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| ID | Type | Description | Link |
|---|---|---|---|
| 2021-003716-12 | EudraCT Number |
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| Name | Class |
|---|---|
| Copenhagen Trial Unit, Center for Clinical Intervention Research | OTHER |
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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| S-ketamine | Active Comparator | S-ketamine is given as a continuous infusion started at a dose of 2.0 mg/kg/hour. The infusion rate will be re-evaluated after 24 hours, where (1) the infusion will be stopped if 24 hours ensue without SDs, (2) maintained at 2.0 mg/kg/hour if the 24-hour incidence of SDs decreases below the rate of the previous 24 hours but SD is not totally abolished, or (3) increased to 3.0 mg/kg/hour if the incidence of SD is at or above the rate of the previous 24 hours. If the infusion rate has been increased to 3.0 mg/kg/hour, the rate will be returned to 2.0 mg/kg/hour if 24 consecutive hours of ECoG show no SD. |
|
| Isotonic saline | Placebo Comparator | Isotonic saline is given as placebo. It will be given as a continuous infusion started at a dose corresponding to a dose of S-ketamine of 2.0 mg/kg/hour, and follow the criteria for increasing/decreasing infusion rates as S-ketamine. The infusion rate is read from a table listing different infusion rates (ml/hour) based on participant weight and if the treatment tier corresponds to a S-ketamine dose of 2 or 3 mg/kg/hour. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| S-ketamine | Drug | S-ketamines is an NMDA-receptor antagonist with sedative and analgesic properties. It will in the present trial be given in sedative doses (2-3 mg/kg/hour) in case of clustered SDs following a dosing algorithm according to SD occurrence. |
| Measure | Description | Time Frame |
|---|---|---|
| Occurrence of SDs after randomisation | Efficacy of S-ketamine on the occurrence of cortical spreading depolarisations | From randomisation to end of ECoG monitoring, expected to be a maximum of 14 days |
| Measure | Description | Time Frame |
|---|---|---|
| Rate of adverse events and adverse reactions | During treatment with S-ketamine or placebo, a maximum of 14 days | |
| Functional outcome at 6 months after randomisation | assessed using modified Rankin Scale |
| Measure | Description | Time Frame |
|---|---|---|
| All-cause mortality | assessed at 6 months after randomisation | |
| Number of participants with signs of ischaemia or infarction on computed tomography (CT) or magnetic resonance imaging (MRI). | Last scan performed on clinical indication before discharge from NICU or semi-intensive care unit |
Inclusion Criteria:
Exclusion Criteria:
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.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Trine H Andreasen, MD | Contact | +4535455982 | trine.hjorslev.andreasen@regionh.dk | |
| Kirsten Møller, Professor | Contact | Kirsten.Moeller.01@regionh.dk |
| Name | Affiliation | Role |
|---|---|---|
| Trine H Andreasen, MD | Rigshospitalet, Denmark | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Rigshospitalet | Recruiting | Copenhagen | Denmark |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27637674 | Background | Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet. 2017 Feb 11;389(10069):655-666. doi: 10.1016/S0140-6736(16)30668-7. Epub 2016 Sep 13. | |
| 19501022 | Background | Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol. 2009 Jul;8(7):635-42. doi: 10.1016/S1474-4422(09)70126-7. Epub 2009 Jun 6. |
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| ID | Term |
|---|---|
| D013345 | Subarachnoid Hemorrhage |
| D002543 | Cerebral Hemorrhage |
| D000070642 | Brain Injuries, Traumatic |
| ID | Term |
|---|---|
| D020300 | Intracranial Hemorrhages |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| C000629870 | Esketamine |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
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|
| Isotonic saline (placebo) | Other | Isotonic saline has the same appearance as S-ketamine with both being clear liquids with no bubbles or other distinguishing features. |
|
| 6 months after randomisation |
| Before discharge from NICU or the semi-intentisive care unit, expected up to be no later than day 21 postrandomisation |
| Occurrence of metabolic crisis (defined as microdialysis (MD)-lactate/pyruvate ratio >40, MD-glucose < 0.8 μmol/L) | Postrandomisation period, expected up to 21 days |
| Occurrence of local cerebral hypoxia (PbtO2 <20 mmHg for more than 20 minutes) | Postrandomisation period, expected up to 21 days |
| Dosage of standard sedatives and analgesics | Postrandomisation period, expected up to 21 days |
| Number of imaging procedures (CT of the brain, CT-angiography, digital subtraction angiography, MRI) | Postrandomisation period, expected up to 21 days |
| Number of episodes of neurological worsening | Postrandomisation period, expected up to 21 days |
| Occurrence of delayed cerebral ischemia (DCI) in participants with aSAH | Postrandomisation period, expected up to 21 days |
| Fraction of participants included in the trial out of all eligible participants | Feasibility outcome | Assessed after 2 years or when one-third of the 160 participants have been randomised |
| Fraction of participants who are randomised of all included | Feasibility outcome | Assessed after 2 years or when one-third of the 160 participants have been randomised |
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| 27907954 | Background | Shah S, Kimberly WT. Today's Approach to Treating Brain Swelling in the Neuro Intensive Care Unit. Semin Neurol. 2016 Dec;36(6):502-507. doi: 10.1055/s-0036-1592109. Epub 2016 Dec 1. |
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| 31173342 | Background | Olsen MH, Orre M, Leisner ACW, Rasmussen R, Bache S, Welling KL, Eskesen V, Moller K. Delayed cerebral ischaemia in patients with aneurysmal subarachnoid haemorrhage: Functional outcome and long-term mortality. Acta Anaesthesiol Scand. 2019 Oct;63(9):1191-1199. doi: 10.1111/aas.13412. Epub 2019 Jun 7. |
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| 24847164 | Background | Budohoski KP, Guilfoyle M, Helmy A, Huuskonen T, Czosnyka M, Kirollos R, Menon DK, Pickard JD, Kirkpatrick PJ. The pathophysiology and treatment of delayed cerebral ischaemia following subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2014 Dec;85(12):1343-53. doi: 10.1136/jnnp-2014-307711. Epub 2014 May 20. |
| 21045864 | Background | Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab. 2011 Jan;31(1):17-35. doi: 10.1038/jcbfm.2010.191. Epub 2010 Nov 3. |
| 31886870 | Background | Hartings JA, Andaluz N, Bullock MR, Hinzman JM, Mathern B, Pahl C, Puccio A, Shutter LA, Strong AJ, Vagal A, Wilson JA, Dreier JP, Ngwenya LB, Foreman B, Pahren L, Lingsma H, Okonkwo DO. Prognostic Value of Spreading Depolarizations in Patients With Severe Traumatic Brain Injury. JAMA Neurol. 2020 Apr 1;77(4):489-499. doi: 10.1001/jamaneurol.2019.4476. |
| 27207168 | Background | Helbok R, Schiefecker AJ, Friberg C, Beer R, Kofler M, Rhomberg P, Unterberger I, Gizewski E, Hauerberg J, Moller K, Lackner P, Broessner G, Pfausler B, Ortler M, Thome C, Schmutzhard E, Fabricius M. Spreading depolarizations in patients with spontaneous intracerebral hemorrhage: Association with perihematomal edema progression. J Cereb Blood Flow Metab. 2017 May;37(5):1871-1882. doi: 10.1177/0271678X16651269. Epub 2016 Jan 1. |
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| 29653188 | Background | Reinhart KM, Shuttleworth CW. Ketamine reduces deleterious consequences of spreading depolarizations. Exp Neurol. 2018 Jul;305:121-128. doi: 10.1016/j.expneurol.2018.04.007. Epub 2018 Apr 10. |
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| 40721263 | Derived | Andreasen TH, Olsen MH, Gluud C, Lindschou J, Fabricius M, Hauerberg J, Moller K. S-ketamine versus placebo for cortical spreading depolarisation in severe acute brain injury (KETA-BID): protocol for a pilot, randomised, blinded clinical trial. BMJ Open. 2025 Jul 28;15(7):e101426. doi: 10.1136/bmjopen-2025-101426. |
| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D001930 | Brain Injuries |
| D006259 | Craniocerebral Trauma |
| D020196 | Trauma, Nervous System |
| D014947 | Wounds and Injuries |
| D017670 |
| Sodium Compounds |