Clinical trial NCT02022592: Comparison of Lormetazepam and Midazolam Used as Sedatives for Patients That Require Intensive Care
Official title: Comparison of Lormetazepam and Midazolam Used as Sedatives for Patients That Require Intensive Care
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Sedation in Intensive Care Unit Patients
Keywords: Sedation management
Midazolam
Lormetazepam
Intensive care unit
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
First posted: 2013-12-30
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Controllability of sedation
timeFrame: Up to 50 hours
Secondary outcomes:
measure: SOFA (Sequential Organ Failure Assessment)
timeFrame: Up to 8 days
measure: Pain-Scores
timeFrame: Up to 28 days
measure: Anxiety-Score
timeFrame: Up to 28 days
measure: Concurrent medication for Analgesia and Sedation
timeFrame: Up to 8 days
measure: Delirium-screening-Instruments
timeFrame: Up to 28 days
measure: Mortality
timeFrame: Up to 90 days
measure: Duration of mechanical ventilation and weaning from mechanical ventilation
timeFrame: Up to 8 days
measure: Length of intensive care unit stay
timeFrame: During intensive care unit stay, an average of 14 days
measure: Length of hospital stay
timeFrame: During hospital stay, an average of 28 days
measure: Follow-up treatment regarding Patient- Documentation-Management-System
timeFrame: During hospital stay, an average of 28 days
measure: Length of sedation
timeFrame: Up to 56 hours
measure: Number of changes in target Richmond agitation sedation scale (RASS)
timeFrame: Up to 56 hours
measure: Wake-up-time
timeFrame: Up to 8 days
measure: Deviation from target Richmond agitation sedation scale (RASS)
timeFrame: Up to 8 days
measure: Quality of Life
timeFrame: Up to 90 days
measure: Cognition 1
timeFrame: Up to 28 days
measure: Cognition 2
timeFrame: Up to 90 days
measure: Posttraumatic stress disorder
timeFrame: Up to 90 days
measure: Bedside measurement of Acetylcholinesterase activity (U/gHb)
timeFrame: Up to 8 days
measure: Organ dysfunctions
timeFrame: Up to 8 days
measure: Depth of sedation 1
timeFrame: During the operation
measure: Depth of sedation 2
timeFrame: Up to 3 days
measure: Photomotor reflex
timeFrame: Up to 8 days
measure: Pain threshold measurement
timeFrame: Up to 3 days
measure: micro ribonucleic acid (rna)
timeFrame: Up to 24 hours
Other outcomes:
Locations:
city: Frankfurt
country: Germany
facility: Clinic for Anesthesiology, Intensive Care Medicine and Painmanagement, Johann-Wolfgang-Goethe-University
state: Frankfurt Am Main
city: Aachen
country: Germany
facility: Clinic for Operative Intensive Care Medicine and Intermediate Care, University of RWTH
city: Berlin
country: Germany
facility: Department of Anesthesiology and Intensive Care Medicine, Charité - University Medicine
Study officials:
affiliation: Charite University, Berlin, Germany
name: Claudia Spies, MD, Univ.- Prof.
role: STUDY_CHAIR
affiliation: University RWTH Aachen
name: Gernot Marx, MD, Univ.-Prof.
role: STUDY_DIRECTOR
References: