Evaluation of the Safety of Inhaled Sedation With Isoflurane in Head Trauma Patients

NCT06311604 | Recruiting DMC

• 1 other identifier: 38RC22.0272
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Intensive care management of patient with severe traumatic brain injury (TBI) includes deep and prolonged sedation with intravenous hypnotics (propofol, midazolam, ketamine) in combination with opioids to prevent and/or treat episodes of intracranial hypertension. However, some patients may develop tachyphylaxis with a gradual increase of administered intravenous hypnotics and opioids to maintain the same level of sedation. This situation leads to a failure in controlling intracranial pressure (ICP) and/or to the risk of adverse effects due to high-dose sedatives: haemodynamic instability, prolonged mechanical ventilation, neuromyopathy, delirium, withdrawal syndrome. Halogenated agents (Isoflurane, Sevoflurane) are a class of hypnotics routinely used in the operating room. However, doses used in surgical patients (\> 1 Minimal Alveolar Concentration, MAC) are not suitable in neuro-intensive care unit (ICU) patients at risk of intracranial hypertension because of the cerebral vasodilator effects of halogenated agents at this dosage, hence the risk of high ICP and compromised cerebral perfusion pressure. The use of halogenated agents has been recently possible in the ICU through dedicated medical devices (Sedaconda ACD, Mirus). Recommended dosage are lower in the ICU, i.e. 0.3-0.7 MAC, because of their association with intravenous hypnotics and the absence of surgical stimuli. Several clinical studies in general ICUs showed improved sedation quality, reduced duration of mechanical ventilation, faster arousal and shorter extubation time, and lower costs in halogenated group compared with control group receiving midazolam or propofol. At low doses, the effects on ICP and intracerebral haemodynamics of halogenated agents are minor according to the available literature. In addition, beneficial effects were found on cerebral ischaemic volume in animal models treated with halogenated agents. However, there is a need to explore the benefit-risk ratio of the use of halogenated agents in the severe TBI population. The investigator hypothesise that 0.7 MAC Isoflurane can be administered in this population without deleterious effect on ICP.

Conditions

Traumatic Brain Injury

Keywords

isoflurane; traumatic brain injury

Outcome Measures

Primary Outcomes (1)

• To assess the safety of sedation with 0.7 MAC of inhaled isoflurane in cranial trauma patients in terms of intracranial pressure.

  Composite criterion : 1. Deaths (attributable to isoflurane) at "H+24 target MAC reached". 2. 2 consecutive hourly averages of ICP \> 20 mmHg during the 24 hours after the target MAC has been reached will be considered as a failure.

  36 hours

Secondary Outcomes (10)

• To assess the effect on cerebral blood flow of inhaled isoflurane sedation in patients with cranial trauma.

  36 hours

• To assess the effect on cerebral blood flow of inhaled isoflurane sedation in patients with cranial trauma.

  36 hours

• To assess the effect on cerebral blood flow of inhaled isoflurane sedation in patients with cranial trauma.

  36 hours

• To assess the effect on cerebral blood flow of inhaled isoflurane sedation in patients with cranial trauma.

  36 hours

• To assess the extra-neurological effects of inhaled isoflurane sedation in head trauma patients

  36 hours

Study Arms (1)

ISOFLURANE SEDATION

EXPERIMENTAL

Inclusions will have 4 phases according to gradual increased doses of isoflurane (0.3 MAC; 0.5 MAC and 0.7 MAC) Upgrading dose of isoflurane in each phase will be validated by an independent data and safety monitoring committee (DSMC). Inclusion of 12-15 additional patients will be included at the 0.7 MAC dose, to have 18 patients exposed to 0.7 MAC isoflurane.

Drug: Isoflurane

Interventions

Isoflurane DRUG

Inclusions will have 4 phases according to gradual increased doses of isoflurane: Phase 1: Inclusion of 3 patients with 0.3 MAC isoflurane. In the absence of an increase of ICP \> 20% from baseline, inhaled sedation is maintained for 24 hours until the primary endpoint is assessed. If there one patient who does not tolerate this threshold, three additional patients will be included in this phase. A maximum of one treatment failure (see definition below) is tolerated in the phase 1 Phase 2: Inclusion of 3 additional patients with isoflurane dosage of 0.5 MAC under the same conditions as phase 1. Phase 3: Inclusion of 3 additional patients with isoflurane dosage of 0.7 MAC under the same conditions as phases 1 and 2. Phase 4: Inclusion of 12-15 additional patients will be included at the 0.7 MAC dose, to have 18 patients exposed to 0.7 MAC isoflurane.

ISOFLURANE SEDATION

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient \> 18 years old
• Hospitalized in surgical intensive care (CPR and RNC) for severe head trauma
• On intravenous hypnotic therapy for at least 24 hours with at least 2 lines of IV hypnotics and requiring continued sedation for at least 24 hours, with a RASS of between -3 and -5
• Initial ICP \< 15 mmHg on introduction of isoflurane
• Functional intracranial pressure sensor
• Transcranial Doppler measurements performed within 24 hours
• Written informed consent from a legal representative/relative/trusted person. In the absence of a legal representative, the patient may be included under the emergency procedure.

You may not qualify if:

• Patients who have had a decompressive craniectomy
• Patients with a personal or family history of malignant hyperthermia
• Patients with a history of long QT syndrome
• Patients taking MAOI-type antidepressants (iproniazid (MARSILID) and moclobemide (MOCLAMIDE))
• Patients with known hypersensitivity to isoflurane or other volatile halogenated anaesthetic agents
• Patients who have experienced liver damage, jaundice, unexplained fever, or eosinophilia after administration of a halogenated anaesthetic.
• Patients expected to die within the next 24 hours
• Technical unavailability of the inhaler
• Persons covered by articles L1121-5 to L1121-8 of the CSP (corresponding to all protected persons: pregnant women, women in childbirth, nursing mothers, persons deprived of their liberty by judicial or administrative decision, persons subject to a legal protection measure).
• No European social security

Sponsors & Collaborators

• University Hospital, Grenoble: lead

Study Sites (1)

University Hospital Grenoble

Grenoble, Choisir Une Région, 38043, France

RECRUITING

Related Publications (5)

• Meiser A, Volk T, Wallenborn J, Guenther U, Becher T, Bracht H, Schwarzkopf K, Knafelj R, Faltlhauser A, Thal SC, Soukup J, Kellner P, Druner M, Vogelsang H, Bellgardt M, Sackey P; Sedaconda study group. Inhaled isoflurane via the anaesthetic conserving device versus propofol for sedation of invasively ventilated patients in intensive care units in Germany and Slovenia: an open-label, phase 3, randomised controlled, non-inferiority trial. Lancet Respir Med. 2021 Nov;9(11):1231-1240. doi: 10.1016/S2213-2600(21)00323-4. Epub 2021 Aug 26.

  PMID: 34454654 BACKGROUND

• Bosel J, Purrucker JC, Nowak F, Renzland J, Schiller P, Perez EB, Poli S, Brunn B, Hacke W, Steiner T. Volatile isoflurane sedation in cerebrovascular intensive care patients using AnaConDa((R)): effects on cerebral oxygenation, circulation, and pressure. Intensive Care Med. 2012 Dec;38(12):1955-64. doi: 10.1007/s00134-012-2708-8. Epub 2012 Oct 25.

  PMID: 23096426 BACKGROUND

• Villa F, Iacca C, Molinari AF, Giussani C, Aletti G, Pesenti A, Citerio G. Inhalation versus endovenous sedation in subarachnoid hemorrhage patients: effects on regional cerebral blood flow. Crit Care Med. 2012 Oct;40(10):2797-804. doi: 10.1097/CCM.0b013e31825b8bc6.

  PMID: 22824929 BACKGROUND

• Codaccioni JL, Velly LJ, Moubarik C, Bruder NJ, Pisano PS, Guillet BA. Sevoflurane preconditioning against focal cerebral ischemia: inhibition of apoptosis in the face of transient improvement of neurological outcome. Anesthesiology. 2009 Jun;110(6):1271-8. doi: 10.1097/ALN.0b013e3181a1fe68.

  PMID: 19417596 BACKGROUND

• Aubanel S, Bruiset F, Chapuis C, Chanques G, Payen JF. Therapeutic options for agitation in the intensive care unit. Anaesth Crit Care Pain Med. 2020 Oct;39(5):639-646. doi: 10.1016/j.accpm.2020.01.009. Epub 2020 Aug 7.

  PMID: 32777434 BACKGROUND

MeSH Terms

Conditions

Brain Injuries, Traumatic

Interventions

Isoflurane

Condition Hierarchy (Ancestors)

Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Methyl Ethers; Ethers; Organic Chemicals

Study Officials

• barthélémy BERTRAND, MD

  University Hospital, Grenoble

  PRINCIPAL INVESTIGATOR

Central Study Contacts

barthélémy BERTRAND, MD

CONTACT

+33 476766879; bbertrand4@chu-grenoble.fr

Anais ADOLLE

CONTACT

+33 476766879; aadolle@chu-grenoble.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Prospective, open-label, single-centre, interventional dose escalation study

Study Record Dates

• First Submitted: August 21, 2023
• First Posted: March 15, 2024
• Study Start: June 20, 2024
• Primary Completion (Estimated): June 20, 2026
• Study Completion (Estimated): March 20, 2027
• Last Updated: July 3, 2024

Record last verified: 2024-06

Locations

FR (1)