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. 2021 Sep 10;10(18):4091.
doi: 10.3390/jcm10184091.

Outcomes in Critically Ill Patients Sedated with Intravenous Lormetazepam or Midazolam: A Retrospective Cohort Study

Björn Weiss  1 , David Hilfrich  1 , Gerald Vorderwülbecke  1 , Maria Heinrich  1   2 , Julius J Grunow  1   2 , Nicolas Paul  1 , Jochen Kruppa  3 , Bruno Neuner  1 , Berthold Drexler  4 , Felix Balzer  3 , Claudia D Spies  1
Affiliations

Outcomes in Critically Ill Patients Sedated with Intravenous Lormetazepam or Midazolam: A Retrospective Cohort Study

Björn Weiss et al. J Clin Med. .

Abstract

The benzodiazepine, midazolam, is one of the most frequently used sedatives in intensive care medicine, but it has an unfavorable pharmacokinetic profile when continuously applied. As a consequence, patients are frequently prolonged and more deeply sedated than intended. Due to its distinct pharmacological features, including a cytochrome P450-independent metabolization, intravenous lormetazepam might be clinically advantageous compared to midazolam. In this retrospective cohort study, we compared patients who received either intravenous lormetazepam or midazolam with respect to their survival and sedation characteristics. The cohort included 3314 mechanically ventilated, critically ill patients that received one of the two drugs in a tertiary medical center in Germany between 2006 and 2018. A Cox proportional hazards model with mortality as outcome and APACHE II, age, gender, and admission mode as covariates revealed a hazard ratio of 1.75 [95% CI 1.46-2.09; p < 0.001] for in-hospital mortality associated with the use of midazolam. After additionally adjusting for sedation intensity, the HR became 1.04 [95% CI 0.83-1.31; p = 0.97]. Thus, we concluded that excessive sedation occurs more frequently in critically ill patients treated with midazolam than in patients treated with lormetazepam. These findings require further investigation in prospective trials to assess if lormetazepam, due to its ability to maintain light sedation, might be favorable over other benzodiazepines for sedation in the ICU.

Keywords: benzodiazepines; intensive care; lormetazepam; midazolam; mortality; sedation; sedation index; survival.

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Conflict of interest statement

BW reports personal fees from Orion Pharma outside the submitted work. DH, GV, MH, JJG, NP, JK, BN, BD, FB declare no conflicts of interest. CDS reports unrestricted research and educational Grant support from Dr. F. Köhler Chemie GmbH in support for studies with lormetazepam. Outside the submitted work, CDS reports grants from Drägerwerk AG & Co. KGaA, grants from Deutsche Forschungsgemeinschaft/German Research Society, grants from Deutsches Zentrum für Luft- und Raumfahrt e. V. (DLR)/German Aerospace Center, grants from Einstein Stiftung Berlin/ Einstein Foundation Berlin, grants from Gemeinsamer Bundesausschuss/Federal Joint Committee (G-BA), grants from Inneruniversitäre Forschungsförderung/Inner University Grants, grants from Projektträger im DLR/Project Management Agency, grants from Stifterverband/Non-Profit Society for Promoting Science and Education, grants from WHOCC, grants from Baxter Deutschland GmbH, grants from Cytosorbents Europe GmbH, grants from Edwards Lifesciences Germany GmbH, grants from Fresenius Medical Care, grants from Grünenthal GmbH, grants from Masimo Europe Ltd., grants from Pfizer Pharma PFE GmbH, personal fees from Georg Thieme Verlag, grants from Sintetica GmbH, grants from Stifterverband für die deutsche Wissenschaft e.V./Philips grants from Stiftung Charité, grants from AGUETTANT Deutschland GmbH, grants from AbbVie Deutschland GmbH & Co. KG, grants from Amomed Pharma GmbH, grants from InTouch Health, grants from Copra System GmbH, grants from Correvio GmbH, grants from Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., grants from Deutsche Gesellschaft für Anästhesiologie & Intensivmedizin (DGAI), grants from Stifterverband für die deutsche Wissenschaft e.V./Metronic, grants from Philips Electronics Nederland BV, grants from BMG, grants from BMBF, grants from Deutsche Forschungsgemeinschaft/German Research Society. In addition, CDS has a patent 10 2014 215 211.9 licensed, a patent 10 2018 114 364.8 licensed, a patent 10 2018 110 275.5 licensed, a patent 50 2015 010 534.8 licensed, a patent 50 2015 010 347.7 licensed, and a patent 10 2014 215 212.7 licensed outside the submitted work.

Figures

Figure 1
Figure 1
Inclusion and exclusion diagram.
Figure 2
Figure 2
Kaplan–Meier curves of (A) the midazolam and lormetazepam groups, and (B) the midazolam and lormetazepam groups, stratified by sedation depth. Survival probability between groups was compared using the log-rank test. Cum. survival, cumulative survival; ICU, intensive care unit.
See this image and copyright information in PMC

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