Research analysis: Midazolam vs. morphine

Research study: Gil V, Domínguez-Rodríguez A, Masip J, Peacock WF, Miró Ò. Morphine Use in the Treatment of Acute Cardiogenic Pulmonary Edema and Its Effects on Patient Outcome: A Systematic Review. Curr Heart Fail Rep. 2019 Aug;16(4):81-88. doi: 10.1007/s11897-019-00427-0. PMID: 31183779.

The population. 111 patients over the age of 18 who presented to one of seven Spanish emergency departments with a diagnosis of acute cardiogenic pulmonary edema (ACPE), dyspnea and anxiety were randomly assigned (1:1) to the intervention group or the comparator group.

The intervention. The experimental group (55 patients) received midazolam 1mg IV, repeated as required to a maximum of 3 mg

The comparator. The control group (56 patients) received morphine 2-4 mg IV, repeated as required to a maximum of 8 mg

The outcome. The purpose was to compare the safety and effectiveness of both head to head. The primary outcomes were:

1. 30 day in-hospital mortality
2. Serious adverse events (SAE)
3. A composite of 30-day mortality and SAE

Memorable quotes

“To the best of our knowledge, this is the first clinical trial to evaluate the clinical outcomes of morphine in patients with ACPE.”

“There was no significant differences in mortality between morphine and midazolam but the rate of serious adverse events was significantly higher in the morphine group, although the number of patients was too small to draw final conclusions.”

“The first minutes of therapy in very sick ACPE patients can be associated with SAEs.”

“Early administration of oxygen supplementation, intravenous diuretics, and intravenous nitroglycerine may relieve symptoms immediately, without the need for any sedative or analgesic agent.”

Results*

1. In-hospital mortality had no significant difference between midazolam versus morphine
   (12.7% vs 17.9%; risk ratio [RR] 0.71, 95% confidence interval [CI] 0.29-1.74, p = 0.60)
2. SAE were more common in morphine versus midazolam
   (42.9% vs 18.2%, RR 0.42, 95% CI 0.22-0.80; p = 0.0007)
3. Composite endpoint favoured midazolam versus morphine
   (23.6% vs 44.6%; RR 0.53, 95% 0.30-0.92; p = 0.03)

*The study was stopped early as a result of safety concerns.

Discussion

Morphine has a long history of use in the acute management of ACPE. Conceptually, it helps to reduce preload, anxiety and dyspnea. The researchers identified two concerns:

1. First, a trend in the literature that suggests an increase in both SAE and possibly mortality with the use of morphine.
2. Second, the lack of evidence support morphine in ACPE. Midazolam, with its anxiolytic ability and reliable safety profile, was felt to be a more ethical choice than placebo to form the second arm of the trial.

Interpreting the study is complicated by a number of factors. The study protocol was published before the trial, but changes were made during the study to address difficulty in recruitment, including eliminating a number of participating hospitals [2]. The study design was open label; meaning the individual clinicians could have been influenced by knowing which drug the patient received. The most significant impact on the validity of the findings is that the study was stopped early. Safety monitoring found statistically significant higher numbers of serious adverse events in the morphine arm. These events were predominantly cardiovascular, including atrial fibrillation, acute coronary syndromes, shock and deaths.

The study is important for a number of reasons. It represents the first prospective attempt to evaluate morphine use in ACPE. This makes the finding more valuable than previous research, which was comprised of retrospective studies and sub-group analysis. It clearly demonstrates the relationship between morphine and SAE, providing new information suggesting that these events are more likely to be cardiovascular, not respiratory as was previously assumed. Concerned that the adverse events could be related to cardiac function, the researchers published further analysis that demonstrated no relationship between atrial fibrillation or impaired left function and the risk of SAE [4,5].

This provides a compelling argument for further study to address issues surrounding blinding, dose equivalency, placebo control and number of participants.

Midazolam vs. morphine takeaways

There are numerous potentials for bias within the study; the results must be interpreted with these in mind. This study alone should not be considered practice changing.

There is a growing body of evidence that morphine in ACPE may increase morbidity and mortality. In the prehospital environment, routine treatment for ACPE, such as diuretics and nitrates should be maximized, and the risk of increased adverse events and death should be weighed, before considering morphine.

References

1. Domínguez-Rodríguez A, Suero-Mendez C, Burillo-Putze G, Gil V, Calvo-Rodriguez R, Piñera-Salmeron P, Llorens P, Martín-Sánchez FJ, Abreu-Gonzalez P, Miró Ò; MIMO (MIdazolam versus MOrphine) Trial Investigators. 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. PMID: 35780488.
2. Dominguez-Rodriguez A, Burillo-Putze G, Garcia-Saiz MDM, Aldea-Perona A, Harmand MG, Mirò O, Abreu-Gonzalez P; MIMO investigators. Study Design and Rationale of “A Multicenter, Open-Labeled, Randomized Controlled Trial Comparing MIdazolam Versus MOrphine in Acute Pulmonary Edema": MIMO Trial. Cardiovasc Drugs Ther. 2017 Apr;31(2):209-213. doi: 10.1007/s10557-017-6722-5. PMID: 28265880
3. Gil V, Domínguez-Rodríguez A, Masip J, Peacock WF, Miró Ò. Morphine Use in the Treatment of Acute Cardiogenic Pulmonary Edema and Its Effects on Patient Outcome: A Systematic Review. Curr Heart Fail Rep. 2019 Aug;16(4):81-88. doi: 10.1007/s11897-019-00427-0. PMID: 31183779.
4. Domínguez-Rodríguez A, Hernandez-Vaquero D, Suero-Mendez C, Burillo-Putze G, Gil V, Calvo-Rodriguez R, Piñera-Salmeron P, Llorens P, Martín-Sánchez FJ, Abreu-Gonzalez P, Miró Ò; MIMO (MIdazolam versus MOrphine) Trial Investigators. Midazolam versus morphine in acute cardiogenic pulmonary edema patients with and without atrial fibrillation: findings from the MIMO trial. Eur J Emerg Med. 2023 Apr 1;30(2):78-84. doi: 10.1097/MEJ.0000000000001005. Epub 2023 Jan 20. PMID: 36727880.
5. Domínguez-Rodríguez A, Hernández-Vaquero D, Suero-Méndez C, Burillo-Putze G, Gil V, Calvo-Rodríguez R, Piñera-Salmerón P, Llorens P, Martín-Sánchez FJ, Abreu-González P, Formica F, Miró Ò; Grupo de Investigadores MIMO (MIdazolam versus MOrfina). Effects of midazolam vs morphine in patients with acute pulmonary edema with left ventricular systolic dysfunction: a secondary analysis of data from the MIMO trial. Emergencias. 2023 Feb;35(1):25-30. English, Spanish. PMID: 36756913.