IsoCOMFORT: Effect & Safety of Inhaled Isoflurane vs IV Midazolam for Sedation in Mechanically Ventilated Children 3-17 Years Old
Study Details
Study Description
Brief 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
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 Design
Arms and Interventions
| 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)
|
Outcome Measures
Primary Outcome Measures
- Percentage of time adequate sedation depth [Minimum of 12 hours up to 48 hours (± 6 hours).]
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.
Secondary Outcome Measures
- Compare the use of opiates [Minimum of 12 hours up to 48 hours (± 6 hours).]
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.
- Compare the need for rescue sedatives [Minimum of 12 hours up to 48 hours (± 6 hours).]
Compare the need for rescue sedatives and other sedatives in isoflurane- vs midazolam-treated patients.
- Compare time from sedation termination to extubation [Time from end of study drug administration to extubation]
Compare time from sedation termination to extubation in isoflurane- vs midazolam-treated patients.
- Compare the proportion of time with spontaneous breathing [During study treatment]
Compare the proportion of time with spontaneous breathing in isoflurane- vs midazolam treated patients.
- Evaluate haemodynamic effect as indicated by inotropic/vasopressor agent [During study treatment period compared to baseline]
Evaluate haemodynamic effect as indicated by inotropic/vasopressor agent administration in patients sedated with isoflurane compared with midazolam.
- Evaluate the frequency of withdrawal symptom [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.]
Evaluate the frequency of withdrawal symptoms in isoflurane- vs midazolam-treated patients.
- Evaluate the frequency of delirium [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 delirium in isoflurane- vs midazolam-treated patients
- Evaluate the frequency of neurological symptoms or psychomotor dysfunction [During study treatment and up to 48 hours after discontinuation of isoflurane and midazolam]
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.
- Compare the 30 days/hospital mortality [From start of study treatment up to 30 days]
Compare the 30 days/hospital mortality in isoflurane- vs midazolam-treated patients
- Compare ventilator-free days [From start of study treatment up to 30 days]
Compare ventilator-free days up to 30 days in isoflurane- vs midazolam-treated patients.
- Compare the time in ICU/hospital [From start of study treatment up to 30 days]
Compare the time in ICU/hospital up to 30 days in isoflurane- vs midazolam-treated patients.
- Compare ICU-free days [From start of study treatment up to 30 days]
Compare ICU-free days up to 30 days in isoflurane- vs midazolam-treated patients.
- Compare the safety profile [Baseline to end of study treatment, safety lab from baseline up to 48hrs post treatment, AEs from start study treatment up to day 30]
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.
Other Outcome Measures
- Exploratory objective [During study treatment]
Determine the isoflurane dosage, end-tidal concentrations and infusion rates, and the midazolam dosage, required for adequate sedation in mechanically ventilated paediatric patients.
- Exploratory objective [During study treatment]
Evaluate frequency and type of AnaConDa-S device deficiencies when used for sedating patients with isoflurane.
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | CHU Amiens-Picardie Site Sud | Amiens | France | ||
| 2 | Hôpital Femme-Mère-Enfant Groupe Hospitalier Est | Lyon | France | ||
| 3 | CHU de NANTES, Hôpital Mère-Enfant | Nantes | France | ||
| 4 | Hopital Universitaire Necker Enfants Malades | Paris | France | ||
| 5 | Hôpital Robert-Debré AP-HP | Paris | France | ||
| 6 | Hôpitaux Universitaires Est Parisien Trousseau La Roche-Guyon | Paris | France | ||
| 7 | Hôpitaux Universitaires Paris Sud Site Bicetre | Paris | France | ||
| 8 | Centre Hospitalier Universitaire de Reims | Reims | France | ||
| 9 | Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre | Strasbourg | France | ||
| 10 | Universitätsklinikum Köln | Cologne | Germany | ||
| 11 | Universitätsklinik Freiburg | Freiburg | Germany | ||
| 12 | Universitätsklinikum Hamburg-Eppendorf (UKE) | Hamburg | Germany | ||
| 13 | Universitätsklinikum Jena | Jena | Germany | ||
| 14 | Klinikum Kassel | Kassel | Germany | ||
| 15 | Hospital Materno Infantil Sant Joan de Deu Hospital | Barcelona | Spain | ||
| 16 | Hospital Universitario Reina Sofía | Córdoba | Spain | ||
| 17 | Hospital General Universitario Gregorio Marañón | Madrid | Spain | ||
| 18 | Hospital Infantil Universitario Niño Jesús Pediatric Intensive Care Unit | Madrid | Spain | ||
| 19 | Hospital Universitario 12 de Octubre | Madrid | Spain | ||
| 20 | Hospital Universitario La Paz | Madrid | Spain | ||
| 21 | Hospital Regional Universitario, Carlos Haya | Málaga | Spain | ||
| 22 | Hospital Universitario Virgen del Rocio de Sevilla | Sevilla | Spain | ||
| 23 | Hospital Universitari i Politecnic La Fe | Valencia | Spain | ||
| 24 | Karolinska Universitetssjukhus Solna | Solna | Sweden |
Sponsors and Collaborators
- Sedana Medical
Investigators
- Study Director: Magnus Falkenhav, MD, Sedana Medical
Study Documents (Full-Text)
None provided.More Information
Publications
- 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.
- Eifinger F, Hünseler 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©-system. Klin Padiatr. 2013 Jul;225(4):206-11. doi: 10.1055/s-0033-1345173. Epub 2013 Jun 24.
- 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. Review.
- 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.
- 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.
- 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. Review.
- 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.
- 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.
- 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. Epub 2006 May 13.
- 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.
- 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.
- 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. Review.
- 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. Review.
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