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Nitric oxide for acute lung injury

Citations: NKJ Adhikari, KEA Burns, JO Friedrich, JT Granton, Cook DJ, MO Meade.  Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis BMJ, doi: 10.1136/bmj.39139.716794.55 (published online 23 March 2007)

Lead author: NJK Adhikari, Interdepartmental Division of Critical Care Medicine, University of Toronto, Canada. neill.adhikari@sunnybrook.ca

Three-part Clinical Question:

Patients: ICU patients with acute lung injury (ALI) / acute respiratory distress syndrome (ARDS)

Intervention: Inhaled nitric oxide.

Outcomes: Oxygenation, mortality, morbidity (duration of ventilation and adverse effects). 

Search Terms: ALI, ARDS, intervention, therapy, RCT, meta-analysis, nitric oxide.

The Review:-

Data Sources: Medline, CINAHL, Embase, CENTRAL. Contact with experts (sourced via bibliographies of retrieved studies, recent review articles and conferences) to identify additional trials.  No language restrictions.

Study Selection: Two independent reviewers screened randomised controlled trials enrolling adults and children (neonates excluded) with >80 % of patients or a separately reported subgroup having ALI or ARDS using the authors’ definition. Trials with co-interventions applied equally in both groups and blinded / non blinded trials were included.

Data Extraction: Primary outcome: mortality in hospital (or, if not available) mortality in the intensive care unit or at 28 or 30 days). Secondary outcomes: duration of ventilation, ventilator-free days to 28 or 30 days and pulmonary physiology. Post-hoc analysis of renal dysfunction data.

 The Evidence:-

1242 studies identified; 12 included in meta-analysis (excluded: not randomised, crossover design, nitric oxide not compared with control, active therapy given to control group, wrong topic or animal study). Twelve randomised controlled trials: 1237 patients, adults and children, variable doses of nitric oxide, median duration of nitric oxide 6.5 days (range 3.5 – 9.0), varying ventilation strategies. Cohen’s co-efficient used to assess agreement between the two reviewers.

The evidence:

There was no difference in mortality, duration of ventilation or ventilator-free days. Oxygenation was improved in the NO group on day one of treatment.  There was some evidence for this improvement persisting until day 4.

Post-hoc analysis (so subject to bias) of 845 patients (4 trials) demonstrated an increased risk of renal dysfunction in the NO groups (RR 1.5) however the pooled results failed to reach statistical significance (95% CI 1.11 to 2.02).

EBM Comments:

1. Do the methods allow accurate testing of the hypothesis? Yes.

2. Do the statistical tests correctly test the results to allow differentiation of statistically significant results? Yes.  Homogeneity assessed for each outcome using Cochran Q statistics, only duration of ventilation showed significant heterogeneity.

3. Are the calculations valid in the light of the results? Yes

4. Did results get omitted and why? No

5. Did they suggest other areas of research? No

6. Did they make any recommendations based on the results and were they appropriate? Although nitric oxide improves oxygenation temporarily, this meta-analysis suggests no survival advantage and possible renal dysfunction with nitric oxide, hence this study did not recommend its routine use for ARDS/ALI.  The data on increased renal dysfunction associated with inhaled nitric oxide therapy was post-hoc analysis (4 trials, 895 patients) and should be interpreted with caution.  The authors did acknowledge that when faced with a patient with life threatening hypoxaemia inhaled nitric oxide remained a possible therapeutic salvage therapy which could be used in conjunction with other supportive therapies.

7. Is the study relevant to my clinical practice? Yes

8. What level of evidence does the study represent? 1⁺⁺

9. What grade of recommendation can I make on this result alone? A

10. What grade of recommendation can I make when this study is considered along with other available evidence? A

11. Should I change my practice because of these results? In an intensive care unit with established nitric oxide use, the evidence suggests rescue therapy with nitric oxide should remain a consideration. For intensive care units with no established nitric oxide use, there remains a lack of evidence to institute such a service.

12. Should I audit my current practice because of these results? Yes. Potential topics could include: renal dysfunction in patients after nitric oxide use, acute lung injury patient groups (routine use for acute lung injury versus salvage therapy), differing concentrations of nitric oxide used nationally.

Appraised by: Katrina Bramley (SHO), Department of Anaesthetics, Stirling Royal Infirmary, Livilands, Stirling, FK8 2AU, 30^th June 2007.
Email: katrinabramley@hotmail.com

Kill or Update By: May 2012

Reviewed & edited by CC & BLT

Citation: EBM Critical Appraisals. Scottish Intensive Care Society EBM Group. 2007 & JICS 2007 Vol8(2). Bramley K. NKJ Adhikari, KEA Burns, JO Friedrich, JT Granton, Cook DJ, MO Meade.  Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis BMJ, doi: 10.1136/bmj.39139.716794.55

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