Inhaled Nitric Oxide Therapy for the Vaso-occlusive Crisis in Sickle Cell Disease

Abstract

Source: Weiner DL, Hibberd PL, Betit P, et al. Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients with sickle cell disease. JAMA. 2003;289:1136–1142.In this placebo-controlled, double-blinded, randomized clinical trial from Children’s Hospital, Boston, the use and efficacy of inhaled nitric oxide (INO) therapy for patients with sickle cell disease (SCD) and acute painful vaso-occlusive crisis (VOC) was investigated. Twenty patients with SCD and VOC were enrolled in the study. Study patients received standard emergency treatment for VOC, which included morphine and intravenous hydration. They were randomized to receive INO (80 ppm with 21% inspired oxygen concentration) by face mask or placebo (21% inspired oxygen) for a 4-hour period followed by observation for 2 additional hours. Morphine was provided for analgesia using a patient controlled administration pump. Pain control was measured using a Visual Analog Scale (VAS).The primary outcome measure was change in pain score after 4 hours of INO therapy. Patient demographics and pain scores were similar between the treatment and placebo groups at presentation. Both groups showed a decrease in VAS scores during the period of inhalation; however, the treatment group showed a significantly greater decrease in VAS 3 hours post-INO therapy (P=.05). This difference was not present at the 4-hour time period. Secondary end points such as total morphine dose (0.29 versus 0.44 mg/kg, P=.03) used for 6 hours and the dose of morphine used per hour were significantly less among patients who received INO. There was a trend towards shorter hospital stay in the INO group (78 versus 100 hours, P=.19). INO therapy was well tolerated, and patients did not develop methemoglobinemia or toxic concentrations of delivered nitrogen dioxide (NO2). The authors concluded that the INO therapy may offer promise as a therapeutic agent for treatment of VOC in SCD, and that further studies were required to evaluate the efficacy, safety and physiological effects of INO in patients with SCD.The use of INO as specific therapy for VOC in SCD patients has not been studied before. Nitric oxide (NO) may be beneficial in VOC of SCD because NO-dependent mechanisms regulate vascular tone and cause vasodilation.1 Furthermore, the reaction of NO with hemoglobin results in nitrosyl-hemoglobin that locks sickle cell hemoglobin (HbS) in relaxed conformation preventing polymerization and sickling. INO has been reported to be beneficial in 3 pediatric patients with SCD and acute chest syndrome (ACS).2,3 In these patients, improved oxygenation and pulmonary vasodilation during INO therapy were thought to ameliorate the underlying vaso-occlusive process in the lungs.In this well-constructed study, patients using INO for a period of 4 hours had better pain scores, and used smaller cumulative doses of morphine and smaller hourly doses of morphine compared to the placebo group. Furthermore, there was a trend towards shorter hospital stay in this study. These data suggest that INO may be a beneficial and specific therapy for children with SCD who have VOC because it decreases pain, narcotic use, and hospital stay. The concentration of INO used in this study (80 ppm) was high. Although the methemoglobin and NO2 levels were in the normal range in this study, careful monitoring should be undertaken if prolonged use of INO is intended.This preliminary study is the first one to suggest that INO may be beneficial for acute vaso-occlusive crisis in patients with sickle cell disease. If subsequent, more rigorous studies confirm effectiveness and demonstrate safety of INO, we can breathe easier since we will have one more therapeutic option for the major complication of sickle cell disease, a complication that results in acute debilitating pain and contributes to all the other adverse effects of this disorder.