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:

Please visit the new Evidence Based Journal Club Reviews

Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults (Cochrane Review).

Sokol J, Jacobs SE, Bohn D.

The Cochrane Library, Issue 4 2002. Oxford: Update Software. [abstract]

Reviewed by Satid Thammasitboon, MD, MHPE, Pediatric Critical Care Medicine, Baylor College of Medicine, Houston, TX, and Supat Thammasitboon, MD, Pulmonary and Critical Care Medicine, Tulane University, New Orleans, LA

Review posted September 24, 2003

---

I. Are the results of the study valid?

A. Primary questions:

1. Did the overview address a focused clinical question?

Debatable. The overview sought to examine the effect on mortality and morbidity of treatment with inhaled nitric oxide (iNO) in patient with acute hypoxemic respiratory failure (AHRF) compared with maximal ventilation therapy with no treatment or placebo inhaled gas. AHRF is a broad clinical syndrome caused by various diseases with wide spectrum of morbidity and mortality. Other clinical outcomes including the ventilator-free days, hospital and intensive care stays and complications were also investigated.

2. Were the criteria used to select articles for inclusion appropriate?

Yes, the very well-defined criteria were used to specify patients, interventions, and outcomes. All outcome measures were objective, e.g., hypoxia score (PaO2/FiO2) and oxygen index. Unfortunately very few studies used or focused on these clinical parameters. The authors included only prospective randomized controlled trials. The confounding factors were minimized by including only studies that specifically reported the outcomes during and after the treatment gas. The studies with multiple cross-over arms and in abstract form only were excluded.

B. Secondary questions:

3. Is it unlikely that important, relevant studies were missed?

No, the review should not miss any relevant studies. The authors performed extensive search without language restriction on multiple bibliographic databases, i.e., MEDLINE. EMBASE, and CINAHL with the proper search strategy. The authors also hand searched other relevant journals and conference proceedings that were not included in the database. All bibliographies of retrieved articles were reviewed. Authors published in the field were contacted to identify the published studies that might have been missed (including studies that are in press or not yet indexed or referenced) and to identify unpublished studies. All these measures minimized the publication bias.

4. Was the validity of the included studies appraised?

Yes, the authors provided detailed information on both the studies that were included and excluded. The authors assessed methodological quality using Schulz's methodology (1) and particularly emphasized on concealment of treatment allocation, generation of allocation sequences, blinding vs. no blinding, and adequacy of withdrawal or dropout analysis. The randomization process was not described clearly in most of the studies. The treatment was not blinded in three out of five studies. No score or grading was used with this evaluation.

5. Were assessments of studies reproducible?

Two independent reviewers extracted and analyzed the data. There was no kappa statistic or other method of inter-observer variability performed.

6. Were the results similar from study to study?

Yes, the results for mortality demonstrated no heterogeneity. The different definitions for ARDS and AHRF were used in five selected studies. The primary and secondary outcomes were quite different. Some of the secondary outcomes were reported inconsistently, such as, ventilator-free days over 30 days and duration of ICU stays. The different indicators were used on measuring oxygenation made the comparison impossible. From the available data, there was no heterogeneity between studies so the fixed effect method was applied. When the data could not be analyzed, descriptive results from each trial were reported. The authors did a good job in documenting important differences in patients, exposures, outcome measures and research methods from study to study.

II. What are the results?

1. What are the overall results of the review?

Categorical outcomes	Number of the studies	Findings	Notes
Mortality at 30 and 90 days	5	RR = 0.98, 95%CI 0.66,1.44 (in trials without cross-over)	3 studies allowed cross-over of treatment failures were analyzed separately.
Improvement in Oxygenation	1	OI was significant lower in treatment group only in the first 96 hours.	The marginally statically significance in OI was not clinically significant.
Ventilator free days over 30 day period	3	No significant differences	Post-hoc showed significant difference between treatment group (5ppm) and placebo (Dellinger 1998) (2)
ICU and hospital stay	1	No significant differences
Adverse effects	5	Methemoglobinemia (level > 5%) with iNO at 40 ppm (1 patient), 80 ppm (2 patient) Nitrogen dioxide formation of > 3 with iNO at 80 ppm (3 patients).	Insufficient data for meta-analysis

2. How precise were the results?

Since the primary outcome, mortality rate, the 95% CI (0.66, 1.44) crosses one, we cannot conclude there is any treatment effect on mortality. One interpretation of these CI's is that the true treatment effect could be as great as a 40% relative risk reduction or increase in mortality. If either of these extremes were true, they would certainly be clinically significant.

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

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

No. Given the poor methodological designs of the studies selected, the conclusion of the findings from this review is not possible. The pathophysiology of acute respiratory failure in newborn infants, children and adult are different. The incidence of increased pulmonary vascular resistance varies in different population. Out of five studies evaluated, there was only one pediatric study included 108 children (Dobyns 1999) (3). Another study (Michael 1998) (4) included adults and children. There was no information provided on how many of them were children. The application of the results to pediatric population should be considered with caution.

2. Were all clinically important outcomes considered?

Yes. All clinically relevant outcomes were considered. Unfortunately, they were inconsistently reported in selected studies precluding complete evaluation.

3. Are the benefits worth the harms and costs?

Unable to justify. Due to inadequate data to conclude any benefits or adverse effect of iNO, the answer for this question is yet to be determined. Although the limited data showed no significant complications directly attributable to iNO, several long-term injuries on the lung are unknown. While awaiting further trials to prove its benefit, iNO should not be either recommended as a standard management or excluded for the treatment of AHRF.

The use of iNO is probably only to modify the lung role in the pathogenesis of AHRF by improve V/Q mismatch and reducing pulmonary hypertension. These modifications could result in transient improvement in oxygenation during critical hypoxemia. It could rescue the patients until other interventions, either other lung-targeted therapies or systemic disease therapies (e.g., sepsis), take their effects. Given the complexity of the AHRF, a single therapy is unlikely to be proven successfully impact the mortality outcome.

References

1. Schulz KF, Chalmers I, Hayes RJ, Alteman DG, Empirical evidence of bias: Dimension of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408-12. [abstract]
2. Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis K, 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. Critical Care Med 1998;26:15-23. [abstract]
3. Dobyns EL, Cornfield DN, Anas NG, Fortenberry JD, Tasker RC, Lynch A, Liu P, Eells PL, Griebel J, Baier M, Kinsella JP, Abman SH. Multicener randomized controlled trial of the effects of inhaled nitric oxide therapy on gas exchange in children with acute hypoxemic respiratory failure. J Pediatr 1999;134:406-412. [abstract]
4. Michael JR, Barton G, Shaffle JR, Mone M, Markewitz BA, Hillier K, Elstad MR, Campbell EJ, Troyer BE, Whatley RE, Liou TG, Samuelson WM, Carveth HJ, Hinson DM, Morris SE, Davis BL, Day RW. Inhaled nitric oxide versus conventional therapy: Effect on oxygenation in ARDS. Am J Respir Crit Care Med 1998;157:1372-1380. [abstract]
5. Troncy E, Collet JP, Shapiro S, Guimond JG, Blair L, Ducruet T, Francoeur M, Charbonneau M, Blaise G. Inhaled nitric oxide in acute respiratory distress syndrome: A pilot randomized controlled study. Am J Respir Crit Care Med 1998;157:1483-1488. [abstract]

Comments

Back to the EB Journal Club Index