Examine patients carefully, especially those with fever, chest or back pain, and abdominal pain or distension; an accurate respiratory rate is simple and critical. A CBC with reticulocyte count is required. It often shows a significant drop in hemoglobin value from baseline, a decrease in platelet count, and an elevated number of nucleated RBCs. Other tests include arterial blood gases; an arterial-alveolar gradient measured in room air greater than 30 mm Hg suggests risk for a more severe clinical course, and it must be remembered that a normal Pco2 in a patient with respiratory distress is ominous and may indicate impending respiratory failure. Chest radiograph may initially be normal or involve one or several lobes and rapidly progress to “white-out” of one or both lungs. Pleural effusions may be present. As radiologic findings may lag behind clinical findings, treatment should precede confirmatory radiograph in children with symptoms and signs of ACS. A specimen for type and screening should be sent to the blood bank with the alert that the patient has SCD. Many blood banks will have a complete red cell phenotype on file to extend the compatibility profile; at a minimum, patients should receive red cells compatible with types C, E, and Kell (historically the most antigenic in sickle cell populations). Because most Rh (D)–negative Caucasian donors are C and E negative as well, if the need for blood is urgent Rh- and Kell-negative units can generally be released promptly and safely. Preserve hydration by offering maintenance fluids or less with close monitoring of intake and output (avoid pulmonary edema–induced worsening of ACS). Careful choice and dosing of analgesic therapy is needed to prevent hypoventilation secondary to splinting and/or sedation/respiratory depression (hypoventilation may lead to atelectasis and hypoxemia); ketorolac use may be desirable in older patients. Incentive spirometry, as prescribed for pain, should be offered, especially if a prolonged stay in the ED is anticipated. All patients with ACS should receive macrolide therapy to cover possible atypical bacteria. Though bacteria, including S pneumoniae, are uncommon pathogens, younger patients (especially nonimmunized) with high fever, high white cell count, or a toxic appearance may also be given antipneumococcal therapy pending culture results. Simple transfusion with packed RBCs is often given for a moderate to severe episode, especially when associated with a drop in hemoglobin concentration. Unless a prolonged stay in the ED is required and a patient is clinically distressed, transfusion should best be administered in the inpatient area. Simple transfusion rather than exchange should be the front-line therapy unless a patient is less anemic than average (ie, Hb > 9 g/dL) and thus cannot safely be given a simple transfusion because of viscosity concerns (posttransfusion Hb should never exceed 11 g/dL in an acutely ill, urgently transfused patient). Activation of various cytokines and upregulation of adhesion molecules are particular manifestations of an often robust and sometimes deleterious inflammatory response. Use of dexamethasone (given every 12 hours for four doses) attenuates the course of ACS but appears to be associated with a high readmission rate for pain shortly after recovery from ACS. An “asthma regimen” of prednisone for 5 to 7 days may be less associated with readmission and perhaps efficacious in reducing the need for transfusion; however, this regimen has not been assessed prospectively and should NOT be initiated in the ED. Because of its variable and often severe clinical course, all patients with ACS should be hospitalized, preferably in an ICU or well-observed bed with oxygen therapy and continuous cardiac and pulse oximetry monitoring. A pediatric hematologist should be consulted for management of a patient with ACS and in decisions about antibiotic coverage, transfusion, and steroid therapy. All patients who experience even a single episode of ACS should be made aware of the role of hydroxyurea therapy in potentially reducing the risk of recurrent ACS and other sickle cell complications.