New Potential Therapy For Sickle Cell Disease; Inhaled Gas May Offer A Novel Treatment Approach

Current treatments (analgesics, fluids) are directed at easing the symptoms of vaso-occlusive crisis and are of only limited effectiveness, said Debra Weiner, MD, PhD, assistant in Emergency Medicine at Children's Hospital Boston and the study's leader. Rather than targeting symptoms, Weiner and her team, including senior investigator and director of Children's Hematology Lab, Carlo Brugnara, MD, were interested in targeting disease processes that underlie vaso-occlusion itself. A key factor in vaso-occlusion is now thought to be a shortage of nitric oxide, a gas produced by cells throughout the body. Nitric oxide dilates blood vessels to help maintain good blood flow, prevents abnormal clotting, and controls inflammation.

The study is based on the idea that providing extra nitric oxide could compensate for this shortage. In a randomized clinical trial, the Children's Hospital Boston team gave 20 young patients with severe vaso-occlusive crisis, aged 10 to 21, either nitric oxide or placebo (room air only) through a face mask for four hours. All patients received routine treatment with fluids and morphine. Respiratory therapists gave treatments; neither Weiner nor the patient knew which treatment was being given. Patients scored their degree of pain on a validated visual scale going from 0 to 10 centimeters. All patients were carefully monitored.

Overall, the 10 patients receiving nitric oxide had a greater decrease in hourly pain scores as compared with the placebo group. This difference was near statistical significance at 3 hours and achieved statistical significance when pain was looked at over the full 4 hours of inhalation. The nitric oxide group also used about a third less morphine over six hours, showed a trend toward shorter hospitalization, and scored well on all measures of safety.

Weiner emphasized that the study was small and that the gas was given for only four hours, which probably was not long enough for nitric oxide to be fully effective. "The fact that we saw differences under these circumstances is very encouraging," Weiner said. "If nitric oxide works, it will be a long-overdue breakthrough for these patients."

Nitric oxide is already used, sometimes at home, to treat respiratory disease and pulmonary hypertension. It is also used in cardiac and surgical settings to prevent reperfusion injury (cellular injury that occurs when blocked blood flow is restored).

Sickle-cell disease affects millions of people worldwide and about 70,000 Americans, primarily people of African descent. About 8 percent of African Americans are carriers, and 1 in 500 African-American newborns have the disease, making it the most common genetic disease in this population.

Although the genetic defect has been known for 50 years, research is still unraveling the complex pathophysiology of sickle-cell disease. The defective gene results in production of abnormal hemoglobin, the oxygen-carrying protein in red blood cells. In low-oxygen conditions, the defective hemoglobin molecules bind together, causing the cell's shape to distort. This "sickling" results in impaired circulation and inadequate delivery of oxygen to tissues. Sickled cells are more easily destroyed than normally shaped red blood cells, and recent work from the National Institutes of Health found that free hemoglobin, released when the cells are destroyed, rapidly scavenges and destroys nitric oxide, making it unavailable for use by the body.

"The idea is that if you give ample nitric oxide to overcome this deficiency, and give it for long enough, you may be able to reverse or stop the vaso-occlusive crisis," Weiner said. "We don't know that nitric oxide works yet, but the results are encouraging and warrant further investigation." Her team plans further studies.

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The Children's Hospital Boston study was funded by an Orphan Products Development grant from the Food and Drug Administration and by the Children's Hospital Boston's General Clinical Research Center National Institutes of Health grant. Pulmonox Medical Corporation (Tofield, Alberta, Canada) donated the nitric oxide.

Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults for over 100 years. More than 500 scientists, including seven members of the National Academy of Sciences, nine members of the Institute of Medicine and nine members of the Howard Hughes Medical Institute comprise Children's research community. Founded in 1869 as a 20-bed hospital for children, Children's Hospital Boston today it is a 300-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. It is also the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital visit: http://www.childrenshospital.org .