Effect & Safety of Inhaled Isoflurane vs IV Midazolam for Sedation in Mechanically Ventilated Children 3-17 Years Old

Sedana Medical94 enrolled

Overview

This is a study to compare safety and efficacy of inhaled isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device (ACD)) versus intravenous midazolam for sedation in mechanically ventilated children admitted to an intensive care unit.

This is a phase III, multi-centre, prospective, randomized, active-controlled, assessor-blind study. Primary endpoint: percentage of time of adequately maintained sedation, in absence of rescue sedation, within the COMFORT-B interval (light, moderate, or deep sedation) prescribed at randomization, monitored every 2 hours for an expected minimum of 12 hours (up to 48 hours).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

Conditions

Sedation

Interventions

MidazolamDRUG

Solution for Injection/Infusion

IsofluraneDRUG

Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)

Eligibility

Sex: ALLMin age: 3 YearsMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Patients at least 3 years to 17 (less than 18) years at the time of randomization, admitted to an ICU/with planned ICU admission. * Expected mechanical (invasive) ventilation and sedation for at least 12 hours. * Informed consent obtained from the patient, patient's legal guardian(s) Exclusion Criteria: * Ongoing seizures requiring acute treatment. * Continuous sedation for more than 72 hours at time of randomization. * Less than 24 hours post cardiopulmonary resuscitation. * Uncompensated circulatory shock. * Known or suspected genetic susceptibility to malignant hyperthermia. * Patients with acute asthma or obstructive lung disease symptoms requiring treatment at inclusion. * Patient with tidal volume below 30 mL or above 800 mL. * Inability to perform reliable COMFORT-B assessment in the opinion of the Investigator * Patients with intracranial pressure (ICP) monitoring or with suspected increase in ICP * Patients with treatment-induced whole-body hypothermia. * Patients with pheochromocytoma. * Patients with prolonged QT interval or with significant risk for prolonged QT interval. * Patient not expected to survive next 48 hours or not committed to full medical care.

Locations (24)

Hôpital Femme-Mère-Enfant Groupe Hospitalier Est

Lyon, France

Outcomes

Primary Outcomes

Percentage of Time of Adequately Maintained Sedation Depth up to 48 Hours (± 6 Hours)

Percentage of time of adequately maintained sedation within the COMFORT-B interval (light, moderate or deep sedation) prescribed at randomisation, monitored every 2 h for a minimum of 12 h (up to 48 h ± 6 h)

Time frame: Minimum of 12 hours up to 48 hours (± 6 hours).

Secondary Outcomes

Compare the Use of Opioids

Dose of opioids from first blinded COMFORT-B assessment (at +2 h from start of study drug) to end of study treatment period. This was a key secondary efficacy endpoint. Dose of opioids was expressed as fentanyl IV equivalents.

Time frame: From first blinded COMFORT-B assessment (at +2 h from start of study drug initiation) to end of the study treatment period

Compare the Use of Opioids

Dose of opioids during the last 4 h of study treatment, as compared to the first 4 h of study treatment after first blinded COMFORT-B assessment. This was a key secondary efficacy endpoint. Dose of opioids is expressed as fentanyl IV equivalents.

Time frame: Last 4 hours of study treatment compared to first 4 hours of study treatment after first blinded COMFORT-B assessment (at +2 h from start of study drug initiation).

Compare Time From End of Study Drug Administration to Extubation

Time from end of study drug administration to extubation if study drug was terminated for extubation

Time frame: From end of study drug administration to extubation or end of extubation attempt

Compare the Proportion of Time With Spontaneous Breathing

Proportion of observations with spontaneous breathing efforts during study treatment. This was a key secondary safety endpoint.

Time frame: From initiation of study drug treatment to End of study treatment (up to 48h +/- 6h)

Data from ClinicalTrials.gov

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CHU de NANTES, Hôpital Mère-Enfant

Nantes, France

Hôpital Robert-Debré AP-HP

Paris, France

Hôpitaux Universitaires Paris Sud Site Bicetre

Paris, France

Centre Hospitalier Universitaire de Reims

Reims, France

Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre

Strasbourg, France

Universitätsklinikum Köln

Cologne, Germany

Universitätsklinik Freiburg

Freiburg im Breisgau, Germany

Universitätsklinikum Hamburg-Eppendorf (UKE)

Hamburg, Germany

Universitätsklinikum Jena

Jena, Germany

...and 14 more locations

Evaluate Haemodynamic Effect as Indicated by Need for Additional Inotropic/Vasopressor Agent

Need for additional inotropic/vasopressor agent defined by change in Vasoactive-Inotropic Score (VIS) during study treatment period compared to baseline. The VIS quantifies the amount of cardiovascular support required by infants postoperatively according to the below calculation: VIS = dopamine (µg/kg/min) + dobutamine (µg/kg/min) + 100 × epinephrine (µg/kg/min) + 100 × norepinephrine (µg/kg/min) + 10 × milrinone (µg/kg/min) + 10,000 × vasopressin (U/kg/min). An increased VIS score correlates to an increase in inotropic/vasopressor agents.

Time frame: From start of study treatment to end of study treatment (up to 48h +/- 6h)

Evaluate the Number of Patients With Withdrawal Symptom

Evaluate the frequency of withdrawal symptoms in isoflurane- vs midazolam-treated patients according to SOS-PD.

Time frame: From > 96 hours sedation (including pre-study sedation period) until the end of the 48-hour post study treatment monitoring or ICU discharge, whichever comes first.

Evaluate the Frequency of Delirium

Evaluate the frequency of delirium in isoflurane- vs midazolam-treated patients

Time frame: Patients admitted to the ICU ≥48 hours (including period prior to study enrolment) until the end of the 48-hour post study treatment monitoring or ICU discharge, whichever comes first.

Evaluate the Frequency of Neurological Symptoms or Psychomotor Dysfunction

Evaluate the frequency of neurological symptoms or psychomotor dysfunction during and up to 48 hours after discontinuation of isoflurane and midazolam treatment, and the association with duration of treatment, and total exposure (MAC hours and midazolam doses) over time.

Time frame: During study treatment and up to 48 hours after discontinuation of isoflurane and midazolam

Compare the 30 Days/Hospital Mortality

Compare the 30 days/hospital mortality in isoflurane- vs midazolam-treated patients

Time frame: From start of study treatment up to 30 days

Compare Ventilator-free Days

Ventilator-free days at 30 days from start of study treatment period.

Time frame: From start of study treatment up to 30 days

Compare the Time in ICU/Hospital

Compare the time in ICU at 30 days from start of study treatment period. This was a secondary safety endpoint. Patients that were withdrawn prior to day 30 were excluded from the analysis. Patients who died before day 30 were not considered withdrawals. For these patients, the days in ICU until day of death were considered ICU days.

Time frame: From start of study treatment up to 30 days

Compare ICU-free Days

Compare ICU-free days up to 30 days in isoflurane- vs midazolam-treated patients.

Time frame: From start of study treatment up to 30 days