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Inhaled nitric oxide does not relieve sickle cell pain

Reuters Health • The Doctor's Channel Daily Newscast

NEW YORK (Reuters Health) – The vasodilatory effect of inhaled nitric oxide does nothing to ease the severity of vaso-occlusive crises in patients with sickle cell disease. That finding is reported by Dr. Mark T. Gladwin with the University of Pittsburgh, Pennsylvania and colleagues, in this week’s Journal of the American Medical Association.

The authors note that vaso-occlusive crisis (VOC) occurs about twice a year in patients with sickle cell disease and causes severe pain, necessitating hospitalization for about 4 or 5 days. As they explain, “Nitric oxide is the critical effector of endothelial-dependent vasodilation and exerts pleiotropic effects on vascular and circulating blood cells, including the inhibition of platelet aggregation, down-regulation of cellular adhesion molecules, and modulation of ischemia-reperfusion injury, all pathways adversely affected during VOC.”

Two small recent trials indicated that inhaled nitric oxide reduced pain during VOC, prompting the researchers to conduct a double-blind randomized trial of inhaled nitric oxide gas versus inhaled nitrogen placebo for up to 72 hours in 150 participants with VOC associated with sickle cell disease.

“The primary end point was the time to resolution of painful crisis, defined by (1) freedom from parenteral opioid use for 5 hours; (2) pain relief as assessed by visual analog pain scale scores of 6 cm or lower (on 0-10 scale); (3) ability to walk; and (4) patient’s and family’s decision, with physician consensus, that the remaining pain could be managed at home,” according to the report.

The ream found that the median time to resolution was 73.0 hours with nitric oxide inhalation compared with 65.5 hours with placebo, a non-significant difference (p=0.87).

Secondary measures also did not differ between the nitric oxide and nitrogen groups. For example, median total opioid use was 2.8 vs. 2.9 mg of morphine equivalents per kg body weight, respectively, and the rate of decline in VAS pain score was similar in both groups.

Why did inhaled nitric oxide not have a positive effect? One possibility is a lack of systemic generation of nitrite, perhaps due to the pulsed delivery of nitric oxide used in the study. This mode “provides a pulse of pure nitric oxide in nitrogen at the ‘front’ of the tidal volume. This reduces mixing of nitric oxide with oxygen in the airways, which can form nitrogen dioxide, dinitrogen trioxide, and nitrite,” the investigators explain.

Another possibility is that tissue injury in VOC may not be reversible once it is recognized clinically.

Whatever the reason, Dr. Gladwin and colleagues conclude, “These results underscore the need for new agents and a sustained clinical trials apparatus for studying VOC, with sufficient numbers of patients to provide adequate power to rapidly test promising therapeutics in patients with sickle cell disease.”

JAMA 2011; 305:893-902.