Evaluation of Opioid Consumption with Nociceptive Monitoring in Neurocritical Patients Undergoing Deep Sedation with Propofol, Isoflurane, and Dobutamine Hydrochloride

The primary objective of this study is to evaluate the **consumption** of intravenous opioids in neurocritical patients indicated for deep sedation. This evaluation will compare patients monitored with objective nociceptive monitoring (NOL) versus those without such monitoring, as well as those with inhaled sedation versus intravenous sedation. This is clinically relevant as it aims to optimize opioid usage, potentially reducing adverse effects and improving patient outcomes in the intensive care unit.

Secondary objectives include:

• Recording the required doses of intravenous opioids for each patient, both monitored and unmonitored with NOL, over a 72-hour period while they are under deep sedation and muscle relaxation.
• Recording episodes of withdrawal upon opioid discontinuation.
• Recording other adverse effects resulting from opioid use.
• Evaluating the application of multimodal analgesia and adjuvants, recording their dosage and duration.

The clinical trial involves **neurocritical patients** who are indicated for deep sedation and require neuromuscular relaxation. The study population includes both male and female participants aged 18 years and older. Participants are expected to have an ICU stay of at least 72 hours. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Key lifestyle considerations such as diet and physical activity are not specified. Participants were selected based on their medical need for deep sedation and neuromuscular relaxation, with conditions such as ARDS, increased intracranial pressure, and status epilepticus being relevant. The use of neuromuscular blocking agents like cisatracurium and rocuronium is monitored to prevent overdosing. Signed informed consent is required from the patient, family member, or legal representative.

The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the consumption of intravenous opioids in patients indicated for deep sedation in the intensive care unit (ICU). The trial will compare the use of neuromuscular relaxants with inhaled sedation monitored with nociception level (NOL) versus without objective nociception monitoring, as well as intravenous sedation with and without NOL monitoring. The study will involve **neurocritical patients** and aims to assess sedation variables, including respiratory, hemodynamic, neuromonitoring, and infectious status variables. The trial is expected to commence on May 5, 2025, and conclude by May 3, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥ 18 years), indication for deep sedation (RASS < -4), need for neuromuscular relaxation, and an expected ICU stay of at least 72 hours. Informed consent must be obtained from the patient, family member, or legal representative. Follow-up visits will be scheduled to monitor sedation variables and adverse effects, including time to awakening, presence or absence of delirium, ICU and hospital length of stay, and mortality rates. The end-of-study visit will occur upon completion of the treatment period or if the participant meets any conditions for early termination, such as withdrawal of consent or adverse events compromising safety.

The expected length of participant involvement is approximately 72 hours, aligning with the minimum ICU stay requirement. Conditions that may lead to early termination from the study include significant adverse effects, withdrawal of consent, or any clinical judgment deeming continued participation unsafe. The trial will utilize **dobutamine hydrochloride**, **isoflurane**, and **propofol** as part of the sedation regimen, with administration routes including intravenous and inhalation. The study is categorized as a Phase IV clinical trial, with a focus on low intervention, ensuring the safety and efficacy of sedation practices in the ICU setting.

The clinical trial involves the administration of **Midazolam**, a pharmaceutical product with the active substance **dobutamine hydrochloride**. This medication is provided in the form of a solution suitable for **intravenous administration**. The dosage is calculated based on the patient's weight, with a maximum daily dose of 0.25 mg/kg/h. The treatment period is limited to a maximum of one day. The administration of Midazolam is monitored to ensure compliance with the dosing schedule.

**Isoflurane** is used as a comparator treatment in this study. It is an inhalation anesthetic with the active substance **isoflurane**. The maximum daily dose is set at 15 units, with the treatment period also restricted to one day. The administration of Isoflurane is conducted via inhalation, and participant compliance is monitored throughout the trial.

**Propofol** is another test medication used in the trial, containing the active substance **propofol**. It is administered intravenously, with a maximum daily dose of 4.5 mg/kg/h. Similar to the other treatments, the administration period is limited to one day. Compliance with the dosing schedule is closely monitored to ensure the accuracy and safety of the treatment.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on sedation variables, including respiratory, hemodynamic, neuromonitoring, and infectious status variables. These parameters will be systematically measured and collected to evaluate the effectiveness of the sedation protocols being tested.

Secondary endpoints will include the observation of adverse effects throughout the study. Specific parameters to be assessed are the time to awakening and the presence or absence of **delirium** during the patient's awakening process. Additionally, the length of stay in the Intensive Care Unit (ICU) and the hospital, as well as ICU and hospital mortality rates, will be evaluated. The study will also monitor for opioid abstinence symptoms.

The trial aims to evaluate the consumption of intravenous opioids in patients indicated for deep sedation, comparing different sedation and monitoring strategies. The study will involve patients who require deep sedation and neuromuscular relaxation, with the use of neuromuscular blocking agents (NMBAs) being monitored to prevent overdosing. The efficacy assessments will be conducted in a structured manner, ensuring that all relevant data is accurately captured and analyzed to determine the outcomes of the trial.