This randomised, blinded, placebo-controlled, parallel-group pilot and feasibility trial (n=400) will investigate the efficacy and safety of using esketamine for the treatment of patients with severe acute brain injury. It will specifically focus on cortical spreading depolarisations (SDs) in TBI, aSAH, or ICH.
Cortical spreading depolarisations (SDs) are pathological depolarisation waves common after severe acute brain injury and linked to worse outcome; S-ketamine inhibits SDs in preclinical and case series.
Patients undergoing craniotomy/craniectomy for TBI, aSAH or ICH are monitored with electrocorticography (ECoG) and other neuromonitoring; those with clustered SDs despite optimisation are randomised 1:1 to S-ketamine infusion or matching saline placebo.
Primary aims are to assess the effect of S-ketamine on SD incidence, safety of sedative-dose infusion, and feasibility of the trial design; survivors will have functional follow-up to six months (mRS).
Continuous S-ketamine infusion titrated 2→3 mg/kg/hour per algorithm to suppress clustered cortical spreading depolarisations (SDs).
Start 2.0 mg/kg/hour; increase to 3.0 mg/kg/hour if SDs persist; reassess at 24 h; stop if 24 h without SDs.
Isotonic saline infusion matching S-ketamine appearance and infusion-rate algorithm.
Isotonic saline infused with ml/hour rates matched to S-ketamine dosing table by weight; follows same escalation/de-escalation algorithm.