title: Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial.
abstract: BACKGROUND
  Inhaled nitric oxide has shown evidence of efficacy in mouse models of sickle cell disease (SCD), case series of patients with acute chest syndrome, and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis (VOC).
  
  
  OBJECTIVE
  To determine whether inhaled nitric oxide gas reduces the duration of painful crisis in patients with SCD who present to the emergency department or hospital for care.
  
  
  METHODS
  Prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled nitric oxide gas vs inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5, 2004, and December 22, 2008. Intervention Inhaled nitric oxide gas vs inhaled nitrogen placebo.
  
  
  METHODS
  The primary end point was the time to resolution of painful crisis, defined by (1) freedom from parenteral opioid use for 5 hours; (2) pain relief as assessed by visual analog pain scale scores of 6 cm or lower (on 0-10 scale); (3) ability to walk; and (4) patient's and family's decision, with physician consensus, that the remaining pain could be managed at home.
  
  
  RESULTS
  There was no significant change in the primary end point between the nitric oxide and placebo groups, with a median time to resolution of crisis of 73.0 hours (95% confidence interval [CI], 46.0-91.0) and 65.5 hours (95% CI, 48.1-84.0), respectively (P = .87). There were no significant differences in secondary outcome measures, including length of hospitalization, visual analog pain scale scores, cumulative opioid usage, and rate of acute chest syndrome. Inhaled nitric oxide was well tolerated, with no increase in serious adverse events. Increases in venous methemoglobin concentration confirmed adherence and randomization but did not exceed 5% in any study participant. Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite.
  
  
  CONCLUSIONS
  Among patients with SCD hospitalized with VOC, the use of inhaled nitric oxide compared with placebo did not improve time to crisis resolution.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00094887.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Vascular Medicine Institute, University of Pittsburgh, 3459 Fifth Ave, 628 NW, Pittsburgh, PA 15213. gladwinmt@upmc.edu
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kato
authors.forename: Debra
authors.initials: D
authors.lastname: Weiner
authors.forename: Onyinye C
authors.initials: OC
authors.lastname: Onyekwere
authors.forename: Carlton
authors.initials: C
authors.lastname: Dampier
authors.forename: Lewis
authors.initials: L
authors.lastname: Hsu
authors.forename: R Ward
authors.initials: RW
authors.lastname: Hagar
authors.forename: Thomas
authors.initials: T
authors.lastname: Howard
authors.forename: Rachelle
authors.initials: R
authors.lastname: Nuss
authors.forename: Maureen M
authors.initials: MM
authors.lastname: Okam
authors.forename: Carole K
authors.initials: CK
authors.lastname: Tremonti
authors.forename: Brian
authors.initials: B
authors.lastname: Berman
authors.forename: Anthony
authors.initials: A
authors.lastname: Villella
authors.forename: Lakshmanan
authors.initials: L
authors.lastname: Krishnamurti
authors.forename: Sophie
authors.initials: S
authors.lastname: Lanzkron
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Castro
authors.forename: Victor R
authors.initials: VR
authors.lastname: Gordeuk
authors.forename: Wynona A
authors.initials: WA
authors.lastname: Coles
authors.forename: Marlene
authors.initials: M
authors.lastname: Peters-Lawrence
authors.forename: James
authors.initials: J
authors.lastname: Nichols
authors.forename: Mary K
authors.initials: MK
authors.lastname: Hall
authors.forename: Mariana
authors.initials: M
authors.lastname: Hildesheim
authors.forename: William C
authors.initials: WC
authors.lastname: Blackwelder
authors.forename: James
authors.initials: J
authors.lastname: Baldassarre
authors.forename: James F
authors.initials: JF
authors.lastname: Casella
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000150:complications*; D004311:Double-Blind Method; D045462:Endothelium-Dependent Relaxing Factors / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D045462:Endothelium-Dependent Relaxing Factors; D009569:Nitric Oxide