Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Lormetazepam | Experimental | The patient is treated on ICU not longer than 2 days. Dosage requirements according to Summary of product characteristics (Sedalam®). |
|
| Midazolam | Active Comparator | The patient is treated on ICU not longer than 2 days. Dosage requirements according to Summary of product characteristics (Midazolam-ratiopharm®, Midazolam-hameln®). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lormetazepam | Drug |
| ||
| Midazolam |
| 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 |
| 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 |
Not provided
Inclusion Criteria:
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
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Claudia Spies, MD, Univ.- Prof. | Charite University, Berlin, Germany | Study Chair |
| Gernot Marx, MD, Univ.-Prof. | University RWTH Aachen | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinic for Anesthesiology, Intensive Care Medicine and Painmanagement, Johann-Wolfgang-Goethe-University | Frankfurt | Frankfurt Am Main | 60590 | Germany |
Not provided
| ID | Term |
|---|---|
| C023842 | lormetazepam |
| D008874 | Midazolam |
| ID | Term |
|---|---|
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
| 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 |
| Clinic for Operative Intensive Care Medicine and Intermediate Care, University of RWTH | Aachen | 52056 | Germany |
| Department of Anesthesiology and Intensive Care Medicine, Charité - University Medicine | Berlin | 13353 | Germany |
| D006571 | Heterocyclic Compounds |