Evaluation of Isoflurane Inhalation Sedation Versus Intravenous Propofol and Midazolam in Neurocritical Care Patients

The primary objective of this study is to evaluate the **efficacy** and safety of using inhalation sedation with **isoflurane** in neurocritical patients compared to conventional intravenous sedation. This is clinically relevant as it may offer an alternative sedation method that could improve patient outcomes in neurocritical care settings. Additionally, the study aims to assess the effectiveness of NOL monitoring as a tool to evaluate the analgesic status of deeply sedated patients, which could enhance pain management strategies in this patient population.

Secondary objectives include:

• Recording the doses required for achieving deep sedation with both intravenous sedation and isoflurane.
• Monitoring respiratory and hemodynamic parameters, as well as the need for vasoactive support before and after the initiation of sedation therapy, to identify statistically significant differences between patient groups.
• Recording NOL values and the required doses of opioids in patients from both study groups.
• Determining the patients' awakening time using BIS system monitoring, assessing the presence of delirium, and comparing these metrics between groups.
• Recording possible adverse effects associated with both sedation therapies.

The clinical trial involves a study population of **neurocritical patients** aged 18 years and older, including both male and female participants. The trial does not involve a vulnerable population. Participants are selected based on their clinical condition, specifically those with intracranial hemorrhage, severe traumatic brain injury, or ischemic or hemorrhagic stroke, who require advanced neurological monitoring and deep sedation in an Intensive Care Unit. The selection process includes obtaining informed consent from a family member or legal representative. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the **efficacy** and safety of inhalation sedation using **isoflurane** compared to conventional intravenous sedation in neurocritical patients. This study is a randomized, double-blind, controlled trial, categorized as a Phase IV study, and is expected to span from March 2024 to February 2026. Participants will be randomly assigned to receive either inhalation sedation with isoflurane or intravenous sedation with **propofol** or **midazolam**. The trial will involve multiple study visits, beginning with an inclusion visit to screen participants based on criteria such as age (18 years or older), neurocritical condition, and the requirement for advanced neurological monitoring and deep sedation. Informed consent must be obtained from a family member or legal representative.

Following the inclusion visit, participants will undergo regular follow-up visits to monitor sedation variables, including the Richmond Agitation-Sedation Scale (RASS), Bispectral Index (BIS), and the required doses of sedation. The placement of the Sedaconda device and the recording of the ISOef value will also be assessed. Secondary endpoints include the observation of adverse effects, awakening time, presence of delirium, and alterations in liver and kidney function. The duration of ICU and hospital stays, as well as mortality rates, will be recorded. The end-of-study visit will conclude the trial, assessing the overall outcomes and safety of the sedation methods.

Participant involvement is expected to last for the duration of their ICU stay, with the maximum treatment period set at one day. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, or any clinical decision by the treating physician that necessitates discontinuation. The trial aims to provide valuable insights into the sedation management of neurocritical patients, ensuring a comprehensive evaluation of both efficacy and safety parameters.

The clinical trial involves the evaluation of three treatments for sedation in neurocritical patients. The first treatment is **Propofol**, a chemical substance with the active ingredient name **Propofol**. It is administered intravenously and is available in the pharmaceutical form coded as PHF742. The maximum daily dose is 4.5 mg/kg/h, and the treatment period is limited to one day. Propofol is classified under the ATC code N01AX10. Participant compliance with the dosing schedule will be monitored to ensure adherence to the prescribed regimen.

The second treatment is **Isoflurane**, used as a comparator in the study. Isoflurane is administered via inhalation and is presented in the pharmaceutical form coded as PHF00113MIG. The maximum daily dose for Isoflurane is 15 units, with a treatment period of one day. It is classified under the ATC code N01AB06. The administration of Isoflurane will be carefully monitored to ensure accurate dosing and participant compliance.

The third treatment is **Midazolam**, another comparator in the trial. Midazolam is administered intravenously and is available in the pharmaceutical form coded as PHF00230MIG. The maximum daily dose is 0.25 mg/kg/h, with a treatment period of one day. It is classified under the ATC code N05CD08. Compliance with the dosing schedule will be monitored to ensure that participants receive the correct dosage as per the study protocol.

The clinical trial aims to evaluate the efficacy of inhalation sedation with **isoflurane** compared to conventional intravenous sedation in neurocritical patients. Efficacy will be assessed using both primary and secondary endpoints. The primary endpoints include sedation variables such as the Richmond Agitation-Sedation Scale (RASS), Bispectral Index (BIS), Delta BIS index, and the required doses of intravenous or inhalation sedation during the study period. Additionally, the placement of the Sedaconda device and the recording of the ISOef value (expiratory fraction gas) will be monitored, with the upper permitted ISOef limit set at 1%. Other parameters include respiratory, hemodynamic variables, neuromonitorization, and infectious status.

Secondary endpoints focus on adverse effects observed throughout the study, awakening time, presence or absence of delirium during the awakening process, and alterations in liver and kidney function. The study will also track the number of days spent in the Intensive Care Unit (ICU) and the hospital, as well as ICU and hospital mortality rates. Data related to analgesia will be collected, including values obtained with the Nociception Level (NOL) index, which indicates the degree of nociception and the required doses of intravenous opioids during the study period. These efficacy parameters will be measured and collected throughout the study duration, ensuring a comprehensive evaluation of the sedation methods in the specified patient population.