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

Sedation Clinical Trial

— IsoCOMFORT  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04684238
• Other study ID #: SED002
• Status: Completed
• Phase: Phase 3
• Start date: January 14, 2021
• Est. completion date: January 19, 2023

Study information

• Verified date: April 2023
• Source: Sedana Medical
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 97
• Est. completion date: January 19, 2023
• Est. primary completion date: January 19, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 17 Years

Eligibility

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.

Related Conditions & MeSH terms

• Sedation

Intervention

Drug:
• Midazolam
Solution for Injection/Infusion
• Isoflurane
Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)

Locations

Country	Name	City	State
France	Hôpital Femme-Mère-Enfant Groupe Hospitalier Est	Lyon
France	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
Germany	Universitätsklinikum Köln	Cologne
Germany	Universitätsklinik Freiburg	Freiburg
Germany	Universitätsklinikum Hamburg-Eppendorf (UKE)	Hamburg
Germany	Universitätsklinikum Jena	Jena
Spain	Hospital Materno Infantil Sant Joan de Deu Hospital	Barcelona
Spain	Hospital Universitario Reina Sofía	Córdoba
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Infantil Universitario Niño Jesús Pediatric Intensive Care Unit	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Regional Universitario, Carlos Haya	Málaga
Spain	Hospital Universitario Virgen del Rocio de Sevilla	Sevilla
Spain	Hospital Universitari i Politecnic La Fe	Valencia
Sweden	Karolinska Universitetssjukhus Solna	Solna
United Kingdom	Leeds Teaching Hospitals NHS Trust	Leeds
United Kingdom	University Hospitals of Leicester NHS Trust	Leicester
United Kingdom	Imperial College Healthcare NHS Trust	London
United Kingdom	Royal Manchester Children's Hospital	Manchester

Sponsors (1)

Lead Sponsor	Collaborator
Sedana Medical

Countries where clinical trial is conducted

France,  Germany,  Spain,  Sweden,  United Kingdom, 

References & Publications (15)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Exploratory objective	Evaluate frequency and type of AnaConDa-S device deficiencies when used for sedating patients with isoflurane.	During study treatment
Primary	Percentage of time adequate sedation depth	To compare the percentage of time adequate sedation depth is maintained within the individually prescribed target range in absence of rescue sedation as assessed according to the COMFORT-B scale, in isoflurane vs midazolam treated paediatric patients for an expected minimum of 12 hours.	Minimum of 12 hours up to 48 hours (± 6 hours).
Secondary	Compare the use of opiates	Compare the use of opiates, and the development of tolerance to the sedative regimen as measured by the change in dose of study drug,opiates and other analgesics, over time in isoflurane- vs midazolam treated patients.	Minimum of 12 hours up to 48 hours (± 6 hours).
Secondary	Compare the need for rescue sedatives	Compare the need for rescue sedatives and other sedatives in isoflurane- vs midazolam-treated patients.	Minimum of 12 hours up to 48 hours (± 6 hours).
Secondary	Compare time from sedation termination to extubation	Compare time from sedation termination to extubation in isoflurane- vs midazolam-treated patients.	Time from end of study drug administration to extubation
Secondary	Compare the proportion of time with spontaneous breathing	Compare the proportion of time with spontaneous breathing in isoflurane- vs midazolam treated patients.	During study treatment
Secondary	Evaluate haemodynamic effect as indicated by inotropic/vasopressor agent	Evaluate haemodynamic effect as indicated by inotropic/vasopressor agent administration in patients sedated with isoflurane compared with midazolam.	During study treatment period compared to baseline
Secondary	Evaluate the frequency of withdrawal symptom	Evaluate the frequency of withdrawal symptoms in isoflurane- vs midazolam-treated patients.	Patients exposed > 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.
Secondary	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.
Secondary	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
Secondary	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
Secondary	Compare ventilator-free days	Compare ventilator-free days up to 30 days in isoflurane- vs midazolam-treated patients.	From start of study treatment up to 30 days
Secondary	Compare the time in ICU/hospital	Compare the time in ICU/hospital up to 30 days in isoflurane- vs midazolam-treated patients.	From start of study treatment up to 30 days
Secondary	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
Secondary	Compare the safety profile	Compare the safety profile in terms of experienced adverse events, safety laboratory values, blood gases, vital signs, body temperature and urinary output in isoflurane- vs midazolam-treated patients.	Baseline to end of study treatment, safety lab from baseline up to 48hrs post treatment, AEs from start study treatment up to day 30