Nitric Oxide for Inhalation in the Acute Treatment of Sickle Cell Pain Crisis
A Randomized Controlled Trial
- Mark T. Gladwin, MD;
- Gregory J. Kato, MD;
- Debra Weiner, MD, PhD;
- Onyinye C. Onyekwere, MD, MS;
- Carlton Dampier, MD;
- Lewis Hsu, MD;
- R. Ward Hagar, MD;
- Thomas Howard, MD;
- Rachelle Nuss, MD;
- Maureen M. Okam, MD, MPH;
- Carole K. Tremonti, RN;
- Brian Berman, MD;
- Anthony Villella, MD;
- Lakshmanan Krishnamurti, MD;
- Sophie Lanzkron, MD;
- Oswaldo Castro, MD;
- Victor R. Gordeuk, MD;
- Wynona A. Coles, RRT;
- Marlene Peters-Lawrence, RN, RRT;
- James Nichols, RN;
- Mary K. Hall, CIP;
- Mariana Hildesheim, MS;
- William C. Blackwelder, PhD;
- James Baldassarre, MD;
- James F. Casella, MD
- for the DeNOVO Investigators
- Author Affiliations: Division of Pulmonary, Allergy, and Critical Care Medicine (Dr Gladwin and Ms Hildesheim) and Vascular Medicine Institute (Drs Gladwin and Krishnamurti), University of Pittsburgh, Pittsburgh, Pennsylvania; Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute (Dr Kato; Mss Coles, Peters-Lawrence, and Hildesheim; and Mr Nichols), and Critical Care Medicine Department, Clinical Center (Ms Hall and Dr Blackwelder), National Institutes of Health, Bethesda, Maryland; Division of Emergency Medicine, Children's Hospital Boston (Dr Weiner), and Brigham and Women's Hospital (Dr Okam and Ms Tremonti), Harvard Medical School, Boston, Massachusetts; Howard University Hospital, Washington, DC (Drs Onyekwere, Castro, and Gordeuk); Emory University School of Medicine, and Children's Healthcare of Atlanta, Atlanta, Georgia (Dr Dampier); Children's Hospital of Oakland, Oakland, California (Dr Hagar); Children's National Medical Center, Washington, DC (Dr Hsu); University of Alabama at Birmingham (Dr Howard); Pediatric Branch, Colorado Sickle Cell Treatment and Research Center, University of Colorado Health Science Center, Denver (Dr Nuss); Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio (Drs Berman and Villella); Division of Hematology and Oncology (Dr Lanzkron), and Division of Pediatric Hematology, Department of Pediatrics (Dr Casella), Johns Hopkins University School of Medicine, Baltimore, Maryland; and Department of Clinical Research, Ikaria, Clinton, New Jersey (Dr Baldassarre).
Abstract
Context 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.
Design, Setting, and Participants 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.
Main Outcome Measures 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.
Conclusion Among patients with SCD hospitalized with VOC, the use of inhaled nitric oxide compared with placebo did not improve time to crisis resolution.
Trial Registration clinicaltrials.gov Identifier: NCT00094887
