Midazolam versus morphine in acute cardiogenic pulmonary oedema: results of a multicentre, open-label, randomized controlled trial

Eur J Heart Fail. 2022 Oct;24(10):1953-1962. doi: 10.1002/ejhf.2602. Epub 2022 Jul 16.


Aims: Benzodiazepines have been used as safe anxiolytic drugs for decades and some authors have suggested they could be an alternative for morphine for treating acute cardiogenic pulmonary oedema (ACPE). We compared the efficacy and safety of midazolam and morphine in patients with ACPE.

Methods and results: A randomized, multicentre, open-label, blinded endpoint clinical trial was performed in seven Spanish emergency departments (EDs). Patients >18 years old clinically diagnosed with ACPE and with dyspnoea and anxiety were randomized (1:1) at ED arrival to receive either intravenous midazolam or morphine. Efficacy was assessed by in-hospital all-cause mortality (primary endpoint). Safety was assessed through serious adverse event (SAE) reporting, and the composite endpoint included 30-day mortality and SAE. Analyses were made on an intention-to-treat basis. The trial was stopped early after a planned interim analysis by the safety monitoring committee. At that time, 111 patients had been randomized: 55 to midazolam and 56 to morphine. There were no significant differences in the primary endpoint (in-hospital mortality for midazolam vs. morphine 12.7% vs. 17.9%; risk ratio[RR] 0.71, 95% confidence interval [CI] 0.29-1.74; p = 0.60). SAE were less common with midazolam versus morphine (18.2% vs. 42.9%; RR 0.42, 95% CI 0.22-0.80; p = 0.007), as were the composite endpoint (23.6% vs. 44.6%; RR 0.53, 95% CI 0.30-0.92; p = 0.03).

Conclusion: Although the number of patients was too small to draw final conclusions and there were no significant differences in mortality between midazolam and morphine, a significantly higher rate of SAEs was found in the morphine group.

Keywords: Acute heart failure; Clinical trial; Midazolam; Morphine; Pulmonary eodema.

Publication types

  • Randomized Controlled Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Heart Failure* / drug therapy
  • Hospital Mortality
  • Humans
  • Midazolam / adverse effects
  • Midazolam / therapeutic use
  • Morphine / therapeutic use
  • Pulmonary Edema* / drug therapy
  • Pulmonary Edema* / etiology


  • Midazolam
  • Morphine