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 Versus Conventional Therapy: Effect on Oxygenation in ARDS

Michael JR, Barton RG, Saffle JR, et al.

Am J Respir Crit Care Med 1998; 157: 1372-1380. [full-text for subscribers only] [abstract]

Reviewed by Gerardo Reyes, M.D., Hope Children's Hospital, Oak Lawn, IL

Review posted September 4, 1998

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I. What is being studied?:

The study objective:

The study aims to answer the following questions: (1) Does iNO therapy improve oxygenation as compared with conventional therapy during the 72 hours after patient randomization?, and (2) Does iNO increase the likelihood that patients will improve sufficiently to be managed with a persistent decrease in FiO2 of 0.15 within 72 hours after randomization?

The study design:

Randomized, controlled clinical trial.

The patients included:

Patients were recruited from the MICU, SICU, or Burn Unit of the hospital. Forty one families were approached. Forty adult patients with ARDS and receiving FiO2 0.8 for at least 12 hours or FiO2 0.65 for at least 24 hours immediately before randomization. No mention is made of how many eligible patients were not considered for enrollment.

The patients excluded:

Pregnancy or not expected to survive hospitalization because of underlying disease.

The interventions compared:

Inhaled NO and conventional mechanical ventilation vs. conventional mechanical ventilation. The iNO was titrated at the discretion of the primary attending (all coinvestigators) from 5 to 20 ppm, adjusted according to the patient's condition and response to the various NO concentrations.

The outcomes evaluated:

1. Improvement in oxygenation: A decrease in FiO2 0.15 within 72 hours after randomization and persisting for at least 24 hours.
2. PaO2/FiO2 at 1 hour and 72 hours to assess correlation (i.e., to determine if short term response predicts long-term response.)
3. Identification of specific clinical features that would predict improved oxygenation over 72 hours.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Patients were randomized using balanced blocks of 14.

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

Was followup complete?

Yes. All 40 patients entered into the study were accounted for. Of the 20 patients on conventional ventilation alone, 2 died within 72 hours after randomization, one crossed over to iNO over after 36 hours because of clinical deterioration, and one crossed over after 48 hours because of failure to improve. Sixteen patients received conventional therapy for the full 72 hours. Four patients randomized to iNO died within the first 72 hours.

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

Yes, but in some analyses, only those patients completing the full 72 hours were included (n = 16 in each group).

Secondary questions:

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

No. Blinding was not done; caregivers and investigators were aware of treatment assignment.

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

Yes. With the exception of age, all other demographic and baseline physiological characteristics were similar in the two groups as presented in table 4. For the conventional ventilation group the age was 41 ± 5 yr (n = 20), and for the iNO group the age was 31 ± 3 yr (n = 20) (p = 0.08).

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

Probably, but few details were provided regarding co-interventions, with the exception of changes in FiO2 and target PaO2.

III. What were the results?

1. How large was the treatment effect?

Eleven of 20 (55%) iNO patients compared to 9 of 20 (45%) controls (p = 0.55) achieved the primary endpoint, i.e., the ability to sustain a decrease in FiO2 0.15 after 72 hours. In addition, when analyzed over the entire study period, there was no significant treatment effect on the course of PaO2, FiO2, or PaO2/FiO2 between the groups.

However, if a patient had an improvement in oxygenation (as defined above), it correlated with reversal of ARDS; 17 of 20 patients with "improved oxygenation" had reversal of ARDS, compared to 6 of 20 patients who did not improve (p = 0.0006). Survival also correlated with an improvement in oxygenation. Patients who did not experience a persistent decrease in FiO2 0.15 within 72 hours had a relative risk of dying of 2.3 (95% CI 1.13, 4.83). These relationships held true for patients randomized to either group.

Acute response to iNO at 1 hour or lack of such a response was not predictive of an improvement in oxygenation within the 72 hours of study period.

There were no clinical features predictive of improvement in oxygenation for the conventional ventilation group. For the iNO group, the best predictor for improved oxygenation was a quasi-static respiratory compliance > 19 ml/cm H2O at randomization, and ARDS for 3 days prior to randomization.

There was no statistically significant difference in mortality between the groups. The only positive finding was a decrease mortality among the patients who had an improvement in oxygenation, regardless of their randomization group. Fourteen of 20 patients who had improvement in oxygenation survived. In contrast, only six patients of 20 who did not improve survived. However, the confidence intervals of the RR of dying for non-responders suggest a true increased in mortality between 13% and 480%.

No significant side effects (e.g., bleeding) were reported in the iNO group.

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

There were no significant difference in outcomes between the groups.

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

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

Yes. Although the study was done in adults, the results clearly show that iNO is not beneficial in the treatment of ARDS. Another recent study did not show a difference in mortality between iNO and conventional mechanical ventilation (1). The only alternative treatment to conventional ventilation that has shown to be beneficial in the treatment of ARDS is high-frequency oscillation ventilation (2).

2. Were all clinically important outcomes considered?

Yes. The study evaluated the long-term effects (72 hours) of iNO on the PaO2/FiO2 ratio in patients with ARDS, as compared to most studies to date that only report immediate effects. In addition, important clinical outcome such as length of stay and mortality were also evaluated.

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

No. Inhaled NO did not prove to be beneficial in the treatment of ARDS.

References

1. Dellinger RP, 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]
2. Arnold J, et al. Prospective, randomized comparison of high-frequency oscillatory ventilation and conventional mechanical ventilation in pediatric respiratory failureCrit Care Med 1994;22:1530-1539.[abstract]

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Related Reviews

1. 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 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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