE SEVERITY
Two studies enrolled infants at moderate disease severity, randomizing them to immediate iNO, compared to a control group, in which inhaled nitric oxide could be commenced later if criteria for severe disease developed. Treating at moderate severity did not reduce the risk of death (typical RR 0.73, 95% CI 0.34, 1.54) or ECMO (typical RR 0.90, 95% CI 0.52, 1.58) or the combined rate of death or ECMO (typical RR 0.85, 95% CI 0.54, 1.32). Treatment at a lower disease severity did prevent progression to severe disease, i.e. fewer of the iNO patients progressed to severe disease, 61%, vs 81% among the controls. Despite this, no other clinically important outcomes were different either in terms of duration of assisted ventilation, duration of oxygen therapy, length of hospitalisation, or incidence of chronic lung disease (not defined). There are no data on longer term outcomes.
Discussion
The results available to date provide support for the use of inhaled NO in doses of 10 - 80 ppm in the near-term, hypoxic, mechanically ventilated neonate with an OI = > 25 or a PaO2 < 100 in an FiO2 = 1. The majority of studies have evaluated physiologic end-points, while the largest trials to date primarily evaluated death or the need for ECMO.
While a single study has demonstrated no difference in physiologic response for doses between 5 and 80 ppm, further research is required to determine the lowest effective dose. In all likelihood, we are currently well above the response threshold with current management, and the use of lower doses can be expected to reduce the likelihood of accumulations of methaemoglobin and NO2. Animal studies have shown relatively little effect of increasing doses above 5 ppm. The study of Cornfield et al (Cornfield 1999) suggested that initial exposure to low dose iNO at 2 ppm may impair the response to higher doses, but that study was not a blinded trial. In addition, the infants who received the initial treatment with 2 ppm had a lesser mortality, although that was not statistically significant.
Of equal or perhaps greater importance is the need to determine whether earlier use of inhaled NO at lesser illness severity would result in significantly better outcomes. Infants who have an OI > 25 or PaO2 < 55 mmHg are quite unstable, and it is possible that waiting to satisfy these criteria in sick newborn infants may result in delays in appropriate transport or institution of other treatments. The use of INO at lesser OIs appears to have decreased progression to severe disease, but the question of delay of referral or transport was not adequately tested in any of the above trials. There were significant differences in the reviewed trials with respect to the use of other therapies, with some allowing high frequency ventilation with the jet or oscillator and surfactant treatment (Ninos 1996; Ninos 1997; Day 1996; Wessel 1996 all allowed both treatments, Clark 2000 "encouraged" both treatments, and Kinsella, hfo/iNO allowed HFOV), whereas others proscribed such management or excluded infants who received such treatments (Barefield 1996 proscribed both, Roberts 1996 disallowed HFOV, Kinsella, hfo/iNO proscribed surfactant, Davidson 1997 excluded infants who received surfactant therapy, and did not allow concurrent high frequency ventilation).
The information available at this time suggests that iNO therapy in hypoxic term and near term neonates will decrease their need for ECMO. It could be questioned whether a decreased need for another therapy, of proven value, is a real benefit. Because ECMO is invasive, expensive, and associated with clinically important complications, a reduction in ECMO requirement using a less invasive and safer treatment does promise to be a therapeutic advance. Inhaled nitric oxide was approved as a therapy for the hypoxic near-term and term neonate by the United States FDA in December 1999. The labelling indicates that this therapy should be used for near-term and term infants (>34 weeks) with hypoxic respiratory failure with clinical or echocardiographic evidence of pulmonary hypertension. We would point out that the Ninos trials did not require the presence of clinical or echocardiographic evidence of pulmonary hypertension, and that clinical or echocardiographic evidence of pulmonary hypertension was not universally present in all the other reported trials, and that such evidence is not required for a positive response (Rossaint 1993). Inhaled NO can improve ventilation/perfusion mismatching and improve oxygenation by this mechanism in infants without documented pulmonary hypertension. There are current studies in progress which are evaluating the earlier use of iNO in near term and term infants. The Ninos 2000 publication provides reassuring information regarding longer-term neurodevelopmental outcome, and demonstrates that infants who received iNO are not at increased risk of neurodevelopmental sequelae, consistent with the observations of Rosenberg et al (Rosenberg 1997), and did not experience more post discharge pulmonary complications, consistent with the report of Dobyns et al (Dobyns 1999).
Inhaled nitric oxide is, at present, the only selective pulmonary vasodilator which has been established by prospective, randomized trials to reduce the need for ECMO in the near-term infant with hypoxic respiratory failure. The lack of effect on systemic haemodynamics coupled with the relative safety of administration, when appropriately monitored, and the lack of significant longer-term neurodevelopmental sequelae, support the use of iNO in preference to other systemically administered vasodilators including prostacyclin and tolazoline.
Toxicity issues:
Nitric oxide reacts with oxygen to form nitrogen dioxide, NO2. Both NO and NO2 are toxic, causing death in dogs at concentrations between 0.1 and 2%, due to methaemoglobinaemia hypoxaemia and pulmonary edema (Greenbaum 1967). In humans, exposure to 2.3 ppm NO2 for five hours produced a 14% decrease in serum glutathione peroxidase activity and a 22% decrease in alveolar permeability 11 hours after the start of exposure, suggesting that even very low concentrations of NO2 may produce a delayed response (Rasmussen 1992). Occupational health guidelines set 25 ppm as the limit for eight hours/day NO exposure in the workplace and 3 ppm (measured as the time weighted average) as the limit for NO2 (MMWR 1988). It has been demonstrated that using 80 ppm inhaled NO in a neonatal ventilator with an FiO2 = .9 could produce 5 ppm NO2 in less than 20 seconds (Bouchet 1993). We have previously discussed the deterioration which can occur when iNO is discontinued, even in infants who have not demonstrated a positive response. Davidson et al (Davidson 1999) reviewed the results of their previous trial (Davidson 1997) and reported a 42 +/- 101% increase in OI when iNO was withdrawn from patients who did not demonstrate a positive response to the iNO. They reported that minimizing the iNO dose to 1 ppm before discontinuation was associated with the least deterioration, and we believe that this practice should be followed for infants who are being weaned from iNO irregardless of their initial response.
Methaemoglobin levels must also be carefully monitored, and significant methaemoglobinaemia has been reported after accidental overdose of a neonate with > 135 ppm of NO (Heal 1995). Long term treatment (up to 23 days for a newborn, 53 days for an adult) has not been problematic in the majority of treated patients. When NO reacts with superoxide, peroxynitrite is rapidly formed which can result in membrane lipid peroxidation (Beckman 1990). There is no human information to date with respect to the actual formation of such peroxynitrites in patients receiving inhaled NO, but the potential remains for resultant tissue injury, especially in the lung, with damage to surfactant and its related proteins (Haddad 1993). NO inhibits platelet aggregation and adhesion and as such plays an important role in vascular homeostasis (Radomski 1993). While it is believed that inhaled NO does not exert systemic effects because of the previously mentioned interaction with haemoglobin, Hogman et al have reported increased bleeding times in rabbits and humans exposed to 30 ppm of inhaled NO (Hogman 1994; Hogman 1993). This is of concern especially if inhaled NO is proposed as treatment for critically ill, hypoxic premature infants at risk for intracranial bleeding who may have been already treated with indomethacin, an agent that also inhibits platelet function.
Reviewers' conclusions
Implications for practice
On the evidence presently available, including the neurodevelopmental and general
medical outcome information, near-term and term infants with hypoxic respiratory
failure unresponsive to other therapy, excluding infants with diaphragmatic
hernia, should have a trial of inhaled nitric oxide. This therapy is very potent
in reducing the need for ECMO, with an NNT of 5.3. It appears to be appropriate
to institute therapy only for those who are severely ill, commencing therapy
earlier does not appear to further reduce ECMO requirements or mortality. Thus
starting therapy when the OI exceeds 25, or when the PaO2 while receiving 100%
O2 is less than 100 mmHg, is consistent with the published evidence.
Implications for research
It remains unclear what is the minimal effective dose, Finer 2001 suggested that starting at 2 ppm was as effective as starting at higher concentrations, whereas Cornfield 1999 suggested that starting at 2 ppm was not effective in preventing worsening. This discrepancy warrants further investigation, in an adequately powered study.
Although treating at less severe criteria for poor oxygenation does not improve mortality or ECMO requirements, or other reported clinical outcomes, compared to waiting to see whether the patient deteriorates, such treatment may prevent disease progression, and it is possible that long term outcomes could be affected by preventing more severe illness. This should be further investigated.
Other unanswered questions include: Does pretreatment with surfactant improve the response to iNO in humans (as it appears to in some animal models)? Is iNO more effective during high frequency ventilation? Will improved or earlier treatments with more conventional modalities including surfactant, and high frequency ventilatory techniques be as effective as iNO? Does the loss of endogenously produced NO in intubated patients result in significant clinical morbidity and require routine replacement therapy? Will iNO prove to be safer and more effective than other selective pulmonary vasodilators including inhaled prostacyclin, some of which can be delivered by inhalation?
Acknowledgements
Potential conflict of interest
Dr Barrington was chair of the iNOtherapeutics Canadian medical advisory committee for a single meeting for which he received expenses and an honorarium.
Dr Finer previously served as a member of the INO Therapeutics Advisory Committee.
Characteristics of included
studies
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Barefield 1996 | Single center randomised study. Masking of allocation; Yes. Masking of intervention; No. Completeness of followup; Yes. Masking of outcome measurement; No. | 17 near term infants > or = 35 weeks with PaO2 <100 on 100% Oxygen on ventilator.
Diaphragmatic hernia patients were excluded. | iNO at 20 to 40 ppm increased to 80 if PaO2 stayed less than 100. Use of iNO allowed in case of failure of control treatment., if PaO2 was (1) less than 80 mm Hg (10.7 kPa) for more than 1 hour (2) less than 40 mm Hg (5.3 kPa) beyond 1 hour or (3) less than 30 mm Hg (4 kPa) beyond 30 minutes.
High frequency ventilation not allowed during study, Attempted to achieve combined metabolic and respiratory acidosis. Muscle relaxants and inotropes also used. | Primary outcome: 'Treatment failure' or meeting ECMO criteria. Treatment failure defined as PaO2 less than 80 mmHg for more than an hour, PaO2 less than 40 mmHg after 1 hour of the study, or less than 30 mmHg after 30 minutes of the study.
Secondary outcomes: Oxygenation index, PaO2, alveolar arterial oxygen gradient, after 30 and 60 minutes; Death and ultimate use of HFV or ECMO. | Admission OI in control group averaged 26, in the treatment group it averaged 38. | A |
| Christou 2000 | Single center randomised study. Masking of allocation; Yes. Masking of intervention; No. Completeness of followup; Yes. Masking of outcome; No. | 42 near term infants > or = 34 weeks with PaO2 <100 on 100% oxygen on ventilator. Diaphragmatic hernia patients were excluded. Some evidence on increased pulmonary artery pressure on echocardiography required. | 40 ppm inhaled nitric oxide reduced to 20 ppm after 1 hour. Combined therapy with high frequency and iNO was allowed. | Death before discharge or requirement for ECMO. Secondary outcomes included changes in oxygenation, and duration of ventilation and O2 therapy. | | A |
| Clark 2000 | Multicenter randomised trial. Masking of allocation; Yes. Masking of intervention; Yes. Completeness of followup; Yes. Masking of outcome; Yes. | 248 near term infants, greater than or equal to 34 weeks, less than or equal to 4 days of age and with an oxygenation index of more than or equal to 25. | 20 ppm inhaled NO or nitrogen placebo. NO gas weaned to 5 ppm after 24 hours for a maximum of 96 hours | Death before discharge, need for ECMO, chronic lung disease, neurological injury. | | A |
| Cornfield 1999 | Three center randomised trial. Masking of allocation; Can't tell. Masking of intervention; No. Completeness of followup: Yes. Masking of outcome; No. | 38 near term infants with oxygenation index greater than or equal to 25, less than 1 wk old, with echocardiographically proven pulmonary hypertension. | Inhaled NO at 2 ppm or no therapy. | Primary outcome: failure, defined as an OI greater than 35 after 1 hour of treatment. | | B |
| Davidson 1997 | Multicenter randomised trial, using nitrogen as the placebo gas.
Masking of allocation; Can't tell. Masking of intervention; Yes. Completeness of followup; Can't tell. Masking of outcome; Can't tell. | 155 term infants with echocardiographically proven pulmonary hypertension. PaO2 between 40 and 100 mmHg in 100% O2. Randomized equally to each of the 4 groups.
Excluded infants with diaphragmatic hernia or other causes of pulmonary hypoplasia.
Not allowed surfactant therapy or concurrent high frequency ventilation. | Nitric oxide at 5, 20 or 80 ppm or control, gas stopped upon 'failure', defined as a PaO2 of less than 40 mmHg for 1/2 hr. | Major sequelae index; a composite index of death, ECMO, neurologic sequelae, or bronchopulmonary dysplasia.
Oxygenation | | B |
| Day 1996 | Single centre randomized study. Masking of allocation; Can't tell. Masking of intervention; No. Completeness of followup; Yes. Masking of outcome; Yes. | 22 term or premature infants with oxygenation index greater than 25 and less than 40, plus, right to left ductal shunting or estimated peak right ventricular pressure >75% of systemic systolic pressure. | 20 ppm inhaled NO. High frequency jet ventilation was allowed concurrently. Backup use of inhaled NO allowed in case of failure of control treatment. Few details of other therapy were given. | Primary outcomes: Oxygenation index, PaO2, echocardiographic doppler changes | If the infants in the controlled trial deteriorated to an OI of >40 then inhaled NO was given.
| B |
| Kinsella, hfo/iNO | Randomized multicenter trial of inhaled NO in comparison to high frequency ventilation. Masking of allocation;Yes. Masking of intervention; No (not feasible). Completeness of followup; Yes. Masking of outcome; No. | 205 near term infants, Oxygenation index >40. Stratified by disease process, infants with diaphragmatic hernias (n=34) were included as a separate stratum. | iNO at 40 ppm compared to high frequency ventilation using Sensormedics oscillator. Initial randomization was followed by backup treatment of the alternate therapy in case of failure. This was followed by further crossover to combination treatment with HFV and iNO if the alternate therapy failed.
iNO therapy administered via a standard time-cycled pressure limited ventilator. HFV aimed at a lung recruitment strategy. Surfactant treatment after enrollment prohibited. iNO dose increased to 40 ppm in case of failure to maintain a PaO2 above 60 mmHg. | Sustained PaO2 greater than or equal to 60. Failure defined as PaO2 <60 after 2 hours of therapy or lack of improvement in PaO2 before 2 hours. Some data on infants with diaphragmatic hernia were presented separately | Complex study design; we only abstracted the results from the initial randomization. All infants who failed were exposed to iNO at some stage in the protocol. Study stopped after interim analysis suggested that there would be no difference between the initial treatment limbs. | A |
| Konduri 2004 | Multicenter randomized trial. Masking of allocation; Yes. Masking of intervention; Yes. Completeness of followup; Yes. Masking of outcome measurement; Yes. | 302 enrolled (3 excluded as they turned out to have congential heart disease) infants were all more than or equal to 34 weeks gestation, with hypoxic respiratory failure and an OI between 15 and 25 while receiving at least 80% oxygen, on 2 blood gases between 15 minutes and 12 hours apart. . | iNO at 5 ppm, iNO could be increased to 20 ppm in the case of partial response, treated up to 14 days. Controls received nitrogen, or iNO if the OI increased to exceed 25. | Primary outcome: occurrence or death or requirement for ECMO.
Secondary hypotheses were that early iNO therapy would 1) reduce the probability of using standard iNO therapy; 2) decrease progression to severe respiratory failure, defined as OI 40; and 3) would not increase neurodevelopmental impairment among surviving infants at 18 to 24 months of age. | Study terminated early because of slowing enrolment, 75% of anticipated sample enrolled, study terminated without knowledge of the results at that point. | A |
| Mercier 1998 | Randomized multicenter trial of inhaled NO. Masking of allocation; Yes. Masking of intervention; No. Completeness of follow up; Yes. Masking of outcome; No. | 204 infants; 107 near term, > or = 33 weeks gestation. oxygenation index 15 to 40, on 2 blood gases 1 hour apart. Congenital diaphragmatic hernias excluded, congenital heart disease excluded, less than 7 days of age only. | iNO at 10 ppm for 2 hours, continued if response. Controls could be treated after 2 hours. | Primary outcome: change in OI at 2 hours after initiating treatment. Secondary outcomes, death, brain injury, long term oxygen therapy, duration of hospitalisation. | ECMO not available as a backup therapy. | A |
| Ninos 1996 | Randomized multicenter study using oxygen as the placebo gas. Masking of allocation; Yes. Masking of intervention; Yes. Completeness of followup; Yes. Masking of outcome; Yes. | 235 near term infants, > or = 34 weeks gestation, oxygenation index >25 on 2 blood gases, 15 minutes apart. Congenital diaphragmatic hernias excluded, congenital heart disease excluded, less than 14 days of age only. | iNO at 20 ppm, trial at 80 ppm if no response to 20 (in treatment group). Compared to control. Both groups received 'maximal therapy' before study entry, including surfactant in the majority, high frequency ventilation in experienced centers, muscle relaxation and inotropes. Induction of alkalosis with a target pH of 7.45 to 7.60 was also used as a guideline. All of these treatment strategies were continued in controls. Investigators were not allowed to start high frequency or administer surfactant after study entry. | Survival to 120 days, or discharge home, without requiring ECMO. Secondary outcomes were oxygenation (OI and PaO2) after 30 minutes, length of hospital stay, days of assisted ventilation, and incidence of air leak or bronchopulmonary dysplasia. Neurodevelopment at 18-24 months. | | A |
| Ninos 1997 | Randomized multicenter trial of inhaled NO in infants with diaphragmatic hernia, oxygen used as the placebo gas. Masking of allocation; Yes. Masking of intervention; Yes. Completeness of followup; Yes. Masking of outcome; Yes. | 53 near term infants with diaphragmatic hernia, > or = 34 weeks gestation, less than 14 days of age. | iNO at 20 ppm, trial at 80 ppm if no response to 20 (in treatment group). Compared to control. Both groups received 'maximal therapy' before study entry, including surfactant in the majority, high frequency ventilation in experienced centers, muscle relaxation and inotropes. Induction of alkalosis with a target pH of 7.45 to 7.60 was also used as a guideline. All of these treatment strategies were continued in controls. Investigators were not allowed to start high frequency or administer surfactant after study entry. | Survival to 120 days, or discharge home, without requiring ECMO. Secondary outcomes were oxygenation (OI and PaO2) after 30 minutes, length of hospital stay, days of assisted ventilation, and incidence of air leak or bronchopulmonary dysplasia. Neurodevelopment at 18-24 months. | | A |
| Roberts 1996 | Multicenter randomized study, Nitrogen used for the placebo gas. Masking of allocation; Probably yes. Masking of intervention; Yes. Completeness of followup; Yes. Masking of outcome; Yes. | 58 'Full term infants' on FiO2 1.0 with PaO2 less than 55mmHg. All had echocardiographic signs of pulmonary hypertension.
Subjects excluded if they had received high frequency ventilation.
Diaphragmatic hernia patients excluded, or other causes of pulmonary hypoplasia | iNO at 80 ppm or control. Control patients received conventional ventilation. Surfactant not allowed during the study. | Primary outcome was 'Success', defined as improved oxygenation index to less than 40, without a fall in PO2 or hypotension.
Secondary outcomes were oxygenation, both OI and PaO2, after 30 minutes of therapy. | | A |
| Sadiq 1998 | Multicenter randomized study. Masking of allocation, adequate. Masking of intervention, not attempted, Completeness of follow up, yes, Masking of outcome assessment, not attempted. | 87 infants >2 kg birthweight, with AaDO2 500-599 after surfactant on 2 gases 1 hour apart on 100% O2 and echocardiographic evidence of PPHN. | iNO at 10 ppm or control, iNO increased up to 80 ppm until no further increases in arterial PO2 occurred. | Primary outcome variable was progression to severe PPHN. Defined as an AaDO2 persistently greater than 600. Secondary outcome variables included death, ECMO rate, length of hospitalization, amount and duration of mechanical ventilation, number of days of oxygen used, and need for supplemental oxygen at 28 days of life. | Study was terminated early after approval of iNO by the federal drug administration, as this impaired recruitment. | A |
| Wessel 1996 | Single centre randomized trial. Masking of allocation; Not clear. Masking of intervention; No. Completeness of followup; Yes. Masking of outcome; No. | 49 near term infants > or = 34 weeks, PaO2 less than 100 on 100% O2, all had evidence of PPHN on echocardiography | iNO at 80 ppm, reduced to 40 ppm after 1 h. All received muscle relaxants and sedation and conventional ventilation. | Primary outcomes were oxygenation as well as Death and need for ECMO.
Secondary outcomes were duration of mechanical ventilation, duration of hospitalisation, and need for oxygen after hospital discharge | | B |
Characteristics of excluded studies
| Study | Reason for exclusion |
| Hoffman 1997 | Non-randomized retrospective study, infants were treated or not based on availability of nitric oxide. The time period over which infants were studied was also different between the control and nitric oxide groups. |
| Pinheiro 1998 | Randomized comparison of inhaled nitric oxide with intravenous nitroprusside. Study was stopped after enrollment of 25 patients due to decreasing enrollment. Nitric oxide produced much greater improvements in oxygenation than nitroprusside. |
References to studies
References to included studies
Barefield 1996 {published data only}* Barefield ES, Karke VA, Phillips JB, Carlo WA. Inhaled nitric oxide in term infants with hypoxemic respiratory failure. Journal of Pediatrics 1996;129:279-86.
Barefield ES, Karke VA, Phillips JB, Carlo WA. Randomized, controlled trial of inhaled NO in ECMO candidates. Pediatric Research 1995;37:195A.
Christou 2000 {published data only}
Christou H, Van Marter LJ, Wessel DL, Allred EN, Kane JW, Thompson JE, Stark AR, Kourembanas S. Inhaled nitric oxide reduces the need for extracorporeal membrane oxygenation in infants with persistent pulmonary hypertension of the newborn. Critical Care Medicine 2000;28:3722-3727.
Clark 2000 {published data only}
Clark RH, Keuser TJ, Walker MW, Southgate MS, Huckaby JL, Perez JA, Roy BJ, Keszler M, Kinsella JP, for the Clinical Inhaled Nitric Oxide Research Group. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. New England Journal of Medicine 2000;342:469-74.
Cornfield 1999 {published data only}
Cornfield DN, Maynard RC, deRegnier RA, Guiang SF 3rd, Barbato JE, Milla CE. Randomized, controlled trial of low-dose inhaled nitric oxide in the treatment of term and near-term infants with respiratory failure and pulmonary hypertension. Pediatrics 1999;104:1089-94.
Davidson 1997 {published data only}
* Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask, M, Straube R, Rhines J, Chang CT. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study. Pediatrics 1998;101:325-34.
Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M, Straube R, Rhines J, and I-NO/PPHN study group. A double masked, randomized, placebo controlled, dose response study of inhaled nitric oxide for the treatment of persistent pulmonary hypertension of the newborn. Pediatric Research 1997;41:144A(abstract).
Day 1996 {published data only}
* Day RW, Lynch JM, White KS, Ward RM. Acute response to inhaled nitric oxide in newborns with respiratory failure and pulmonary hypertension. Pediatrics 1996;98:698-705.
Day RW, Lynch JM. Acute hemodynamic and blood gas effects of inhaled nitric oxide in newborns with lung disease and pulmonary hypertension. Pediatric Research 1996;39:330A.
Kinsella, hfo/iNO {published data only}
Kinsella JP, Truog WE, Walsh WF, Goldberg RN, Bancalari E, Clark RH, Mayock DE, Redding GJ, deLemos RA, Sardesai S, McCurnin DC, Yoder BA, Moreland SG, Cutter GR, Abman SH. Randomized, multicenter trial of inhaled nitric oxide and high frequency ventilation in severe persistent pulmonary hypertension of the newborn. Pediatric Research 1996;39:222A.
* Kinsella JP, Truog WE, Walsh WF, Goldberg RN, Bancalari EE, Mayock DE, et al. Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. Journal of Pediatrics 1997;131:55-62.
Konduri 2004 {published data only}
Konduri GG, Solimano A, Sokol GM, Singer J, Ehrenkranz RA, Singhal N, Wright LL, Van Meurs K, Stork E, Kirpalani H, Peliowski A; Neonatal Inhaled Nitric Oxide Study Group. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics 2004;113:559-64.
Mercier 1998 {published data only}
* Franco-Belgium collaborative NO trial group. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. Lancet 1999;354:1066-71.
Mercier JC, Dehan M, Breart G, Clement S, O'Nody P. Inhaled nitric oxide in neonatal respiratory failure. Pediatric Research 1998;43:290A.
Ninos 1996 {published and unpublished data}
The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in term and near-term infants: Neurodevelopmental follow-up of the The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Journal of Pediatrics 2000;136:611-7.
* The Neonatal Inhaled Nitric Oxide Study Group: Inhaled nitric oxide in full-term and nearly full term infants with hypoxic respiratory failure. New England Journal of Medicine 1997;336:597-604.
Ninos 1997 {unpublished data only}
* The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 1997;99:838-45.
The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in term and near-term infants: Neurodevelopmental follow-up of the The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Journal of Pediatrics 2000;136:611-7.
Roberts 1996 {published data only}
Roberts JD Jr. , Fineman J, Morin FC III, Shaul PW, Rimar S, Schreiber MD, Polin RA, Thusu KG, Zayek M, Zwass MS, Zellers TM, Wylam ME, Gross I, Zapol WM, Heymann MA. Inhaled nitric oxide gas improves oxygenation in PPHN. Pediatric Research 1996;39:241A.
* Roberts JD Jr., Fineman J, Morin FC III, Shaul PW, Rimar S, Schreiber MD, Polin RA, Zwass MS, Zayek MM, Gross I, Heymann MA, Zapol WM.. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. New England Journal of Medicine 1997;336:605-10.
Sadiq 1998 {published and unpublished data}
Sadiq FH, Illinois multicenter trial. Treatment of persistent pulmonary hypertension of the newborn with nitric oxide: a randomized trial. Pediatric Research 1998;43:192A.
* Sadiq HF, Mantych G, Benawra RS, Devaskar UP, Hocker JR. Inhaled nitric oxide in the treatment of moderate persistent pulmonary hypertension of the newborn: a randomized controlled, multicenter trial. Journal of Perinatology 2003;23:98-103.
Wessel 1996 {published data only}
Ellington M, O'Reilly D, Allred EN, McCormick MC, Wessel DL, Kourembanas S. Child Health Status, Neurodevelopmental Outcome, and Parental Satisfaction in a Randomized Controlled Trial of Nitric Oxide for Persistent Pulmonary Hypertension of the Newborn. Pediatrics 2001;107:1351-6.
Wessel D, Adatia I, Thompson J, Kane J, Van Marter L, Stark A, Kourembanas S. Improved oxygenation in a randomized trial of inhaled nitric oxide for PPHN. Pediatric Research 1996;39:252A.
* Wessel DL, Adatia I, Van Marter LJ, Thompson JE, Kane JW, Stark AR, Kourembanas S. Improved oxygenation in a randomized trial of inhaled nitric oxide for persistent pulmonary hypertension of the newborn. Pediatrics 1997;100:http://www.pediatrics.org/cgi/content/full/100/5/e7.
References to excluded studies
Hoffman 1997 {published data only}Hoffman GM, Ross GA, Day SE, Rice TB, Nelin LD. Inhaled nitric oxide reduces the utilization of extracoropreal membrane oxygenation in persistent pulmonary hypertension of the newborn. Critical Care Medicine 1997;25:352-9.
Pinheiro 1998 {published data only}
Pinheiro JMB, Carey T. Inhaled NO vs. intravenous nitroprusside in neonatal pulmonary hypertension: randomized trial at a center without ECMO. Pediatric Research 1998;43:294A.
* indicates the primary reference for the study
Other references
Additional references
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Beckman 1990
Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxides. Proceedings of the National Academy of Sciences of the United States of America 1990;87:1620-4.
Bouchet 1993
Bouchet M, Renaudin MH, Raveau C, Mercier JC Dehan M, Zupan V. Safety requirement for use of inhaled nitric oxide in neonates. Lancet 1993;341:968-9.
Burke-Wolin 1991
Burke-Wolin T, Abate CJ, Wolin MS, Gurtner GH. Hydrogen peroxide-induced pulmonary vasodilation: role of guanosine 3',5'-cyclic monophosphate. American Journal of Physiology 1991;261:L393-8.
Cornfield 1992
Cornfield DN, Chatfield BA, McQueston JA, McMurtry IF, Abman SH. Effects of birth-related stimuli on L-arginine-dependent pulmonary vasodilation in ovine fetus. American Journal of Physiology 1992;262:H1474-81.
Davidson 1999
Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M, Straube R, Rhines J, Chang CT. Safety of withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn. Pediatrics 1999;104:231-6.
Dobyns 1999
Dobyns EL, Griebel J, Kinsella JP, Abman SH, Accurso FJ. Infant lung function after inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn. Pediatric Pulmonology 1999;28:24-30.
Edwards 1995
Edwards AD. The pharmacology of inhaled nitric oxide. Archives of Disease in Childhood 1995;72:F127-30.
Etches 1994
Etches PC, Finer NN, Barrington KJ, Graham AJ, Chan WKY. Nitric oxide reverses pulmonary hypertension in the newborn piglet. Pediatric Research 1994;35:15-9.
Fineman 1994
Fineman JR, Wong J, Morin FC, Wild LM, Soifer SJ. Chornic nitric oxide inhibition in utero produces persistent pulmonary hypertension in newborn lambs. Journal of Clinical Investigation 1994;93:2675-83.
Finer 1994
Finer NN, Etches PC, Kamstra B, Tierney AJ, Peliowski A, Ryan CA. Inhaled nitric oxide in infants referred for extracorporeal membrane oxygenation: Dose response. Journal of Pediatrics 1994;124:302-8.
Fratacci 1991
Fratacci MD, Frostell CG, Chen TY, Wain JC, Robinson DR, Zapol WM. Inhaled nitric oxide - A selective pulmonary vasodilator of heparin-protamine vasoconstriction in sheep. Anesthesiology 1991;75:990-9.
Frostell 1991
Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide - A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991;83:2038-47.
Gerlach 1993
Gerlach H, Rossaint R, Pappert D, Falke KJ. Time-course and dose-response of nitric oxide inhalation for systemic oxygenation and pulmonary hypertension in patients with adult respiratory distress syndrome. European Journal of Clinical Investigation 1993;23:499-502.
Greenbaum 1967
Greenbaum R, Bay J, Hargreaves MD, Kain ML, Kelman GR, Nunn JF, Prys-Roberts C, Siebold K. Effects of higher oxides of nitrogen on the anaesthetized dog. British Journal of Anaesthesia 1967;39:393-404.
Gruetter 1981
Gruetter CA, Gruetter DY, Lyon JE, Kadowitz PJ, Ignarro LJ. Relationship between cyclic guanosine 3':5'-monophosphate formation and relaxation of coronary arterial smooth muscle by glyceryl trinitrate, nitroprusside, nitrite and nitric oxide: Effects of methylene blue and methemoglobin. Journal of Pharmacology and Experimental Therapeutics 1981;219:181-6.
Haddad 1993
Haddad IY, Ischiropoulos H, Holm B. A, Beckman JS, Baker JR, Matalon S. Mechanisms of peroxynitrite-induced injury to pulmonary surfactants. American Journal of Physiology 1993;265:L555-64.
Heal 1995
Heal CA, Spencer SA. Methaemoglobinaemia with high-dose nitric oxide administration. Acta Paediatrica 1995;84:1318-9.
Higenbottam 1988
Higenbottam T, Pepke-Zaba J, Scott J, Wollman P, Coutts C, Wallwork J. Inhaled "endothelium-derived relaxing factor" (EDRF) in primary hypertension (PPH). American Review of Respiratory Disease 1988;137:A107.
Hogman 1993
Hogman M, Frostell C, Arnberg H, Hedenstierma G. Bleeding time prolongation and NO inhalation. Lancet 1993;341:1664-5.
Hogman 1994
Hogman M, Frostell C, Arnberg H, Sandhagen B, Hedenstierna G. Prolonged bleeding time during nitric oxide inhalation in the rabbit. Acta Physiologica Scandinavica 1994;151:125.
Ignarro 1986
Ignarro LJ, Adams JB, Horwitz PM, Wood KS. Activation of soluble guanylate cyclase by NO-hemoproteins involves NO-heme exchange. Journal of Biological Chemistry 1986;261:4997-5002.
Kinsella 1992a
Kinsella JP, McQueston JA, Rosenberg AA, Abman SH. Hemodynamic effects of exogenous nitric oxide in ovine transitional pulmonary circulation. American Journal of Physiology 1992;263:H875-80.
Kinsella 1992b
Kinsella JP, Neish SR, Shaffer E, Abman SH. Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:819-20.
Kinsella 1993
Kinsella JP, Neish SR, Ivy DD, Shaffer E, Abman SH. Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide. Journal of Pediatrics 1993;123:103-8.
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Lipkin PH, Davidson D, Spivak L, Straube R, Rhines J, Chang CT. Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide. Journal of Pediatrics 2002;140:306-10.
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Lowson SM, Rich GF, McArdle PA, Jaidev J, Morris GN. The response to varying concentrations of inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesthesia and Analgesia 1996;82:574-81.
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National Institute for Occupational Safety and Health. NIOSH recommendations for occupational safety and health standards. MMWR 1988;37:21.
Ninos 2000
Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in term and near-term infants: neurodevelopmental follow-up of the neonatal inhaled nitric oxide study group (NINOS). Journal of Pediatrics 2000;136:611-7.
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Palmer RMJ, Rees DD, Ashton DS, Moncada S. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochemical and Biophysical Research Communications 1988;153:1251-6.
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Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilation in pulmonary hypertension. Lancet 1991;338:1173-4.
Pison 1993
Pison U, Lopez FA, Heidelmeyer CF, Rossaint R, Falke KJ. Inhaled nitric oxide reverses hypoxic pulmonary vasoconstriction without impairing gas exchange. Journal of Applied Physiology 1993;74:1287-92.
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Putensen C, Rasanen J, Lopez FA. Improvement in VA/Q distributions during inhalation of nitric oxide in pigs with methacholine-induced bronchoconstriction. American Journal of Respiratory and Critical Care Medicine 1995;151:116-22.
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Radomski MW, Moncada S. Regulation of vascular homeostasis by nitric oxide. Thrombosis and Haemostasis 1993;70:36-41.
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Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:818-9.
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Other published versions of this review
Finer 1997Finer NN, Barrington KJ. Nitric oxide in respiratory failure in full-term and nearly full-term newborn infants (Cochrane Review). In: The Cochrane Library, Issue 4, 1997. Oxford: Update Software.
Finer 1999
Finer NN, Barrington KJ. Nitric oxide in respiratory failure in full-term and nearly full-term newborn infants (Cochrane Review). In: The Cochrane Library, Issue 1, 1999. Oxford: Update Software.
Finer 2001
Finer NN, Barrington KJ. Nitric oxide in respiratory failure in full-term and nearly full-term newborn infants (Cochrane Review). In: The Cochrane Library, Issue 2, 2001. Oxford: Update Software.
Comparisons and data
| Comparison or outcome |
Studies |
Participants |
Statistical method |
Effect size |
| 01 Inhaled NO versus control |
| 01 Death or requirement for ECMO |
9 |
915 |
RR (fixed), 95% CI |
0.68 [0.59, 0.79] |
| 02 Death |
9 |
916 |
RR (fixed), 95% CI |
0.91 [0.60, 1.37] |
| 03 Requirement for ECMO |
8 |
810 |
RR (fixed), 95% CI |
0.63 [0.54, 0.75] |
| 04 Failure to improve oxygenation (PaO2) |
|
|
RR (fixed), 95% CI |
No total |
| 05 Oxygenation index 30 to 60 minutes after treatment |
6 |
698 |
WMD (fixed), 95% CI |
-9.59 [-12.50, -6.68] |
| 06 PO2 30 to 60 minutes after treatment |
6 |
699 |
WMD (fixed), 95% CI |
45.49 [34.66, 56.33] |
| 07 Change in oxygenation index after treatment |
1 |
233 |
WMD (fixed), 95% CI |
-15.10 [-20.52, -9.68] |
| 08 Change in PO2 after treatment |
1 |
233 |
WMD (fixed), 95% CI |
50.40 [32.14, 68.66] |
| 09 Neurodevelopmental disability at 18 to 24 months among
survivors |
2 |
301 |
RR (fixed), 95% CI |
0.97 [0.66, 1.44] |
| 10 Hearing impairment in at least one ear among survivors |
1 |
157 |
RR (fixed), 95% CI |
1.14 [0.71, 1.84] |
| 11 Cerebral palsy among survivors |
2 |
299 |
RR (fixed), 95% CI |
1.02 [0.49, 2.14] |
| 12 Bayley MDI more than 2SD below the mean |
2 |
283 |
RR (fixed), 95% CI |
0.66 [0.38, 1.12] |
| 13 Bayley PDI more than 2 SD below the mean |
2 |
283 |
RR (fixed), 95% CI |
0.48 [0.25, 0.94] |
| 02 Inhaled NO versus control in infants with
diaphragmatic hernia |
| 01 Death or need for ECMO |
2 |
84 |
RR (fixed), 95% CI |
1.09 [0.95, 1.26] |
| 02 Death |
2 |
84 |
RR (fixed), 95% CI |
1.20 [0.74, 1.96] |
| 03 Need for ECMO |
2 |
84 |
RR (fixed), 95% CI |
1.27 [1.00, 1.62] |
| 04 Failure to improve oxygenation (PaO2) |
1 |
51 |
RR (fixed), 95% CI |
0.83 [0.70, 1.00] |
| 05 Oxygenation index 30 to 60 mins after treatment |
1 |
44 |
WMD (fixed), 95% CI |
-16.10 [-38.04, 5.84] |
| 06 PaO2 30 to 60 minutes after treatment |
1 |
44 |
WMD (fixed), 95% CI |
15.10 [0.64, 29.56] |
| 07 Change in oxygenation index after treatment |
1 |
44 |
WMD (fixed), 95% CI |
-6.70 [-18.39, 4.99] |
| 08 Change in PO2 after treatment |
1 |
44 |
WMD (fixed), 95% CI |
6.70 [-2.32, 15.72] |
| 09 Neurodevelopmental disability at 18 to 24 months among
survivors |
0 |
0 |
RR (fixed), 95% CI |
Not estimable |
| 10 Hearing impairment in at least one ear among survivors |
1 |
21 |
RR (fixed), 95% CI |
0.93 [0.39, 2.19] |
| 11 Cerebral palsy among survivors |
1 |
22 |
RR (fixed), 95% CI |
8.33 [0.45, 154.78] |
| 03 Inhaled NO at moderate compared to severe
criteria for illness severity |
| 01 Death or requirement for ECMO |
2 |
384 |
RR (fixed), 95% CI |
0.85 [0.54, 1.32] |
| 02 Death |
2 |
384 |
RR (fixed), 95% CI |
0.73 [0.34, 1.54] |
| 03 Requirement for ECMO |
2 |
384 |
RR (fixed), 95% CI |
0.90 [0.52, 1.58] |
01 Inhaled NO versus control
01.01 Death or requirement for ECMO
01.01.01 Death or requirement for ECMO; studies which did not allow backup
use of iNO in controls
01.01.02 Death or requirement for ECMO; studies which allowed backup use of
iNO in controls
01.02 Death
01.02.01 Death; studies which did not allow backup use of iNO in controls
01.02.02 Death; studies which allowed backup use of iNO in controls
01.03 Requirement for ECMO
01.03.01 Requirement for ECMO; studies which did not allow backup use of iNO
in controls
01.03.02 Requirement for ECMO; studies which allowed backup use of iNO in controls
01.04 Failure to improve oxygenation (PaO2)
01.05 Oxygenation index 30 to 60 minutes after
treatment
01.06 PO2 30 to 60 minutes after treatment
01.07 Change in oxygenation index after treatment
01.08 Change in PO2 after treatment
01.09 Neurodevelopmental disability at 18 to 24
months among survivors
01.10 Hearing impairment in at least one ear among
survivors
01.11 Cerebral palsy among survivors
01.12 Bayley MDI more than 2SD below the mean
01.13 Bayley PDI more than 2 SD below the mean
02 Inhaled NO versus control in infants with diaphragmatic hernia
02.01 Death or need for ECMO
02.02 Death
02.03 Need for ECMO
02.04 Failure to improve oxygenation (PaO2)
02.05 Oxygenation index 30 to 60 mins after treatment
02.06 PaO2 30 to 60 minutes after treatment
02.07 Change in oxygenation index after treatment
02.08 Change in PO2 after treatment
02.09 Neurodevelopmental disability at 18 to 24
months among survivors
02.10 Hearing impairment in at least one ear among
survivors
02.11 Cerebral palsy among survivors
03 Inhaled NO at moderate compared to severe criteria for illness severity
03.01 Death or requirement for ECMO
03.02 Death
03.03 Requirement for ECMO
Contact details for co-reviewers
Dr Keith J Barrington
Director of Neonatology
Pediatrics
Royal Victoria Hospital
687 av des Pins O
Montreal
P. Quebec CANADA
H3A 1A1
Telephone 1: 514 842 1231 extension: 4876
Facsimile: 514 843 1741
E-mail: kbarri@po-box.mcgill.ca
| This review is published as a Cochrane review in The Cochrane Library,
Issue 4, 2006 (see http://www.thecochranelibrary.com for information).
Cochrane reviews are regularly updated as new evidence emerges and in response
to feedback. The Cochrane Library should be consulted for the most recent
version of the review. |
