Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Inhaled Nitric Oxide and Hypoxic Respiratory Failure in Infants With Congenital Diaphragmatic Hernia.

The Neonatal Inhaled Nitric Oxide Study Group (NINOS)

Pediatrics 1997; 99: 838-845. [abstract]

Reviewed by George Ofori-Amanfo, MD, Cardiology/Critical Care Fellow, College of Physicians and Surgeons, Children's Hospital of New York

Review posted June 13, 2003

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I. What is being studied?:

The study objective:

The impact of Inhaled Nitric Oxide (INO) on the outcome of term and near term infants (≥ 34wks gestational age) with Congenital Diaphragmatic Hernia (CDH). This study was a sub study of a larger trial from the Neonatal Inhaled Nitric Oxide Study Group (NINOS) investigating the role of INO in newborns with hypoxic respiratory failure (1).

The study design:

Prospective, randomized, double-blind, controlled multicenter trial

The patients included:

Infants ≥ 34wks gestational age with CDH and requiring assisted mechanical ventilation for hypoxemic respiratory failure (with two oxygenation indices ³ 25 at least 15 minutes apart). (n=53)

The patients excluded:

The patients excluded:

• Infants with structural heart disease
• Infants > 14 days of age at the time of randomization
• Those in conflicting trials
• Those with limitation of care orders

The interventions compared:

Use of INO, 20 or 80ppm in non-responders (study group), and 100% FiO2 (control) group

The outcomes evaluated:

The primary outcome was to determine whether iNO would decrease the occurrence of death by 120 days or discharge home (whichever came first) or cause a decrease in the use of Extracorporeal Membrane Oxygenation (ECMO) in term and near term infants with CDH.

Secondary outcomes were those relevant to the main trial and they included the following: The administration of iNO would result in:

• Increased PaO2, decreased Oxygenation Index (OI) and A-aDO2 measured 30 minutes after the initiation of iNO
• Decreased hospital stay
• No increase in days of assisted ventilation, incidence of air leak syndromes, nor bronchopulmonary dysplasia
• No increase in the incidence of neurodevelopmental disability at 18 to 24 months of age

Secondary outcomes evaluated improvement in oxygenation as measured by improvement in PaO2, OI and A-aDO2, length of hospital stay and complications of mechanical ventilation such as development of air leak syndromes and bronchopulmonary dysplasia.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Patients were stratified by center and then randomized by a permuted block design to study/control arms.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Yes.

Was followup complete?

Yes. Follow up was complete for all patients.

Were patients analyzed in the groups to which they were randomized?

Yes. All patients were accounted for and included in the data analysis. This study did not allow for cross-over therapy.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes. The clinical team involved in the patient management were blinded to the therapy. Administration of gas and mock adjustments were made by designated, unmasked individuals (respiratory therapists, research nurses, physicians). Study gas tanks and analyzers were also masked.

4. Were the groups similar at the start of the trial?

Yes. There was no significant difference between the two groups with regard to demographics, pre-randomization treatment, Oxygenation index, and mode of ventilation (conventional vs high frequency oscillator ventilation) There was also no difference in the time period between randomization and initiation of study drug between the two groups.

5. Aside from the experimental intervention, were the groups treated equally?

Probably. Pre-enrollment management varied in each center. However, following randomization each center managed the patients in conformity to general guidelines proposed by the study protocol for management of ventilation and hemodynamic support. Use of therapies such as sedation, neuromuscular blockade and steroids was permitted but not standardized. In this regard patients on each arm of the study probably received equal treatments, but there is no comparison of use of these aspects of management between the groups.

III. What were the results?

1. How large was the treatment effect?

The main study (iNO for respiratory failure not caused by CDH) was discontinued by the Data and Safety Monitoring Committee (DSMC) after an interim evaluation showed an impressive reduction in the primary outcome. At the same time the CDH parallel trial was also terminated on the recommendation of the DSMC because of lack of observable benefit, and the very low likelihood of such an effect with continued enrollment. A total of 53 patients were enrolled, 28 to the control arm and 25 to the iNO treatment arm.

There was no difference in the primary outcome between the two groups, 82% of the control group met the primary outcome vs. 96% in the in the iNO treated group. This reflects an absolute risk increase of 14% with confidence intervals, -3 to 31%. Forty three percent of control infants died while 48% of the iNO treated infants died (not significant). More patients in the iNO treated group required ECMO support. 80% vs. 54%, p=0.043. There were fewer deaths among control infants who received ECMO (26.7%) than iNO-treated infants who received ECMO (40%, not significant). The overall mortality was 46%: 35% in infants receiving ECMO and 67% in the remaining infants.

2. How precise was the estimate of the treatment effect?

Not very precise. The study indicated 82% of the control group met end-point while 96% of the iNO treated group met end-point; a 14% difference, 95% confidence interval -31%, 3.2%. That the confidence intervals cross zero suggests that this difference is not statistically significant. The authors acknowledge that they were unlikely to recruit enough infants with CDH in two years to demonstrate a significant difference in outcomes. That the treated infants, if anything, tended to do worse suggested no need for a larger trial. There was no risk reduction with iNO intervention.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Yes. The physiology of pulmonary hypertension in CDH suggests that iNO should be of therapeutic benefit. Clinically, inhaled nitric oxide has been used as an intervention to obviate the need for ECMO in newborns with CDH who present with profound hypoxic respiratory failure. The results of this study suggest that the use of iNO may not be beneficial and therefore should not delay initiation of ECMO.

2. Were all clinically important outcomes considered?

Virtually all clinically important outcome parameters were considered although in my opinion the degree of residual pulmonary hypertension may have offered yet another means of assessing the effect of the intervention.

3. Are the likely treatment benefits worth the potential harms and costs?

No. There was no significant difference in the incidence of serious adverse events between the two groups. Toxicity secondary to elevated NO2 or methemoglobin levels requiring discontinuation of study gas was not seen in this study. While toxicity was not observed, the use of NO is associated with significant medical expense. Judicious use will ultimately minimize cost of patient care.

References:

1. Neonatal Inhaled Nitric Oxide Study Group. Inhaled Nitric Oxide in Full-Term and Nearly Full-Term Infants with Hypoxic Respiratory Failure. N Engl J Med 1997; 336: 597-604. [abstact]

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