Details

Autor(en) / Beteiligte

• Quinn, Charles T.
• Stuart, Marie J.
• Kesler, Karen
• Ataga, Kenneth I.
• Wang, Winfred C.
• Styles, Lori
• Smith-Whitley, Kim
• Wun, Ted
• Krishnan, Suba
• Kuypers, Frans A.
• Setty, Yamaja
• Key, Nigel S.
• Rhee, Seungshin
• Buchanan, George R.

Titel

A Pilot Study of Tapered Oral Dexamethasone for the Acute Chest Syndrome of Sickle Cell Disease

Ist Teil von

• Blood, 2009-11, Vol.114 (22), p.1515-1515

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2009

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Abstract 1515 Poster Board I-538 Acute chest syndrome (ACS) is a common cause of morbidity and mortality for individuals with sickle cell disease (SCD). The treatment of ACS is mainly supportive. Prior studies have shown that intravenous pulse-dose corticosteroids, such as dexamethasone, can decrease the duration and morbidity of ACS. However, such treatment may also precipitate ‘rebound‘ episodes of vaso-occlusive pain in some individuals that might negate the overall benefit of corticosteroids. Tapered corticosteroid therapy might decrease the rebound effect while maintaining therapeutic benefit. Therefore, we designed a prospective study to begin to test this hypothesis and to assess biomarkers that might clarify the therapeutic and toxic mechanisms of corticosteroids in SCD, predict outcome, and guide therapy. We conducted a multi-center, placebo-controlled pilot study to test the feasibility and safety of high-dose oral dexamethasone followed by a taper for ACS. Children and adults with SCD and ACS of any severity were randomized to dexamethasone (0.3 mg/kg q12h x 2, 0.3 mg/kg q24h x 2, 0.2 mg/kg q24h x 2, 0.1 mg/kg q24h x2, then stop) or placebo to start within 24 hours of diagnosis. All subjects received standard, protocol-directed supportive care for ACS. We defined the duration of ACS using a novel, objective tool that assessed rate and effort of breathing, oxygen saturation in room air, thoracic pain, and use of supplemental oxygen and ventilatory support. The primary outcomes were the duration of ACS and the duration of hospitalization for ACS. We also measured a panel of biomarkers before, during and after therapy. Inflammatory biomarkers included high sensitivity C-reactive protein and secretory phospholipase A2 (sPLA2). White cell and endothelial activation markers included sVCAM-1, sICAM-1, vWF:Ag and vWF:RCoF, sE-selectin, sP-selectin, sL-selectin, nitric oxide metabolites (NO), and whole blood tissue factor. We used generalized linear mixed models controlling for age to test for differences between treatment groups. We enrolled 12 subjects (9 children, 3 adults; mean age 17.3 years, range 5 - 45) with homozygous sickle cell anemia at 4 centers and randomized 11 (1 drop-out) to either dexamethasone (N=5) or placebo (N=6). The objective ACS assessment tool was completed on all subjects without difficulty. In this pilot study, dexamethasone reduced the duration of hospitalization (41.5 vs 62.3 hrs; P=0.024), but not the duration of ACS (log of duration 2.4 vs 3.5 hrs; P=0.127), supplemental oxygen (17.5 vs 41.2 hrs; P=0.876), hypoxemia (13.8 vs 34.3 hrs; P=0.770), or total opioid usage in morphine equivalents (54.4 vs 68.8 mg; P=0.885). There were no statistically significant differences in adverse events between arms. However, 3 patients treated with dexamethasone had a painful event in the 2 weeks after hospital discharge (1 required re-hospitalization), compared to 1 patient in the placebo group (0 re-hospitalizations). No marked leukocytosis occurred in either treatment group, but the leukocyte count at 1-week follow-up had decreased less from baseline in the dexamethasone group compared to placebo (-17.7 vs -37.6%; P=0.028). The baseline sPLA2 concentration was 3 100 ng/mL in 4/5 and 4/6 patients in the dexamethasone and placebo arms. The white cell activation marker, sL-selectin was significantly decreased at 1-week follow-up in the dexamethasone group compared to placebo (573.8 ng/mL vs 742.8; change from baseline -121.2 vs 57.2; P<0.001). Patients who had rebound pain (N=4) had a significantly higher sL-selectin concentration after 24 hours of study drug (746.0 ng/mL vs 568.7, P=0.042). NO metabolites were significantly decreased after 24 and 48 hours of dexamethasone group compared to placebo (6.5 nMol/mL vs 9.1; change from baseline -2.7 vs 4.4; P=0.041). A multi-center, randomized trial of tapered oral dexamethasone is feasible. Our novel ACS assessment tool is also feasible and useful for objective clinical ratings of ACS. Dexamethasone shortened the duration of hospitalization for ACS in this pilot study. Rebound vaso-occlusive pain occurred in both treatment groups. The WBC activation marker sL-selectin appears to be a promising biomarker of ACS therapy and rebound vaso-occlusion. Our results justify a definitive study of tapered oral dexamethasone for ACS that incorporates objective assessment tools and biomarkers. Off Label Use: Dexamethasone is a corticosteroid agent. We test its use for acute chest syndrome in this study.