Inhaled nitric oxide to treat intermediate risk pulmonary embolism: A multicenter randomized controlled trial

Jeffrey A. Kline, Michael A. Puskarich, Alan E. Jones, Ronald A. Mastouri, Cassandra L. Hall, Anthony Perkins, Emily E. Gundert, Tim Lahm

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


OBJECTIVE: To test the hypothesis that adjunctive inhaled NO would improve RV function and viability in acute PE.

METHODS: This was a randomized, placebo-controlled, double blind trial conducted at four academic hospitals. Eligible patients had acute PE without systemic arterial hypotension but had RV dysfunction and a treatment plan of standard anticoagulation. Subjects received either oxygen plus 50 parts per million nitrogen (placebo) or oxygen plus 50 ppm NO for 24 h. The primary composite endpoint required a normal RV on echocardiography and a plasma troponin T concentration <14 pg/mL. The secondary endpoint required a blood brain natriuretic peptide concentration <90 pg/mL and a Borg dyspnea score ≤ 2. The sample size of N = 76 tested if 30% more patients treated with NO would achieve the primary endpoint with 80% power and alpha = 5%.

RESULTS: We randomized 78 patients and after two withdrawals, 38 were treated per protocol in each group. Patients were well matched for baseline conditions. At 24 h, 5/38 (13%) of patients treated with placebo and 9/38 (24%) of patients treated with NO reached the primary endpoint (P = 0.375). The secondary endpoint was reached in 34% with placebo and 13% of the NO (P = 0.11). In a pre-planned post-hoc analysis, we examined how many patients with RV hypokinesis or dilation at enrollment resolved these abnormalities; 29% more patients treated with NO resolved both abnormalities at 24 h (P = 0.010, Cochrane's Q test).

CONCLUSIONS: In patients with severe submassive PE, inhaled nitric oxide failed to increase the proportion of patients with a normal troponin and echocardiogram but increased the probability of eliminating RV hypokinesis and dilation on echocardiography.


Original languageEnglish (US)
Pages (from-to)60-68
Number of pages9
JournalNitric Oxide - Biology and Chemistry
StatePublished - Mar 1 2019

Bibliographical note

Funding Information:
The trial was sponsored by the National Institutes of Health ( UM1HL113203-01 ) and by an investigator initiated grant from Mallinckrodt Pharmaceuticals and Roche Diagnostics in 2015. The sponsors had no role in the protocol design, data analysis or manuscript writing.

Publisher Copyright:
© 2019 Elsevier Inc.


  • Brain natriuretic peptide
  • Echocardiography
  • Heart failure
  • Nitric oxide
  • Pulmonary embolism
  • Pulmonary hypertension
  • Randomized trial
  • Troponin
  • Double-Blind Method
  • Humans
  • Middle Aged
  • Administration, Inhalation
  • Male
  • Ventricular Dysfunction, Right/drug therapy
  • Pulmonary Embolism/drug therapy
  • Troponin T/metabolism
  • Nitric Oxide/administration & dosage
  • Adult
  • Female
  • Aged

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Randomized Controlled Trial
  • Multicenter Study
  • Journal Article
  • Research Support, N.I.H., Extramural


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