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Multicenter randomized controlled trial of the effects of inhaled nitric oxide on gas exchange in children with acute hypoxemic respiratory failure.

Dobyns EL, Cornfield DN, Anas NG, Fortenberry JD, Tasker RC, Lynch A, Liu P, Eells PL, Griebel J, Baier M, Kinsella JP, Abman SH.

J Pediatr 1999;134:406-412. [abstract]

Reviewed by Al Torres, MD, MS, University of Illinois College of Medicine at Peoria

Review posted August 23, 1999

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I. What is being studied?:

The study objective:

To determine "if inhaled nitric oxide (iNO) would improve oxygenation in an acute manner, slow the rate of decline in gas exchange, and decrease the number of patients who meet preestablished oxygenation failure criteria."

The study design:

A randomized, double-blind, controlled trial at 7 sites

The patients included:

108 children (median age 2.5 yr) with severe acute hypoxemic respiratory failure (oxygenation index defined as mean airway pressure x FiO2 x 100/PaO2; OI > or = 15 x 2 values measured by serial ABGs within 6 hours of each other)

The patients excluded:

Exclusion criteria included patients with congenital heart disease, cardiovascular surgery within the previous 14 days, or whether the family and medical team had decided not to provide full support (i.e., treatment considered futile).

The interventions compared:

iNO at 10 ppm for a minimum of 72 hours was delivered to the 53 patients in the treatment group and mechanical ventilation alone (with placebo gas) was administered to the 55 patients in the control group.

The outcomes evaluated:

The primary outcome measure was to determine whether fewer patients treated with iNO would met predefined and clinically relevant treatment failure criteria (OI > 40 for 3 hours or OI > 25 for 6 hours, systolic BP < 50 mmHg or severe metabolic acidosis with pH < 7.20 that was unresponsive to colloid infusions and cardiotonic medications, methemoglobin concentration > 5% or nitrogen dioxide concentration > 2 ppm). Secondary endpoints included mean change in PaO2/FiO2 ratio and OI at 4 and 12 hours and proportion of patients who had improvement in oxygenation during 72 hours of treatment with OI > 25 at enrollment, immunocompromised at enrollment, and all responders (OI < 25). It is not clear from this paper whether these secondary endpoints were prospectively determined, or performed just on a post hoc basis.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Randomization was assigned by unblinded investigators at each site using randomization cards. There is no mention of block strategies or stratified randomization by treating PICU.

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

Was followup complete?

Yes. All patients enrolled were accounted for through the 72 hour period of study.

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

Yes. Although patients were allowed to crossover, this procedure was not permitted until the patient meeting treatment failure criteria was accounted for in the group they were assigned. Authors do not state how many patients in the control group crossed over into the treatment group and vice versa.

Secondary questions:

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

No, not all. Specific investigators at each site (usually a research nurse and a respiratory therapist) were aware of the assigned treatment. These unblinded investigators performed the randomization, monitored the iNO and NO2 concentrations, and monitored the methemoglobin concentrations. There was adequate concealment of treatment vs. placebo. All NO tank regulators were covered to prevent unmasking of assignment to the treatment group. Control group patients had NO tanks attached to their ventilators without delivery of the gas. Risk of investigator bias existed since the unblinded investigators may have been involved in patient management.

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

Yes. Differences in age, gender, conventional vs. high frequency oscillatory ventilation, hours of ventilation at enrollment, PRISM score, and primary diagnosis were not significantly different. Amount of FiO2, PEEP, and mean airway pressure and pH, PaO2, PaCO2, PaO2/FiO2 ratio, and OI were also similar between both groups. Although the difference did not reach statistical significance, there were almost twice as many immunocompromised patients in the control vs. treated groups.

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

Unknown. The authors agreed to general guidelines for mechanical ventilation (adjustments made to maintain an SpO2 > 90% with an FiO2 < 0.6 and a PaCO2 between 45 and 55 mm Hg. Higher PaCO2 were tolerated as long as the arterial pH was > 7.20. Attempts were made to maintain peak airway pressures < 35 to 40 cm H2O by limiting tidal volume and PEEP. The use of inotropic agents, fluid mangement, diuretics, steroids, muscle relaxants, intravenous sedation, and high-frequency ventilation was left to the discretion of the individual investigators. The authors did not report these variables for both groups making it difficult to estimate any influence these other therapies may have had on the outcomes assessed.

III. What were the results?

1. How large was the treatment effect?

The number of treatment failures (54% of control group and 46% of the iNO group) was not different between groups despite iNO treatment appearing to slow the rate of failure early in the study period. Although oxygenation improved in both the treatment and control groups, the improvement was significantly greater in the iNO group compared to the control group.

PaO2/FiO2 ratios over time

Group	PaO2/FiO2 @ 0 hours	4 hours	12 hours	p value (comparing change between treated vs. control values)
Treatment	78 +/- 30	112 +/- 48	125 +/- 66	.016 (at 4 hr)
Control	84 +/- 33	98 +/- 33	101 +/- 39	.003 (at 12 hr)

OI over time

Group	OI @ 0 hours	4 hours	12 hours	p value (comparing change between treated vs. control values)
Treatment	35 +/- 22	25 +/- 19	26 +/- 11	.014 (at 4 hr)
Control	30 +/- 15	27 +/- 9	27 +/- 8	.007 (at 12 hr)

The Kaplan-Meier curve of patients with an OI > 25 at enrollment demonstrated a sustained and greater proportion of responders at 72 hours than the control group (p = .046). Patients in the immunosuppressed group who were treated with iNO also had a sustained response at 72 hours than the controls (p = .033).

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

The authors did not provide confidence intervals for any of the results provided. However, we can assume that the lower limit of the 95% confidence interval for the relative risk reduction must approach zero in the subgroup of patients with OI > 25 because the p value is close to .05.

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

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

Yes. The patients enrolled in this multicenter trial of several tertiary care PICUs are similar to those at most tertiary care PICUs with AHRF.

2. Were all clinically important outcomes considered?

No. The authors state mortality could not be considered an outcome of the trial because of its crossover design. The authors do not reveal how many patients crossed over from each group to the other. Length of stay and time to extubation were not evaluated because the length of the study was only 72 hours. The incidence of air leaks in each group was not compared. Cost data were not provided.

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

No. The proportion of responders for both groups was not significantly different at 72 hours. Caution must be exercised when interpreting the positive results of the subgroup analysis. These findings were not hypothesized a priori, the possibility that the results may have occurred by chance (i.e., p values close to .05), and the lack of intuitive reasoning why these subgroups would benefit, are some of the reasons to have concern. Although there were no adverse effects reported (e.g., increased NO2 or methemoglobin concentrations), the statistically significant improvements in PaO2/FiO2 ratios or OI were not clinically significant enough to warrant routine use of NO in all AHRF patients. Other recently published studies of NO use in adults with ARDS have had similarly disappointing results. (1 - 3)

References

1. Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Crit Care Med 1998; 26: 15-23. [abstract] [link to PedsCCM EB Journal Club review]
2. Michael JR, Barton RG, Saffle JR, et al. Inhaled Nitric Oxide Versus Conventional Therapy: Effect on Oxygenation in ARDS. Am J Respir Crit Care Med 1998; 157: 1372-1380. [full-text for subscribers only] [abstract] [link to PedsCCM EB Journal Club review]
3. Troncy E, Collet JP, Shapiro S, et al. Inhaled Nitric Oxide in Acute Respiratory Distress Syndrome: A Pilot Randomized Controlled Study. Am J Respir Crit Care Med 1998; 157: 1483-1488. [abstract] [full-text for subscribers only] [link to PedsCCM EB Journal Club review]

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