Journal Article

Brain Injury and Ketamine study (BIKe): a prospective, randomized controlled double blind clinical trial to study the effects of ketamine on therapy intensity level and intracranial pressure in severe traumatic brain injury patients

Guïza, Fabian, Ledoux, Didier, Boonen, Eva, Wouters, Pieter, Lormans, Piet, Bourgeois, Marc, De Sloovere, Veerle, Depreitere, Bart, Maréchal, Hugues, Meyfroidt, Geert, Dubois, Jasperina, Van der Hauwaert, Emmanuel, Mebis, Liese

2025

Overview

Background In severe traumatic brain injury (TBI), sedatives are often used to control intracranial pressure (ICP), to reduce brain metabolism, to allow for other treatments such as mechanical ventilation or targeted temperature management, or to control paroxysmal sympathetic hyperactivity. Prolonged sedation is often necessary. The most commonly used sedatives in TBI are propofol and midazolam, often in combination, but both have significant side effects when used at high doses for several days. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, provides sedation and analgesia with minimal respiratory depression or haemodynamic instability. However, ketamine carries a US Food and Drug Administration (FDA) precaution regarding its use in patients with pre-anaesthetic elevated cerebrospinal fluid pressure, which discourages its use in TBI patients. Several observational studies and two large meta-analyses do not suggest that the use of ketamine as an induction agent or sedative in sedated and mechanically ventilated TBI patients would increase the ICP. Off-label use of ketamine for this indication is increasing worldwide. To date, no prospective randomized clinical trial (RCT) has demonstrated the safety of ketamine in TBI patients. Methods The Brain Injury and Ketamine (BIKe) study is a prospective multicentre double-blind placebo-controlled RCT, to evaluate the safety, and effect on therapeutic intensity to reduce ICP, of ketamine as an adjunct to a standard sedation regimen in patients with severe TBI. Adult TBI patients, admitted to the intensive care unit (ICU), requiring sedation and ICP monitoring within 72 h of admission, will be randomized to ketamine or placebo. The study drug will be started within 6 h of randomization. The dose of the investigational medicinal product (IMP) is 1 mg/kg/h, by continuous infusion. The IMP will be stopped when the last ICP control sedative is discontinued. Data collection will stop when the patient is discharged from the ICU. All patients will be followed for 6 months post-trauma. The study is powered for the safety endpoint of detecting a clinically relevant increase of two episodes in the median number of episodes of high intracranial pressure episodes per ICU stay. A total of 100 patients are required to meet these objectives. We hypothesize a clinically relevant reduction in the therapeutic intensity level (TIL) score of at least 3 points. Discussion This study is the first prospective RCT to investigate the safety of ketamine as an adjunct to a standard sedation regimen in TBI patients. Trial registration ClinicalTrials.gov NCT05097261. Registered on October 28, 2021.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Analgesics / Anesthesia / Aspartate / Attention-deficit hyperactivity disorder / Biomedicine / Brain / Brain Injuries, Traumatic - diagnosis / Brain Injuries, Traumatic - drug therapy / Brain Injuries, Traumatic - physiopathology / Brain injury / Central nervous system / Clinical trials / Coma / Cranio-cerebral trauma / Delirium / Dexmedetomidine / Double-Blind Method / Drug dosages / Health Sciences / Hemodynamics / Humans / Hypnotics and Sedatives - administration & dosage / Hypnotics and Sedatives - adverse effects / Hypnotics and Sedatives - therapeutic use / Hypotheses / Informed consent / Injuries / Intervention / Intracranial Hypertension - diagnosis / Intracranial Hypertension - etiology / Intracranial Hypertension - physiopathology / Intracranial pressure / Intracranial Pressure - drug effects / Ketamine / Ketamine - administration & dosage / Ketamine - adverse effects / Ketamine - therapeutic use / Medical research / Medicine / Medicine & Public Health / Medicine, Experimental / Metabolism / Methyl aspartate / Patients / Physiological aspects / Prospective Studies / Randomized Controlled Trials as Topic / Statistics for Life Sciences / Study Protocol / Time Factors / Traumatic brain injury / Traumatic wounds / Treatment Outcome / Ventilation / Ventilators