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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Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial

Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis KD, Hyers TM, Papadakos P, Inhaled Nitric Oxide in ARDS Study Group.

Crit Care Med 1998; 26: 15-23. [abstract]

Reviewed by Scot Bateman, MD, Children's Hospital, Boston

Review posted June 15, 1998

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I. What is being studied?:

The study objective:

To evaluate the safety, physiologic response, and clinical outcome of various doses of inhaled nitric oxide (NO) in patients with acute respiratory distress syndrome.

The study design:

Prospective, multi-center, randomized, double-blind, placebo controlled study.

The patients included:

Thirty sites in the US enrolled adult patients with primary ARDS, as defined by the American-European Consensus Conference, if the onset of disease was within 72 hrs of randomization.

The patients excluded:

Any history of immunocompromise, non-pulmonary infection source as the cause of ARDS, persistent hypotension, use of vasopressor or inotropic support, non-pulmonary organ failure, or second/third degree burns over > 20% of the body surface area.

The interventions compared:

Standard management with placebo gas (nitrogen) vs. inhaled NO at concentrations of 1.25, 5, 20, 40, or 80 ppm.

The outcomes evaluated:

Acute increases in PaO2, decreased in mean pulmonary arterial pressure, intensity of mechanical ventilation and oxygenation index. Dose effect on outcome measures of mortality, and number of days alive and off mechanical ventilation.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Investigators, blinded to patient allocation, used a masked randomization code to allocate patients into groups, blocked for each site. The six groups were placebo (nitrogen gas), 1.25, 5, 20, 40, or 80 ppm NO.

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

Was followup complete?

Yes. One hundred seventy seven patients were enrolled, but 56 excluded after randomization because they had "treatment gas prematurely discontinued before meeting the oxygenation threshold criteria." This threshold was defined as a PaO2 > 63 in the setting of low FiO2 (< 0.40) and low PEEP (< 8) that was deemed acceptable for extubation. Table 3 gives the exact breakdown of reasons for dropout. The authors state that analysis was on an "intention to treat" base, so even these "dropouts" were presumably included in the analysis (though its not clear whether the ones who didn't die but were "out" were considered alive or dead, on or off mechanical ventilation at 28 days).

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

Yes. No crossover occurred. All the NO dose ranges were pooled for data analysis.

Secondary questions:

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

Yes. Shrouded gas cylinders were provided by an unblinded member who did not take part in the care of the patient. All laboratory monitoring of the drug, i.e., MetHgb, was kept confidential from the care team. The NO2 analyzer was shielded.

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

Yes. All of the patients needed to meet general entry criteria for acute lung injury. A breakdown on the cause of ARDS in the groups showed similarities between the groups. The numbers were too small however to assess any statistically significant differences in causes. Baseline respiratory dysfunction was similar among the groups.

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

Unclear. The authors describe a generally accepted guideline for weaning the ventilator and the study gases. They state that compliance with the mechanical ventilation guidelines was acceptable based on mean inspiratory plateau pressure and PEEP level, but they do not show the data. The use of co-interventions (i.e., pressor, transfusions, antibiotics) was not standardized. Corticosteroid use was used in approximately 10 to 20% of the patients in each group.

III. What were the results?

1. How large was the treatment effect?

The authors had four major outcomes 1) acute response to inhaled NO, 2) sustained physiologic changes, 3) long-term outcomes, and 4) safety. The authors admit that the study was not powered to show statistically significant benefit in any outcome measure. The most significant data was the acute response to PaO2 changes over the first four hours in "responders" (defined as at least a 20% increase in PaO2) in the pooled NO groups vs. placebo. Approximately 60% responded in pooled NO groups vs. 24% in placebo group (the p values for all iNO groups were <0.001). They also report a statistically significant change in PA pressure (decrease of 2 mm Hg) comparing pooled NO vs. placebo, although they do not mention how many in each group had PA catheters (67% overall). FiO2, PaO2/FiO2, MPAP, and OI were significantly improved in pooled NO patients at 24 hours, but only OI remained better in treated groups on Days 2 and 3. After Day 3, the groups were indistinguishable in terms of physiologic parameters. They were unable to analyze after 7 days because a high number of patients had extubated or died.

Long term outcomes were death (30% each in pooled NO and placebo) and days alive after extubation (ranging from 7.2 ± 9.6 in the placebo groups to 4.0 ± 6.0 for the 40 ppm NO group, with no differences noted). Because 50% of patients had zero days alive and off mechanical ventilation, they performed a post-hoc analysis of this data at 28 days. The authors report a significant difference of 5 ppm vs. placebo at 28 days in the percent of patients alive and off mechanical ventilation; 60% vs. 45% (although the significance is lost when adjusted for multiple comparisons).

Safety data did not show any difference between groups. They report 366 adverse events, pneumothorax (16% of all patients) cardiac arrest (12%), infection (10%) and renal failure (7% of all patients). There was no increase in renal failure in the NO groups (11% in inhaled NO vs. 9% in placebo) as reported in other large studies of NO in ARDS. NO2 and MetHgb levels were reported and showed a maximum reached at 24 hours which then remained constant. Values for 40 and 80 ppm NO were increased compared with placebo at all time points. Four patients had MetHgb levels >5% (one placebo, one 40 ppm, and two 80 ppm subjects). Only three patients had NO2 concentrations >3 ppm and they were all in the 80 ppm NO group which was dropped.

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

Assuming the "risk" of being alive and being off the ventilator in the placebo group is 0.4 and for the 5 ppm group is 0.55, the RR is 0.72, with 95% CI's that come out to 0.47 and 1.1. We can then be 95% certain that the risk of being dead or still on the ventilator at 28 days in patients treated with 5 ppm of NO compared to placebo is either about 50% better or 10% worse.

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

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

Maybe. No pediatric patients were included in the analysis. ARDS in the PICU population, however, has historically been managed similarly to treatment in adults. Many treatment modalities for pediatric ARDS have been extrapolated from adult data, so this study probably could be used the same way.

2. Were all clinically important outcomes considered?

No. Much of the paper was focused on the acute physiologic changes, which may or may not be clinically important. Important parameters not considered were time to extubation, long term pulmonary disease, mode of ventilation, and causes of death. The authors state that they did not have enough power to show a statistically significant benefit but they probably would have had enough power to show a 50% reduction.

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

Unclear. Although the use of NO does acutely increase PaO2 in those patients, there is no evidence that it improves the morbidity or mortality of patients with ARDS. This paper does establish that the use of high doses of NO is not necessary to achieve the acute changes in PaO2.

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Related Reviews:

1. 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]
2. 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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