Clinical trial NCT05095857: The Anaesthetic Ketamine as Treatment for Patients With Severe Acute Brain Injury
Official title: S-ketamine for Cortical Spreading Depolarisation in Patients With Severe Acute Brain Injury
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Subarachnoid Hemorrhage, Aneurysmal
Intracerebral Hemorrhage
Traumatic Brain Injury
Keywords: Cortical Spreading Depolarisation
Ketamine
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Copenhagen Trial Unit, Center for Clinical Intervention Research
First posted: 2021-10-27
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Cortical spreading depolarisations are pathological depolarisation waves that occur frequently after severe acute brain injury and has been associated with poor outcome. S-ketamine has been shown to inhibit cortical spreading depolarisations. The aim of the present study is to examine the efficacy and safety of using S-ketamine for treatment of patients with severe acute brain injury, as well as the feasibility of the trial design.

Detailed description: Severe acute brain injury caused by traumatic brain injury (TBI), aneurysmal subarachnoid haemorrhage (aSAH) or intracerebral haemorrhage (ICH) carries a high morbidity and mortality. In all these conditions, clinical neurological deterioration may occur as a consequence of so-called secondary brain injury, which reduces the chance of a good outcome. Thus, neurological deterioration after the initial injury is generally associated with a worse outcome. Cortical spreading depolarisations (SDs) are pathological depolarisation waves that occur frequently after both TBI, SAH, and ICH and have been related to poor outcome. The SDs, which can be detected by electrocorticography (ECoG, using electrodes placed directly on the brain cortex), propagate across the cerebral cortex and are followed by an excessive upregulation of cerebral metabolism and decrease in cerebral blood flow. In vulnerable brain tissue such as in patients after acute primary brain injury, this combination of hypermetabolism and hypoperfusion is thought to increase the risk of ischaemia and infarction. The anaesthetic drug ketamine, which is an NMDA-receptor antagonist, appears to inhibit SDs both in vitro and in patient series.

The present trial is a randomised, blinded, placebo-controlled, parallel-group pilot and feasibility trial, where participants with clustered SD despite physiological optimisation are allocated 1:1 to infusion of S-ketamine versus matching placebo. In the present trial, participants admitted to the neurointensive care unit with TBI, aSAH or ICH and undergoing craniotomy or craniectomy (for clipping of an aneurysm or removal of a space-occupying haematoma). Patients are monitored at the neurointensive care unit, Rigshospitalet and sedated using standard sedatives. Patients will be monitored both with ECoG, intracranial pressure (ICP), brain tissue oxygen tension (PbtO2), and microdialysis. Patients in whom SDs occur will be subjected to a protocol of physiological optimisation targeting ICP, PbtO2, blood glucose and core temperature following clinical guidelines. If clustered SDs occur despite optimisation, patients are randomly allocated to infusion of either S-ketamine or matching placebo (isotonic saline) at a 1:1 allocation ratio with full blinding of the treatment allocation.

The present trial will continue until 160 participants have been randomised. Since only participants with clustered SDs are randomised, the investigators expect to include no more than 400 participants for ECoG monitoring.

The present trial aims to examine the efficacy of S-ketamine on SDs, the safety, and the feasibility of the trial design. Furthermore, surviving patients will be followed up until six months after the injury, and functional outcome will be recorded by the modified Rankin Scale (mRS).

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years.
* Admitted to the NICU with a diagnosis of traumatic brain injury (TBI), aneurysmal subarachnoid haemorrhage (aSAH) or spontaneous intracerebral haemorrhage (ICH).
* Planned for surgery with a supratentorial craniotomy or craniectomy.
* Expected to continue sedation and mechanical ventilation after surgery.

Exclusion Criteria:

* Neither patient or next of kin understand Danish or English.
* Known allergy to S-ketamine (the active pharmaceutical ingredient or the excipients).
* Wake-up call to occur immediately after surgery.
* Pregnancy (all female participants aged ≤ 50 years will have a urine or blood hCG taken to control for pregnancy).
* Active anti-psychotic treatment before admission.
* Current abuse of ketamine.
* Decision to withdraw active treatment.
* ICH secondary to a known brain tumour at the time of inclusion.

Since this is an emergency trial informed consent will be obtained from a trial guardian before inclusion of the participant, and informed consent will be sought from next of kin as soon as possible.

Primary outcomes:
measure: Occurrence of SDs after randomisation
timeFrame: From randomisation to end of ECoG monitoring, expected to be a maximum of 14 days
Secondary outcomes:
measure: Rate of adverse events and adverse reactions
timeFrame: During treatment with S-ketamine or placebo, a maximum of 14 days
measure: Functional outcome at 6 months after randomisation
timeFrame: 6 months after randomisation
Other outcomes:
measure: All-cause mortality
timeFrame: assessed at 6 months after randomisation
measure: Number of participants with signs of ischaemia or infarction on computed tomography (CT) or magnetic resonance imaging (MRI).
timeFrame: Before discharge from NICU or the semi-intentisive care unit, expected up to be no later than day 21 postrandomisation
measure: Occurrence of metabolic crisis (defined as microdialysis (MD)-lactate/pyruvate ratio >40, MD-glucose < 0.8 μmol/L)
timeFrame: Postrandomisation period, expected up to 21 days
measure: Occurrence of local cerebral hypoxia (PbtO2 <20 mmHg for more than 20 minutes)
timeFrame: Postrandomisation period, expected up to 21 days
measure: Dosage of standard sedatives and analgesics
timeFrame: Postrandomisation period, expected up to 21 days
measure: Number of imaging procedures (CT of the brain, CT-angiography, digital subtraction angiography, MRI)
timeFrame: Postrandomisation period, expected up to 21 days
measure: Number of episodes of neurological worsening
timeFrame: Postrandomisation period, expected up to 21 days
measure: Occurrence of delayed cerebral ischemia (DCI) in participants with aSAH
timeFrame: Postrandomisation period, expected up to 21 days
measure: Fraction of participants included in the trial out of all eligible participants
timeFrame: Assessed after 2 years or when one-third of the 160 participants have been randomised
measure: Fraction of participants who are randomised of all included
timeFrame: Assessed after 2 years or when one-third of the 160 participants have been randomised
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet
Study officials:
affiliation: Rigshospitalet, Denmark
name: Trine H Andreasen, MD
role: PRINCIPAL_INVESTIGATOR
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