Clinical trial NCT06473415: Electroencephalography and Sleep Quality With Lormetazepam in the Intensive Care Unit
Official title: Electroencephalography and Sleep Quality With Lormetazepam in the Intensive Care Unit
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Critical Illness
Delirium
Sleep Disorders, Circadian Rhythm
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
First posted: 2024-06-25
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: 50 male and female critically ill patients aged 18 years or older

Brief summary: The goal of this clinical trial is to test the effect of continuous lormetazepam infusion on EEG patterns in critically ill patients who are given continuous infusion of lormetazepam in an intensive care unit setting. The main questions it aims to answer are:

• How does the continuous infusion of lormetazepam affect EEG readings in terms of specific patterns related to sleep quality and sedation depth?

Participants will be asked to:

* Receive continuous infusion of lormetazepam, administered as per the guidelines and judgment of the on-duty ward physician.
* Undergo up to three EEG measurements over a period of 24 hours each using the X8 Sleep Profiler RTA device. These measurements will monitor brain activity and other related signals in order to assess the sedation depth and sleep quality.
* These EEG readings will be performed after at least two hours of initiation of continuous lormetazepam infusion, potentially at different stages of their ICU stay.

There is no direct comparison group in this study. However, after initial data from the first 15 patients is collected, an interim analysis will be performed. This will help researchers understand the ability to measure sleep quality and defined EEG parameters in this setup, and if necessary, adapt the study design or measurement procedures for better outcomes.

Detailed description: The misadjusted use of sedatives in critically ill patients, especially the state of deep sedation stages, is associated with an increased occurrence of delirium and increased hospital mortality. Drug sedation should be avoided according to current recommendations of care guidelines and should only be used in symptom-oriented therapy. However, the administration of drugs with a sedative effect profile remains necessary not only for patients for brain pressure therapy or positioning maneuvers in severe lung failure, but is often necessary to achieve a patient who is awake and at the same time stress-free. A variety of drugs from different substance classes are available for this. Given that a large proportion of intensive care patients develop an acute substantial disruption of the circadian rhythm, which very often goes hand in hand with pathological sleep and delirium, sedatives, which are often given continuously over a longer period, should support good sleep quality and the physiological sleep-wake rhythm. However, studies show that commonly used sedatives such as propofol worsen sleep quality. Especially for the group of benzodiazepines, there are indications from several studies that the application, even compared to α2-agonists such as dexmedetomidine, significantly favors the risk of delirium. Lormetazepam for intravenous use has only been approved for continuous use in intensive care patients for a few years. Initial studies document very good anxiolysis and the avoidance of over-sedation compared to midazolam. Currently, there are no published works that have systematically investigated the effects of continuous lormetazepam infusion on the EEG and sleep quality in intensive care patients. However, these data are necessary in order to take sleep quality and neuroprotection into account when selecting and dosing sedatives in the future and to avoid chronodisruption and cognitive damage. Studies from dementia research but also a few from intensive care medicine provide indications for potentially brain-protective EEG patterns, which promote the glymphatic clearance of the cerebrospinal fluid. This includes not only primarily sleep-associated characteristics such as Slow Wave Sleep (SWS) and spindle activity but also frontal gamma oscillations, which can have memory-consolidating effects. Corresponding patterns are to be investigated in this pilot study under continuous lormetazepam infusion. The study involves further investigations according to primary and secondary endpoints, including EEG measurements. These EEG measurements are already part of the current care guidelines, but have not yet been comprehensively implemented in the ICU. The objective is to use EEG measurements in the future for more precise monitoring of the sedation depth of critically ill patients. Implementing this in the study may potentially allow for more adequate sedation management by being able to immediately respond to specific EEG patterns (e.g., burst-suppression) with an adjustment of sedation.

Given the described data situation, this is initially an exploratory pilot study.

The main Hypothesis: Intensive care patients who receive a continuous lormetazepam infusion exhibit an electroencephalographically detectable REM portion of at least 20%.

The EEG measurements are carried out up to three times over 24 hours using the X8 Sleep Profiler RTA (Advanced Brain Monitoring). It is a single-channel EEG measuring device that captures up to five channels of electrophysiological signals with just three electrodes, a photoplethysmographic (PPG) signal, and detects noise as well as movement and position. The X8 system can record and store data in its internal memory. The Sleep Profiler RTA software offers a visual display of the recordings in near real-time.

The study plans to enroll 50 patients in a prospective pilot study at the Charité Mitte Campus 101i ICU ward. It will include ICU patients expected to require intensive treatment for 48 hours or longer and an expected continuous lormetazepam infusion of at least 24 hours. The indications and duration of intravenous lormetazepam therapy will be determined by the on-duty ward physician in accordance with the internal clinic standards. Episodic EEG measurements will be conducted. The patient screening takes place immediately after admission to the ICU and will be reevaluated every day for meeting inclusion criteria.

The EEG recordings will be made in periods of 24 hours and will start at least two hours after the initiation of the continuous lormetazepam infusion. An EEG-P is only considered complete if the measurement within the core measurement time was not interrupted.

Eligibility criteria: Inclusion Criteria:

* Patient capable of giving consent or additional legal guardian/authorized representative/spouse available for non-consenting patient in the intensive care unit
* An expected continuous lormetazepam therapy ≥ 24 hours
* Male and female patients aged ≥18 years
* Expected duration of intensive care treatment ≥ 48 hours
* Mechanical ventilation (invasive, NIV and/or nasal high-flow \> 6h)

Exclusion Criteria:

* Laboratory evidence of sedative/opiate intoxication
* Active alcohol abuse
* Brain surgery, cranial malformation
* History of sleep-related movement disorder (symptomatic restless legs syndrome)
* Allergy to electrode contact material
* History of severe cognitive impairment following a stroke
* Status post cardiopulmonary resuscitation requiring/undergoing therapeutic hypothermia
* Lack of consent for the pseudonymized disease data to be stored and passed on in the context of this clinical study
* Patient is housed in an institution on court or official order
* History of sleep-related breathing disorder
* Suspicion of hypoxic brain damage (including intracranial hemorrhages)
* Suspicion of increased intracranial pressure
* Existing power of attorney or patient's will, in which the patient fundamentally excludes participation in studies
* The patient's consent or that of the legal representative cannot be obtained in a timely manner
* Patients with a survival probability \< 24h
* Narcolepsy

Primary outcomes:
measure: REM portion (%) during nocturnal sleep
timeFrame: through study completion per patient, an average of 3 days
Secondary outcomes:
measure: Total sleep time attributed to stages N2, N3 or rapid eye movement (REM) sleep during the noctural period i.e., between the hours of 22:00 and 06:00
timeFrame: through study completion per patient, an average of 3 days
measure: Total minutes of all stages of sleep (including N1, AN3, NREM hypertonia) during the awake period i.e., between the hours of 06:00 and 22:00.
timeFrame: through study completion per patient, an average of 3 days
measure: Total and % time atypical N3 sleep (AN3) i.e. polymorphic delta or or sepsis associated encephalopathy
timeFrame: through study completion per patient, an average of 3 days
measure: Gamma oscillations
timeFrame: through study completion per patient, an average of 3 days
measure: Theta-Gamma Coupling
timeFrame: through study completion per patient, an average of 3 days
measure: Polymorphic Delta/Theta Ratio
timeFrame: through study completion per patient, an average of 3 days
measure: Slow Wave Sleep (SWS) Characteristics
timeFrame: through study completion per patient, an average of 3 days
measure: Pathological N3-Slow Wave Sleep Characteristics
timeFrame: through study completion per patient, an average of 3 days
measure: Sleep Spindle Characteristics
timeFrame: through study completion per patient, an average of 3 days
measure: Pseudo Spindle Characteristics supression and/or medications
timeFrame: through study completion per patient, an average of 3 days
measure: K-Complex Characteristics
timeFrame: through study completion per patient, an average of 3 days
measure: Burst-Suppression
timeFrame: through study completion per patient, an average of 3 days
measure: Total sleep time
timeFrame: through study completion per patient, an average of 3 days
measure: Sleep latency
timeFrame: through study completion per patient, an average of 3 days
measure: Nocturnal sleep efficiency (%)
timeFrame: through study completion per patient, an average of 3 days
measure: Eye movements during sleep
timeFrame: through study completion per patient, an average of 3 days
measure: REM latency
timeFrame: through study completion per patient, an average of 3 days
measure: REM-Sleep-Pressure-Index
timeFrame: through study completion per patient, an average of 3 days
measure: Delirium incidence in intensive care unit measured with the Confusion Assessment Method
timeFrame: through study completion per patient, an average of 3 days
measure: Delirium severity in intensive care unit measured with the Intensive Care Delirium Screening Checklist
timeFrame: through study completion per patient, an average of 3 days
measure: Sedation depth: Richmond Agitation Sedation Scale
timeFrame: through study completion per patient, an average of 3 days
measure: Analgesia level: Numeric Rating Scale Visualized (NRS-V) or Faces Pain Scale Revised (FAS-R) Behavioural Pain Scale (BPS) or Behavioural Pain Scale for non-intubated patients (BPS-NI)
timeFrame: through study completion per patient, an average of 3 days
measure: Total amount of intravenously administered opioids per ICU treatment day
timeFrame: through study completion per patient, an average of 3 days
measure: Total amount of administered neuroleptics per ICU treatment day
timeFrame: through study completion per patient, an average of 3 days
measure: Duration of invasive and non-invasive ventilation
timeFrame: through study completion per patient, an average of 3 days
measure: Intensive care duration at the center
timeFrame: through study completion, an average of 1 year
measure: Hospital treatment duration at the center
timeFrame: through study completion, an average of 1 year
measure: Sepsis/Septic Shock
timeFrame: through study completion per patient, an average of 3 days
measure: Sequential Organ Failure Assessment
timeFrame: through study completion per patient, an average of 3 days
measure: Simplified Acute Physiology Score
timeFrame: through study completion per patient, an average of 3 days
measure: Therapeutic Intervention Scoring System
timeFrame: through study completion per patient, an average of 3 days
measure: Acute Physiological And Chronic Health Evaluation
timeFrame: through study completion per patient, an average of 3 days
measure: Age
timeFrame: through study completion per patient, an average of 3 days
measure: Gender
timeFrame: through study completion per patient, an average of 3 days
measure: Fever
timeFrame: through study completion per patient, an average of 3 days
measure: Respiratory insufficiency/Asthma (yes/no)
timeFrame: through study completion per patient, an average of 3 days
measure: Cardiac arrest/Cardiac decompensation
timeFrame: through study completion per patient, an average of 3 days
measure: Pneumonia
timeFrame: through study completion per patient, an average of 3 days
measure: Urinary tract infection
timeFrame: through study completion per patient, an average of 3 days
measure: Exacerbated COPD
timeFrame: through study completion per patient, an average of 3 days
measure: Hypervolemia
timeFrame: through study completion per patient, an average of 3 days
measure: Meningitis
timeFrame: through study completion per patient, an average of 3 days
measure: Pancreatitis
timeFrame: through study completion per patient, an average of 3 days
measure: Cirrhosis
timeFrame: through study completion per patient, an average of 3 days
measure: Kidney insufficiency
timeFrame: through study completion per patient, an average of 3 days
measure: Thrombocytopenia
timeFrame: through study completion per patient, an average of 3 days
measure: Leukocytosis
timeFrame: through study completion per patient, an average of 3 days
measure: Leukopenia
timeFrame: through study completion per patient, an average of 3 days
measure: Hypotonia
timeFrame: through study completion per patient, an average of 3 days
measure: Death
timeFrame: through study completion per patient, an average of 3 days
Other outcomes:
Locations:
city: Berlin-Mitte
country: Germany
facility: Charité - Universitätsmedizin Berlin
state: Berlin
Study officials:
References: