De Sloovere Veerle, Mebis Liese, Wouters Pieter, Guïza Fabian, Boonen Eva, Bourgeois Marc, Dubois Jasperina, Ledoux Didier, Lormans Piet, Maréchal Hugues, Van der Hauwaert Emmanuel, Depreitere Bart, Meyfroidt Geert
Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium.
Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Trials. 2025 May 28;26(1):177. doi: 10.1186/s13063-025-08835-5.
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.
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.
This study is the first prospective RCT to investigate the safety of ketamine as an adjunct to a standard sedation regimen in TBI patients.
ClinicalTrials.gov NCT05097261. Registered on October 28, 2021.
在重度创伤性脑损伤（TBI）中，镇静剂常用于控制颅内压（ICP）、降低脑代谢、以便进行其他治疗，如机械通气或目标温度管理，或控制阵发性交感神经过度兴奋。通常需要长时间镇静。TBI中最常用的镇静剂是丙泊酚和咪达唑仑，常联合使用，但高剂量连续使用数天时，二者均有显著副作用。氯胺酮是一种N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，能提供镇静和镇痛作用，且呼吸抑制或血流动力学不稳定的风险最小。然而，美国食品药品监督管理局（FDA）对氯胺酮用于麻醉前脑脊液压力升高患者使用提出了预防措施，这使得其在TBI患者中的使用受到限制。多项观察性研究和两项大型荟萃分析并未表明，在接受镇静和机械通气的TBI患者中，使用氯胺酮作为诱导剂或镇静剂会增加ICP。氯胺酮在该适应症下的超说明书使用在全球范围内呈上升趋势。迄今为止，尚无前瞻性随机临床试验（RCT）证明氯胺酮在TBI患者中的安全性。
脑损伤与氯胺酮（BIKe）研究是一项前瞻性多中心双盲安慰剂对照RCT，旨在评估氯胺酮作为标准镇静方案辅助用药，对重度TBI患者的安全性以及降低ICP的治疗强度效果。入住重症监护病房（ICU）、入院72小时内需要镇静和ICP监测的成年TBI患者，将被随机分为氯胺酮组或安慰剂组。研究药物将在随机分组后6小时内开始使用。研究用药品（IMP）的剂量为1mg/kg/h，持续输注。当最后一种ICP控制镇静剂停药时，停止使用IMP。患者从ICU出院时停止数据收集。所有患者将在创伤后随访6个月。该研究的效能是检测出每例ICU住院期间高颅内压发作中位数增加两例这一具有临床意义的安全性终点事件。共需要100名患者来实现这些目标。我们假设治疗强度水平（TIL）评分在临床上有至少3分的显著降低。
本研究是第一项前瞻性RCT，旨在研究氯胺酮作为标准镇静方案辅助用药在TBI患者中的安全性。
ClinicalTrials.gov NCT05097261。于2021年10月28日注册。
