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

Condition(s) studied

Investigational drug(s) / intervention(s)

Isoflurane: 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.

Study 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.

Eligibility

Primary outcome measure(s)

• To assess the safety of sedation with 0.7 MAC of inhaled isoflurane in cranial trauma patients in terms of intracranial pressure. — 36 hours
  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.

Trial sites (1)

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