University of Michigan
Department of Pediatrics
Evidence-Based Pediatrics Web Site

Question

• In term newborns with hypoxic respiratory failure, does inhaled nitric oxide make a difference in death or need for ECMO when compared with newborns who do not receive inhaled nitric oxide?

Clinical Bottom Lines

1. Initiating inhaled nitric oxide at 20 ppm for hypoxic respiratory failure reduces the need for ECMO.¹
2. This therapy also improves the oxygentaion index and oxygentaion.
3. There are no impacts in neurodevelopmental outcomes.

Summary of Key Evidence

1. Meta-analysis of 12 RCT trials evaluating the ability of inhaled nitric oxide in newborns with hypoxic respiratory failure to improve oxygenation, reduce mortality, and need for ECMO.¹
2. Hypoxic respiratory failure most likely due to either primary or secondary pulmonary hypertension excluding congenital heart defects/shunting.
3. One study looked at infants specifically with congenital diaphragmatic hernias and was evaluated separately.
4. 10 different types of outcomes were explored; however, not every study measured each outcome specifically. Main outcomes were death, requirement for ECMO, changes in oxygenation and oxygen index, and neurodevelopmental outcomes.
5. Sample size ranged from n=17 to n=235 with eligibility criteria described as "reasonably homogenous."
6. Requirements for hypoxemic respiratory failure was not the same in each study; however on the above endpoints, the test for heterogeneity was not significant, providing some reassurance that this did not have an effect on results.
7. In addition, there were different modes of intervention among studies such as type of mechanical ventilation, surfactant, cross-over to the intervention group.
8. The article was valid in that it appeared to be an exhaustive search, methodology among studies varied greatly-therefore not all studies were included in each outcome. When similar studies were evaluated, reproducibility of results occurred.
9. Inhaled nitric oxide reduces the requirement for ECMO as demonstrated by a meta-analysis of eight RCTs: RR 0.63 (95%CI 0.54, 0.75); ARR 0.19 (CI 0.12, 0.26); NNT= 6.
   
10. Oxygenation Index decreased at 30 to 60 minutes after treatment demonstrated by a meta-analysis of six RCTs: weighted mean difference ; -9.59 (CI -12.50, -6.68).
    
11. PaO2 increased 30 to 60 minutes after treatment, as demonstrated in a meta-analysis of six studies: weighted mean difference 45.5 mmHg (CI 34.7, 56.3).
    
12. Neurodevelopmental outcomes measured at 18 to 24 months were not significantly different between newborns who received inhaled nitric versus those that did not: RR 1.14 (CI 0.74, 1.77).

Additional Comments

• The overall summary of this Cochrane review was that initiating inhaled nitric oxide at 20 ppm for hypoxic respiratory failure reduced the need for ECMO. There were significantly different levels of nitric oxide used in the 12 studies reviewed.
• FDA guidelines² and AAP policy³ recommend clinical or echocardiographic evidence of pulmonary hypertension are required; however, one study suggested that this is not needed and is included in the results of this review.
• Future research regarding lowest effective does of inhaled nitric oxide are needed to reduce the chances of toxic exposures.
• Toxic metabolites of nitric oxide include methemoglobin and nitrate. These should be checked periodically during treatment. Cessation of therapy is recommended for a methemoglobin level >4-7% and nitrate level >3ppm.
• Nitric Oxide should be weaned rather than abruptly discontinued secondary to rebound pulmonary hypertension.
  

Citation

1. Finer, NN, Barrington, KJ. Nitric Oxide for respiratory failure in infants born at or near term. The Cochrane Database of Systematic Reviews. 2005. Volume 1.
2. http://www.fda.gov
3. Committee on Fetus and Newborn Use of Inhaled Nitric Oxide. Pediatrics 2000;106: 344-5.

CAT Author: Jessica Hanks, MD

CAT Appraisers: John Frohna, MD

Date appraised: March 30, 2005