Inhaled Nitric Oxide for Sickle Crisis?
Inhaled Nitric Oxide for Sickle Crisis?
ABSTRACT & COMMENTARY
Synopsis: In this combined in vitro and in vivo study, inhaled nitric oxide (NO) increased the oxygen affinity of sickle cell hemoglobin (hemoglobin S). Inhaled NO could thus represent an important new therapy for acute sickle crisis and other aspects of sickle cell disease.
Source: Head AC. J Clin Invest 1997;100:1193-1198.
This recent study examined the impact of no on red blood cells in vitro, and of inhaled NO on the blood of nine volunteers with hemoglobin S and three control volunteers with normal hemoglobin (A). None of the sickle hemoglobin patients were in acute pain crisis. Sickle hemoglobin is known to have an elevated P50, the partial pressure of oxygen at which 50% of hemoglobin is saturated with oxygen. The P50 value is inversely related to the hemoglobin affinity for oxygen.
In the in vitro arm of the study, the SS erythrocytes had an elevated P50, which, following a 15-minute exposure to 80 ppm NO gas, was reduced by an average of 15% (4.8 ± 1.7 mmHg). In contrast, P50 in the control erythrocytes did not change significantly. The change in the P50 of hemoglobin S lasted for two hours following exposure to NO.
In the in vitro portion of the study, nine patients were treated with 80 ppm inhaled NO for 45 minutes via a nonrebreathing circuit. P50 was again reduced, by an average of 4.6 ± 2.0 mmHg, in the sickle cell anemia patients, and this change was sustained for one hour in five of seven patients who were retested. No changes occured in the hemoglobin of the three normal volunteers. There were no clinically important changes in pH, methemoglobin concentration, or clinical variables.
COMMENT BY MARK T. GLADWIN, MD
Sickle cell anemia is an autosomal recessive disorder characterized by a single amino acid substitution (glutamic acid to valine) in the beta-subunit of the hemoglobin tetrameric protein. Upon deoxygenation, sickle cell hemoglobin (hemoglobin S) undergoes conformational changes that expose a hydrophobic region surrounding the valine moiety in the beta-subunit. Polymerization with other beta-globin moieties occurs with the formation of long polymer chains that ultimately distort the erythrocyte membrane (Bunn HB. N Engl J Med 1997;337:762-769). Sickle cell disease is the most common genetic disease affecting African Americans: approximately three out of 2000 African American children are homozygous for sickle cell disease (0.15%), and 8% have sickle cell trait (i.e., are heterozygous for hemoglobin S).
Acute pain crisis and acute chest syndrome (ACS) are common complications of sickle cell anemia. ACS accounts for 25% of premature deaths in patients with sickle cell disease (Vichinsky EP, et al. Blood 1997;89:1787-1792). The pathophysiology of adult ACS is complex and involves sludging in the pulmonary microvasculature secondary to sickled erythrocytes, infarction of the pulmonary parenchyma, bone marrow fatty embolization from infarcted bone, microvasculature thrombosis, macrovascular pulmonary embolism, and infection (Scully RE, et al. N Engl J Med 1997;337:1293-1301). These processes often occur in concert and may also result in hypoxia, fever, leukocytosis, and infiltrates on chest radiograph, and they often progress to acute respiratory distress syndrome (ARDS). Regional hypoxia likely contributes to further sickling of erythrocytes, because deoxygenated hemoglobin S undergoes conformational changes that promote polymerization and ultimately distort the erythrocyte membrane. Acute pain crises are the most common cause of hospitalization, especially for a large subset of sickle cell anemia patients, and are a major burden both to the affected individuals and to society.
Inhaled NO has been considered as a possible therapy for ACS and in anecdotal reports has been described to rapidly improve the hypoxemia and duration of ACS (Atz AM, Wessel DL. Anesthesiology 1997;87:988-990.) Improvement in regional ventilation/perfusion matching would potentially improve hemoglobin saturation and reduce sickling in the pulmonary vasculature, as well as in distal organs. The present study suggests that NO may have a favorable impact on SS hemoglobin at the molecular level as well.
Any potential clinical benefit to SS patients of increasing oxygen affinity remains to be clinically determined. In fact, should NO therapy downregulate endogenous NO production, patients could have rebound pain crises following withdrawal. At this stage, the "molecule of the decade" is still a small molecule in search of an adult clinical application.
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