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

A Randomised Active-controlled Study to Compare Efficacy & Safety of Inhaled Isoflurane Delivered by the AnaConDa-S (Anaesthetic Conserving Device) vs IV Midazolam for Sedation in Mechanically Ventilated Paediatric Patients 3-17 Years Old

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.

Study Overview

• Status: Completed
• Conditions: Sedation
• Intervention / Treatment: Drug: Midazolam; Drug: Isoflurane

Detailed Description

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
• Enrollment (Actual): 94
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Lyon, France
    • Hôpital Femme-Mère-Enfant Groupe Hospitalier Est
  • Nantes, France
    • CHU de NANTES, Hôpital Mère-Enfant
  • Paris, France
    • Hôpital Robert-Debré Ap-Hp
  • Paris, France
    • Hôpitaux Universitaires Paris Sud Site Bicetre
  • Reims, France
    • Centre Hospitalier Universitaire de Reims
  • Strasbourg, France
    • Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre
• Germany
  • Cologne, Germany
    • Universitätsklinikum Köln
  • Freiburg, Germany
    • Universitätsklinik Freiburg
  • Hamburg, Germany
    • Universitätsklinikum Hamburg-Eppendorf (UKE)
  • Jena, Germany
    • Universitatsklinikum Jena
• Spain
  • Barcelona, Spain
    • Hospital Materno Infantil Sant Joan de Deu Hospital
  • Córdoba, Spain
    • Hospital Universitario Reina Sofia
  • Madrid, Spain
    • Hospital General Universitario Gregorio Marañón
  • Madrid, Spain
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain
    • Hospital Universitario La Paz
  • Madrid, Spain
    • Hospital Infantil Universitario Niño Jesús Pediatric Intensive Care Unit
  • Málaga, Spain
    • Hospital Regional Universitario, Carlos Haya
  • Sevilla, Spain
    • Hospital Universitario Virgen del Rocío de Sevilla
  • Valencia, Spain
    • Hospital Universitari i Politècnic La Fe
• Sweden
  • Solna, Sweden
    • Karolinska Universitetssjukhus Solna
• United Kingdom
  • Leeds, United Kingdom
    • Leeds Teaching Hospitals NHS Trust
  • Leicester, United Kingdom
    • University Hospitals of Leicester NHS Trust
  • London, United Kingdom
    • Imperial College Healthcare NHS Trust
  • Manchester, United Kingdom
    • Royal Manchester Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Drug: Midazolam; Midazolam for sedation in the ICU	Drug: Midazolam; Solution for Injection/Infusion
Experimental: Drug: Isoflurane; Volatile for sedation in the ICU	Drug: Isoflurane; Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Minimum of 12 hours up to 48 hours (± 6 hours).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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	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.	From initiation of study drug treatment to End of study treatment (up to 48h +/- 6h)
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.	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.	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	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.	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	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.	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.	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.	From start of study treatment up to 30 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory objective	Determine the isoflurane dosage, end-tidal concentrations and infusion rates, and the midazolam dosage, required for adequate sedation in mechanically ventilated paediatric patients.	During study treatment
Exploratory objective	Evaluate frequency and type of AnaConDa-S device deficiencies when used for sedating patients with isoflurane.	During study treatment

Collaborators and Investigators

• Sponsor: Sedana Medical
• Investigators: Study Director: Peter Sackey, MD, PhD, Sedana Medical

Publications and helpful links

General Publications

• Sackey PV, Martling CR, Granath F, Radell PJ. Prolonged isoflurane sedation of intensive care unit patients with the Anesthetic Conserving Device. Crit Care Med. 2004 Nov;32(11):2241-6. doi: 10.1097/01.ccm.0000145951.76082.77.
• Eifinger F, Hunseler C, Roth B, Vierzig A, Oberthuer A, Mehler K, Kribs A, Menzel C, Trieschmann U. Observations on the effects of inhaled isoflurane in long-term sedation of critically Ill children using a modified AnaConDa(c)-system. Klin Padiatr. 2013 Jul;225(4):206-11. doi: 10.1055/s-0033-1345173. Epub 2013 Jun 24.
• Ariyama J, Hayashida M, Shibata K, Sugimoto Y, Imanishi H, O-oi Y, Kitamura A. Risk factors for the development of reversible psychomotor dysfunction following prolonged isoflurane inhalation in the general intensive care unit. J Clin Anesth. 2009 Dec;21(8):567-73. doi: 10.1016/j.jclinane.2009.01.011.
• Grant MJ, Balas MC, Curley MA; RESTORE Investigative Team. Defining sedation-related adverse events in the pediatric intensive care unit. Heart Lung. 2013 May-Jun;42(3):171-6. doi: 10.1016/j.hrtlng.2013.02.004.
• Hoemberg M, Vierzig A, Roth B, Eifinger F. Plasma fluoride concentrations during prolonged administration of isoflurane to a pediatric patient requiring renal replacement therapy. Paediatr Anaesth. 2012 Apr;22(4):412-3. doi: 10.1111/j.1460-9592.2012.03814.x. No abstract available.
• Kruessell MA, Udink ten Cate FE, Kraus AJ, Roth B, Trieschmann U. Use of propofol in pediatric intensive care units: a national survey in Germany. Pediatr Crit Care Med. 2012 May;13(3):e150-4. doi: 10.1097/PCC.0b013e3182388a95.
• Kudchadkar SR, Yaster M, Punjabi NM. Sedation, sleep promotion, and delirium screening practices in the care of mechanically ventilated children: a wake-up call for the pediatric critical care community*. Crit Care Med. 2014 Jul;42(7):1592-600. doi: 10.1097/CCM.0000000000000326.
• Nolent P, Laudenbach V. [Sedation and analgesia in the paediatric intensive care unit]. Ann Fr Anesth Reanim. 2008 Jul-Aug;27(7-8):623-32. doi: 10.1016/j.annfar.2008.04.014. Epub 2008 Jul 9. French.
• Meiser A, Laubenthal H. Inhalational anaesthetics in the ICU: theory and practice of inhalational sedation in the ICU, economics, risk-benefit. Best Pract Res Clin Anaesthesiol. 2005 Sep;19(3):523-38. doi: 10.1016/j.bpa.2005.02.006.
• Meyburg J, Dill ML, von Haken R, Picardi S, Westhoff JH, Silver G, Traube C. Risk Factors for the Development of Postoperative Delirium in Pediatric Intensive Care Patients. Pediatr Crit Care Med. 2018 Oct;19(10):e514-e521. doi: 10.1097/PCC.0000000000001681.
• Mody K, Kaur S, Mauer EA, Gerber LM, Greenwald BM, Silver G, Traube C. Benzodiazepines and Development of Delirium in Critically Ill Children: Estimating the Causal Effect. Crit Care Med. 2018 Sep;46(9):1486-1491. doi: 10.1097/CCM.0000000000003194.
• Playfor S, Jenkins I, Boyles C, Choonara I, Davies G, Haywood T, Hinson G, Mayer A, Morton N, Ralph T, Wolf A; United Kingdom Paediatric Intensive Care Society Sedation; Analgesia and Neuromuscular Blockade Working Group. Consensus guidelines on sedation and analgesia in critically ill children. Intensive Care Med. 2006 Aug;32(8):1125-36. doi: 10.1007/s00134-006-0190-x. Epub 2006 May 13.
• Sackey PV, Martling CR, Radell PJ. Three cases of PICU sedation with isoflurane delivered by the 'AnaConDa'. Paediatr Anaesth. 2005 Oct;15(10):879-85. doi: 10.1111/j.1460-9592.2005.01704.x.
• Tobias JD. Tolerance, withdrawal, and physical dependency after long-term sedation and analgesia of children in the pediatric intensive care unit. Crit Care Med. 2000 Jun;28(6):2122-32. doi: 10.1097/00003246-200006000-00079.
• Vet NJ, Ista E, de Wildt SN, van Dijk M, Tibboel D, de Hoog M. Optimal sedation in pediatric intensive care patients: a systematic review. Intensive Care Med. 2013 Sep;39(9):1524-34. doi: 10.1007/s00134-013-2971-3. Epub 2013 Jun 19.

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2021
• Primary Completion (Actual): January 19, 2023
• Study Completion (Actual): January 19, 2023

Study Registration Dates

• First Submitted: December 18, 2020
• First Submitted That Met QC Criteria: December 23, 2020
• First Posted (Actual): December 24, 2020

Study Record Updates

• Last Update Posted (Actual): May 25, 2025
• Last Update Submitted That Met QC Criteria: May 7, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: pediatric; midazolam; sedation; isoflurane; mechanically ventilation
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anesthetics; Central Nervous System Depressants; Neurotransmitter Agents; Adjuvants, Anesthesia; Hypnotics and Sedatives; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; GABA Modulators; GABA Agents; Anesthetics, Inhalation; Midazolam; Isoflurane
• Other Study ID Numbers: SED002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No