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

Highlighted lines and questions below provide links to the pertinent description of criteria in The EBM User's Guide, now available at the Canadian Centres for Health Evidence

Article Reviewed:

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Inhaled Nitric Oxide in Acute Respiratory Distress Syndrome: A Pilot Randomized Controlled Study.

Troncy E, Collet JP, Shapiro S, Guimond JG, Blair L, Ducruet T, Francoeur M, Charbonneau M, Blaise G.

Am J Respir Crit Care Med 1998; 157: 1483-1488. [abstract] [full-text for subscribers only]

Reviewed by Maher Eldadah, MD, Hillcrest Medical Center, Tulsa, OK

Review posted March 4, 1999

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I. What is being studied?:

The study objective:

To determine the impact of inhaled nitric oxide (inhNO) on lung function, morbidity and mortality of adult respiratory distress syndrome (ARDS) patients.

The study design:

A pilot clinical study that is randomized and controlled.

The patients included:

Thirty patients with ARDS (Murray's Lung Injury Score 2.5) between 18-75 years old who were admitted to the medical or surgical ICU of a large University Hospital were included. Acuity of illness was assessed using Lung Injury Score (LIS) of Murray and colleagues and APACHE II system.

The patients excluded:

Patients who were pregnant, had cardiogenic pulmonary edema or suffered end stage neoplasia were excluded.

The interventions compared:

Patients in the treatment group initially received 2.5 ppm NO. The inhaled NO was incrementally increased to a maximum of 40 ppm. The study parameters were collected at baseline and then 10 minutes after each change in inhaled NO. The optimal fraction of inhaled NO (FiNO) was determined initially by increasing the FiNO until the increase in PaO2 was smaller than 5% from the previous level. Similar daily stepwise decreases in FiNO were performed.

Control patients and treatment patients both received mechanical ventilation following a standardized protocol.

The outcomes evaluated:

Therapeutic success was defined as weaning from mechanical ventilation and extubation within 30 days after inclusion in the study. Therapeutic failure was defined as death before 30 days or continued need for mechanical ventilation after 30 days.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. The authors do not describe the method of randomization.

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

Was followup complete?

Yes. All patients were accounted for at the end of the trial. Patients who died were assigned the maximum possible length of mechanical ventilation - 30 days.

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

Yes. No patients crossed over to the other group.

Secondary questions:

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

The authors do not state that this study was a blind study. Other inhNO studies have managed to be blind the care providers, with an uninvolved respiratory therapist making changes and monitoring the gas system closely. This is a significant flaw in this study.

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

Yes, both groups were similar with regard to demographics and factors such as smoking history or alcholism. The NO group had higher APACHE II scores and a lower HS (hypoxia score = PaO2/FiO2), but the study does not state whether these differences are statistically significant.

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

Yes. Patients in both groups were mechanically ventilated, provided nutrition, and transfused according to similar protocols. The study does not spell out these protocols. All patients were sedated and received neuromuscular blockade. They were similarly monitored with arterial and pulmonary catheters, pulse oximetry and capnography.

III. What were the results?

1. How large was the treatment effect?

Significant improvement in initial gas exchange was documented with inhNO; PaO2 increased by 66.2%, PaCO2 reduction by 7%, as well as reduction in mean pulmonary artery pressure without systemic hemodynamic effects. The mean initial optimal FiNO was 8.5 ppm. After this initial effect, no differences were observed between groups with regard to lung function.

The mortality rate as well as the ventilator days were similar in both groups; 9 deaths and 22.3 +/- 2.5 days (mean +/- standard error) of ventilation in the inhNO group compared to 8 deaths and 24.1 +/- 2.5 days of ventilation in the controls (n = 15 in both groups). In the subgroup analysis of survivors, treated patients were ventilated 10.8 +/- 1.2 days compared to controls ventilated for 12.8 +/- 4.2 days; this difference was not significant. The final "therapeutic success" rate was slightly higher (40%) and achieved earlier (Day 15) in the treated group compared to the controls (33% on Day 30).

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

There is no clear effect on a stated outcome measurement.

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

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

Maybe. Aside from the initial changes seen in the pulmonary artery pressure and PaO2, inhaled NO failed to show sustained improvement in oxygenation. The continued administration of inhaled NO was not shown to alter mortality nor the days of mechanical ventilation. The study had a small number of patients, and was therefore likely underpowered to demonstrate any effect on the primary outcomes. In addition, all patients were adults.

The results of this study are entirely consistent with similar trials (1, 2) that failed to show clinically significant improvements in outcome in patients with ARDS treated with NO.

2. Were all clinically important outcomes considered?

Almost. Ideally one would like to see more information about other organ failure or the development of chronic lung disease. Given the small sample size, it would seem unrealistic that any differences would emerge.

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

Unlikely, since the study fails to show significant improvement short of the initial phase. Potential side effects of NO were not addressed in the study.

References

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. 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. 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 PedCCM EB Journal Club review]

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