Comparison of Lormetazepam and Midazolam Used as Sedatives for Patients That Require Intensive Care

A goal directed , demand-driven administration of sedative drugs is an integral part of every intensive care treatment. During long-term application of sedatives, Midazolam is the most commonly used sedative in Europe.

One major objective is the problem of oversedation and agitation during an intensive care treatment due to the lack of controllability of available substances.

The Love-Mi RCT investigates the clinical controllability of Midazolam versus the newly available intravenous drug Lormetazepam.

Study Overview

• Status: Completed
• Conditions: Sedation in Intensive Care Unit Patients
• Intervention / Treatment: Drug: Midazolam; Drug: Lormetazepam

Detailed Description

Midazolam is almost exclusively metabolized intrahepatically. The methyl-group at position 1 of the imidazole ring is oxidized by liver enzymes. The product is a-OH-midazolam. This reaction is catalyzed by a p450-dependent oxidase in the liver.

Active a-OH-midazolam is inactivated by a biotransformation type II reaction after conjugation. The water soluble, conjugated midazolam can be excreted by the kidney.

During an intensive care treatment, the p450 dependent metabolization is known to be a "bottleneck of elimination" as many drugs are inactivated by this pathway.

As the phase II (glucuronidation) is non-saturable in practice - the phase I reaction limits the metabolic capacity. This leads to unpredictable prolongation of midazolam effects.

In contrast, Lormetazepam is glucuronized directly at its OH-group during a phase II reaction. Since the glucuronidation is non-saturable, Lormetazepam is metabolized with nearly constant kinetics even if repeatedly administered.

Due to the pharmacokinetics we hypothesize that Lormetazepam has an improved controllability compared to midazolam. As this leads to less frequent agitation and over-sedation, we hypothesize that there are multiple beneficial clinical outcomes for patients treated with lormetazepam instead of midazolam.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany, 52056
    • Clinic for Operative Intensive Care Medicine and Intermediate Care, University of RWTH
  • Berlin, Germany, 13353
    • Department of Anesthesiology and Intensive Care Medicine, Charité - University Medicine
  • Frankfurt Am Main
    • Frankfurt, Frankfurt Am Main, Germany, 60590
      • Clinic for Anesthesiology, Intensive Care Medicine and Painmanagement, Johann-Wolfgang-Goethe-University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Mechanically ventilated ICU patients with the need for sedatives to achieve or maintain the intended target-RASS (surgical/ nonsurgical).
• Age ≥ 18 years
• Patients who are incapable of giving consent at study inclusion: Written informed consent by patient's legal representative or an independent medical consultant, patients give informed consent subsequent if they are capable.
• Patients who are able to give informed consent at study inclusion: Written informed consent by patients for planned postoperative prolonged ventilatory support who undergo heart surgery
• Consensable patients for inclusion: with necessary intubation with analgosedation

Exclusion Criteria:

• Any bolus administration of benzodiazepines until 72hrs before inclusion (except from premedication due to anaesthesia).
• Continuous administration of benzodiazepines within the last 7 days before start of study drug application
• Titration phase: No way that a target RASS between -3 and 0 can be determined by the attending physician
• Known drug intolerance or allergy against lormetazepam, midazolam or one of the additional components.
• Addictive disorder
• Increased intracranial pressure
• Acute intoxication with alcohol, analgesics, sedatives, antipsychotics (neuroleptics, anti-depressives, lithium).
• Patients with cerebrale Pathology, which changes the controllability of sedation or die consciousness (e.g. patients known mental retardation due to syndromatic disorders or an infantile brain damage)
• Patients with a suspected or secured hypoxic brain damage
• Patients with intracranial surgery during actual hospital care
• Tetraplegic patients
• Myasthenia Gravis
• Cerebellar or spinal Ataxia
• Moribund patients with an expected lifespan of less than 24 hours.
• Sickle cell anaemia
• Thallassemia
• Enzyme related disorders that are associated with a severe decreased activity of UDP-glucoronyltransferase (e.g. M. Crigler- Najjar)
• Chronic liver insufficiency CHILD C with MELD Score > 17 before access to intensive care unit
• Diagnosed propofol intolerance/anamnestic propofol infusion Syndrome
• Known depression/suicidality
• Pregnancy (positive beta-HCG test from urine or positive beta-HCG laboratory test from serum (in anuric patients the serum beta-HCG test is obliged) or lactation
• Woman of child-bearing potential who are not using a highly effective contraception (Pearl - Index <1) until 3 months after study inclusion and during this trial

• Referral following an order of official authorities (court order or administrative decision) according to German Drug Law (AMG)

  §40 (1) 4

• Participation in clinical trials according to the German Drug Law (AMG) 30 days to and during the study
• Local staff

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lormetazepam; The patient is treated on ICU not longer than 2 days. Dosage requirements according to Summary of product characteristics (Sedalam®).	Drug: Lormetazepam
Active Comparator: Midazolam; The patient is treated on ICU not longer than 2 days. Dosage requirements according to Summary of product characteristics (Midazolam-ratiopharm®, Midazolam-hameln®).	Drug: Midazolam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Controllability of sedation	Controllability of sedation is defined as the percentage share of measures where the actual depth of sedation (measured with the Richmond Agitation and Sedation Scale) (RASS)) matches the target depths of sedation. The individual sedation target is defined by the attending physician. . It will be measured until 5 days after terminationduring administration of study drug until 2 hours after its termination.	Up to 50 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SOFA (Sequential Organ Failure Assessment)		Up to 8 days
Pain-Scores	NRS-V (Numeric Rating Scale -V) and FPS-R (Faces Pain Scale-Revised) and BPS (Behavioral Pain Scale) and BPS-NI (Non-Intubated BPS) according to German consensus guidelines	Up to 28 days
Anxiety-Score	Faces Anxiety Scale score	Up to 28 days
Concurrent medication for Analgesia and Sedation	dose/time.	Up to 8 days
Delirium-screening-Instruments	CAM-ICU (Confusion Assessment Method for Intensive Care Unit) ICDSC ( Intensive Care Delirium Screening Checklist) Nu-DESC (Nursing Delirium Screening Scale)	Up to 28 days
Mortality		Up to 90 days
Duration of mechanical ventilation and weaning from mechanical ventilation		Up to 8 days
Length of intensive care unit stay		During intensive care unit stay, an average of 14 days
Length of hospital stay		During hospital stay, an average of 28 days
Follow-up treatment regarding Patient- Documentation-Management-System	Discharge Mode	During hospital stay, an average of 28 days
Length of sedation	During administration of study drug until 8 hours after its termination.	Up to 56 hours
Number of changes in target Richmond agitation sedation scale (RASS)	During administration of study drug	Up to 56 hours
Wake-up-time	During administration of study drug until 5 days after its termination	Up to 8 days
Deviation from target Richmond agitation sedation scale (RASS)	During administration of study drug	Up to 8 days
Quality of Life	Questionnaire designed to measure quality of life (EQ-5D-3L)	Up to 90 days
Cognition 1	Minimental State Examination (MMSE)	Up to 28 days
Cognition 2	Mehrfach-Wortschatz-Intelligenztest (MWT)	Up to 90 days
Posttraumatic stress disorder	The Post-Traumatic Stress Syndrome 14-Questions Inventory	Up to 90 days
Bedside measurement of Acetylcholinesterase activity (U/gHb)	The Acetylcholinesterase activity will be measured on every study day out of a blood sample (10µl); It will be measured until 5 days after termination of study drug.	Up to 8 days
Organ dysfunctions	It will be measured until 5 days after termination of study drug.	Up to 8 days
Depth of sedation 1	Depth of sedation is measured by Electroencephalography and Electromyography (only surgical patients in the Centers Charité and Gießen)	During the operation
Depth of sedation 2	Depth of sedation 2 is measured by Electroencephalography and Electromyography (intensive care unit patients only Center Charité)	Up to 3 days
Photomotor reflex	Photo motor reflex variations are measured by video pupillometry (only Center Charité)	Up to 8 days
Pain threshold measurement	Automatic measurement of specific pain reflexes	Up to 3 days
micro ribonucleic acid (rna)	micro rna panel is analysed (only Center Charité)	Up to 24 hours

Collaborators and Investigators

• Sponsor: Claudia Spies
• Investigators: Study Chair: Claudia Spies, MD, Univ.- Prof., Charite University, Berlin, Germany; Study Director: Gernot Marx, MD, Univ.-Prof., University RWTH Aachen

Study record dates

Study Major Dates

• Study Start (Actual): July 17, 2014
• Primary Completion (Actual): December 12, 2019
• Study Completion (Actual): March 12, 2020

Study Registration Dates

• First Submitted: December 12, 2013
• First Submitted That Met QC Criteria: December 23, 2013
• First Posted (Estimate): December 30, 2013

Study Record Updates

• Last Update Posted (Actual): April 13, 2022
• Last Update Submitted That Met QC Criteria: April 8, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Intensive care unit; Midazolam; Sedation management; Lormetazepam
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam; Lormetazepam
• Other Study ID Numbers: LoveMi