Inhaled Nitric Oxide in Episodes of Severe Pain in Patients with SCD

Sickle cell disease (SCD) is an autosomal-recessive disorder of the beta globin gene, in which mutant hemoglobin S polymerizes in erythrocytes, causing occlusion of the small blood vessels. The occlusion manifests clinically as episodes of severe pain (vaso-occlusive crisis [VOC]), damage to vital organs, and early death. Absent treatment, VOC occurs at a rate of approximately 2 episodes per person-year; mean length of hospitalization during VOC is 4.5 days for children 10 to 14 years of age. Up to 20% of patients hospitalized for VOC develop acute chest syndrome, an acute lung injury that extends the length of stay to 14 days (mean). It is estimated that the national expenditure for inpatient sickle cell medical care is $571 million (in 2010 dollars). A small placebo-controlled trial for the treatment of VOC with inhaled nitric oxide in children with SCD found evidence of decreased pain severity and reduced opioid analgesic use, with trends toward reductions in length of hospital stay. A more recent 18-patient, multicenter, placebo-controlled study of inhaled nitric oxide in adults found a significantly greater reduction in pain and a trend toward decreased narcotic use. Researchers recently conducted a phase 2, randomized, double-blind, placebo-controlled, multicenter study of nitric oxide inhalation for up to 72 hours in 150 patients with SCD presenting with VOC. The study was designed to determine whether inhaled nitric oxide gas reduces the duration of painful crisis in patients with SCD who present to the emergency department (ED) or hospital for care. Study results were reported in the Journal of the American Medical Association [2011;303(9):893-902]. The intervention in the study was inhaled nitric oxide gas versus inhaled nitrogen placebo. The primary end point was the time to resolution of the painful crisis, defined as (1) freedom from parenteral opioid use for 5 hours, (2) pain relief as assessed by visual analog pain scale scores of ≤6 cm (on a scale of 0-10), (3) ability to walk, and (4) the patient’s and family’s decision, with physician consensus, that the pain could be managed at home. The participants had known SCD, were ≥10 years of age, and were identified for study inclusion during presentation with VOC to the ED or other appropriate unit; they were randomized by site and age at entry (10-15 years and >15 years), in blocks of 4, in a 1:1 ratio of placebo to inhaled nitric oxide. Nitric oxide for inhalation was supplied at a concentration of 800 ppm balanced with nitrogen; placebo gas was 100% grade 5 nitrogen gas. Both were delivered with air and mixed with oxygen to achieve a constant fraction of inspired oxygen of 24%. Those in the nitric oxide group received 80 ppm for 4 hours, followed by 40 ppm for 4 hours. There was no significant difference in time to VOC resolution between the 2 groups; estimated median time to resolution of crisis in the inhaled nitric oxide group was 73.0 hours (95% confidence interval [CI], 46.0-91.0) and 65.5 hours (95% CI, 48.1-84.0) in the placebo group (P=.87). Likewise, there were no significant differences between the 2 groups in secondary outcome measures: median length of hospitalization (4.1 days for the inhaled nitric oxide group vs 3.1 days for the placebo group; P=.30); mean visual analog scale scores at 24 hours (6.1 cm for the nitric oxide group vs 6.0 cm for the placebo group; P=.90); and median opioid use (2.8 mg of morphine equivalents/kg of body weight vs 2.9 mg of morphine equivalent/kg of body weight for the nitric oxide group and the placebo group, respectively; P=.73). Study limitations cited by the researchers included the small sample size and the broad but overlapping CIs for the medians of the primary outcome variable, creating the possibility that a small treatment effect may have been missed. In summary, the researchers noted that the “results of this study indicate that inhaled nitric oxide in the doses and methods of administration used in the study does not reduce VOC severity in SCD.” They concluded by stating that the 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 SCD.”