Beneficial effects of nitric oxide breathing in adult patients with sickle cell crisis

Abstract

In a cohort of children with sickle cell disease (SCD) and vaso-occlusive pain visits served through South Carolina's Medicaid system over a 6-year period (N 5 523), we compared the number of vaso-occlusive pain or acute chest syndrome (ACS)/pneumonia episodes, and outpatient or acute service costs in those treated or not treated with hydroxyurea (HU). HU may be an underused intervention for SCD in this practice setting, for a variety of reasons. Treatment with HU varied greatly, appears to have been administered to more severely ill children, but was associated with a reduction in vaso-occlusive pain episodes, hospitalizations, and total costs of care within the HU cohort during a 2-3 year period of active HU treatment. Those receiving care through specialized SCD clinics were less likely to have pain or acute care episodes (RR 5 0.79, P < 0.0001; RR 5 0.90, P 5 0.01). Compared with the non-HU cohort, the HU group evinced a significantly higher risk of experiencing vaso-occlusive pain episodes (RR 5 3.32, P < 0.0001) and ACS/pneumonia episodes (RR 5 2.66, P < 0.0001), and higher outpatient, inpatient/emergency, and total service costs (RR 5 1.85, 2.11, 2.10, and P < 0.0001, respectively) over time. HU is clinically effective in reducing pain episodes, hospitalizations, and total care costs, but those receiving it might be more severely ill.Erythrocytes in children with sickle cell disease (SCD) become deoxygenated, dehydrated, and crescent-shaped, and tend to aggregate or stick to blood vessel walls, blocking blood flow within limbs and organs, causing painful episodes. These patients are frequently seen in emergency departments and hospitalized for these severe pain episodes [1]. SCD poses an enormous personal burden to these young patients and is also costly to the family and third-party payer, especially for low-income children [2]. Interventions designed to control vaso-occlusive pain episodes, and avoid hospitalizations may reduce the significant personal and economic burdens of the disease [3,4].Hydroxyurea (HU), a myelosuppressive agent, which raises the levels of Hb F [5] and of hemoglobin [6][7][8], effectively decreases the rate of painful vaso-occlusive and acute chest syndrome (ACS) episodes by 50% in adults [9][10][11][12], and is generally safe and well-tolerated in children older than 5 years of age [13]. There is strong evidence that HU reduces the frequency of hospitalization in children with SCD and moderate evidence that it decreases the frequency of painful crises [14]. Given the short-term safety profile of HU in children and its established efficacy in adults, HU is commonly used, off-label, in children with multiple painful episodes (3 per year) to reduce episode frequency and acute services utilization [15][16][17], even in children as young as 9 months.Results from a multicenter study of HU in sickle-cell anemia demonstrated that adult patients treated with HU had a 44% decrease in hospitalizations compared with those taking placebo, which accounted for the majority of cost savings in ...

Pulmonary Complications of Sickle Cell Disease

“…Despite positive early small phase II trials (53,54), we observed no effect of inhaled NO therapy on the duration of pain crisis, narcotic use, pain scores, or the development of ACS (18).…”

Molecular mechanisms underlying synergistic adhesion of sickle red blood cells by hypoxia and low nitric oxide bioavailability

“…Our result showing a marked reduction in sRBC adhesion following NO breathing may be relevant to a physiological basis for the clinical improvements SCD patients experienced after NO inhalation during vaso-occlusive crisis 27 as well as to pain reduction. 28,29 Also, given that SCD patients with low NO metabolite levels experience higher levels of pain, 10 our results suggest that lower NO bioavailability increases the risk of vasoocclusive crisis under hypoxia. 26 Thus, the differences in the risk for cell adhesion might contribute to the clinical heterogeneity among SCD patients because sRBC adhesion is a crucial determinant for clinical severity.…”

“…NO inhalation for SCD patients under vaso-occlusive crisis reduced pain scores 28,29 ; however, another clinical trial was unable to reproduce the beneficial effects of NO inhalation. 34 Results from this study may suggest possible clues to the mechanisms underlying these conflicting results.…”

“…The role for p38 kinases in P-selectin expression was further confirmed by studies using siRNAs ( Figure 6C-D). It is possible that selective inhibitors of p38 kinases can be developed as sRBC adhesion inhibitors to treat SCD.NO inhalation for SCD patients under vaso-occlusive crisis reduced pain scores 28,29 ; however, another clinical trial was unable to reproduce the beneficial effects of NO inhalation. 34 Results from this study may suggest possible clues to the mechanisms underlying these conflicting results.…”

Nitric Oxide / Cyclic Nucleotide Regulation of Globin Genes in Erythropoiesis

“…The role of NO in erythrocyte function, sickle cell anemia, malaria, and damage to banked blood has been already reviewed, as well as the use of NO targeted therapies for erythrocyte disease (Maley et al, 2010). Pain from vaso-occlusive crisis is the major cause of hospitalization in patients with sickle cell disease, where beneficial therapeutic effects of inhaled NO have been demonstrated (Head et al, 2010). Decreased exhaled nitric oxide levels (FE NO ) have been described in patients with sickle cell disease, together with deficiency in plasma arginine.…”