Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis

A randomized controlled trial

Mark T. Gladwin, Gregory J. Kato, Debra Weiner, Onyinye C. Onyekwere, Carlton Dampier, Lewis Hsu, R. Ward Hagar, Thomas Howard, Rachelle Nuss, Maureen M. Okam, Carole K. Tremonti, Brian Berman, Anthony Villella, Lakshmanan Krishnamurti, Sophie Lanzkron, Oswaldo Castro, Victor R. Gordeuk, Wynona A. Coles, Marlene Peters-Lawrence, James Nichols & 5 others Mary K. Hall, Mariana Hildesheim, William C. Blackwelder, James Baldassarre, James F Casella

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)893-902
Number of pages10
JournalJournal of the American Medical Association
Volume305
Issue number9
DOIs
StatePublished - Mar 2 2011

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Inhalation
Nitric Oxide
Randomized Controlled Trials
Pain
Placebos
Sickle Cell Anemia
Acute Chest Syndrome
Gases
Pain Measurement
Opioid Analgesics
Therapeutics
Nitrogen
Outcome Assessment (Health Care)
Confidence Intervals
Methemoglobin
Aptitude
Random Allocation
Nitrites
Nitrates
Hospital Emergency Service

ASJC Scopus subject areas

  • Medicine(all)

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Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis : A randomized controlled trial. / Gladwin, Mark T.; Kato, Gregory J.; Weiner, Debra; Onyekwere, Onyinye C.; Dampier, Carlton; Hsu, Lewis; Hagar, R. Ward; Howard, Thomas; Nuss, Rachelle; Okam, Maureen M.; Tremonti, Carole K.; Berman, Brian; Villella, Anthony; Krishnamurti, Lakshmanan; Lanzkron, Sophie; Castro, Oswaldo; Gordeuk, Victor R.; Coles, Wynona A.; Peters-Lawrence, Marlene; Nichols, James; Hall, Mary K.; Hildesheim, Mariana; Blackwelder, William C.; Baldassarre, James; Casella, James F.

In: Journal of the American Medical Association, Vol. 305, No. 9, 02.03.2011, p. 893-902.

Research output: Contribution to journalArticle

Gladwin, MT, Kato, GJ, Weiner, D, Onyekwere, OC, Dampier, C, Hsu, L, Hagar, RW, Howard, T, Nuss, R, Okam, MM, Tremonti, CK, Berman, B, Villella, A, Krishnamurti, L, Lanzkron, S, Castro, O, Gordeuk, VR, Coles, WA, Peters-Lawrence, M, Nichols, J, Hall, MK, Hildesheim, M, Blackwelder, WC, Baldassarre, J & Casella, JF 2011, 'Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: A randomized controlled trial', Journal of the American Medical Association, vol. 305, no. 9, pp. 893-902. https://doi.org/10.1001/jama.2011.235
Gladwin, Mark T. ; Kato, Gregory J. ; Weiner, Debra ; Onyekwere, Onyinye C. ; Dampier, Carlton ; Hsu, Lewis ; Hagar, R. Ward ; Howard, Thomas ; Nuss, Rachelle ; Okam, Maureen M. ; Tremonti, Carole K. ; Berman, Brian ; Villella, Anthony ; Krishnamurti, Lakshmanan ; Lanzkron, Sophie ; Castro, Oswaldo ; Gordeuk, Victor R. ; Coles, Wynona A. ; Peters-Lawrence, Marlene ; Nichols, James ; Hall, Mary K. ; Hildesheim, Mariana ; Blackwelder, William C. ; Baldassarre, James ; Casella, James F. / Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis : A randomized controlled trial. In: Journal of the American Medical Association. 2011 ; Vol. 305, No. 9. pp. 893-902.
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T1 - Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis

T2 - A randomized controlled trial

AU - Gladwin, Mark T.

AU - Kato, Gregory J.

AU - Weiner, Debra

AU - Onyekwere, Onyinye C.

AU - Dampier, Carlton

AU - Hsu, Lewis

AU - Hagar, R. Ward

AU - Howard, Thomas

AU - Nuss, Rachelle

AU - Okam, Maureen M.

AU - Tremonti, Carole K.

AU - Berman, Brian

AU - Villella, Anthony

AU - Krishnamurti, Lakshmanan

AU - Lanzkron, Sophie

AU - Castro, Oswaldo

AU - Gordeuk, Victor R.

AU - Coles, Wynona A.

AU - Peters-Lawrence, Marlene

AU - Nichols, James

AU - Hall, Mary K.

AU - Hildesheim, Mariana

AU - Blackwelder, William C.

AU - Baldassarre, James

AU - Casella, James F

PY - 2011/3/2

Y1 - 2011/3/2

N2 - 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.

AB - 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.

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