The Anesthetic Ketamine as Treatment for Patients With Severe Acute Brain Injury

Traumatic Brain Injury Clinical Trial

— KETA-BID  

Official title:

S-ketamine for Cortical Spreading Depolarisation in Patients With Severe Acute Brain Injury

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05095857
• Other study ID #: H-21056972
• Secondary ID: 2021-003716-12
• Status: Recruiting
• Phase: Phase 4
• Start date: September 15, 2023
• Est. completion date: December 1, 2026

Study information

• Verified date: September 2023
• Source: Rigshospitalet, Denmark
• Contact: Trine H Andreasen, MD
• Phone: +4535455982
• Email: trine.hjorslev.andreasen[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: December 1, 2026
• Est. primary completion date: December 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age = 18 years.

• Admitted to the NICU with a diagnosis of TBI, aneurysmal SAH or spontaneous ICH.

• Planned for surgery with a craniotomy or craniectomy.

• Expected to continue sedation and mechanical ventilation after surgery.

Exclusion Criteria:

• Patient and next of kin do not read or understand spoken Danish.

• 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 blood hCG taken to control for pregnancy).

• Active anti-psychotic treatment before admission

• Current abuse of ketamine.

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.

Related Conditions & MeSH terms

• Brain Injuries
• Brain Injuries, Traumatic
• Cerebral Hemorrhage
• Hemorrhage
• Intracerebral Hemorrhage
• Subarachnoid Hemorrhage
• Subarachnoid Hemorrhage, Aneurysmal
• Traumatic Brain Injury
• Wounds and Injuries

Intervention

Drug:
• S-ketamine
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.

Other:
• Isotonic saline (placebo)
Isotonic saline has the same appearance as S-ketamine with both being clear liquids with no bubbles or other distinguishing features.

Locations

Country	Name	City	State
Denmark	Rigshospitalet	Copenhagen

Sponsors (2)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark	Copenhagen Trial Unit, Center for Clinical Intervention Research

Country where clinical trial is conducted

Denmark, 

References & Publications (26)

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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. — View Citation

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. — View Citation

Hertle DN, Dreier JP, Woitzik J, Hartings JA, Bullock R, Okonkwo DO, Shutter LA, Vidgeon S, Strong AJ, Kowoll C, Dohmen C, Diedler J, Veltkamp R, Bruckner T, Unterberg AW, Sakowitz OW; Cooperative Study of Brain Injury Depolarizations (COSBID). Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury. Brain. 2012 Aug;135(Pt 8):2390-8. doi: 10.1093/brain/aws152. Epub 2012 Jun 19. — View Citation

Hertle DN, Heer M, Santos E, Scholl M, Kowoll CM, Dohmen C, Diedler J, Veltkamp R, Graf R, Unterberg AW, Sakowitz OW. Changes in electrocorticographic beta frequency components precede spreading depolarization in patients with acute brain injury. Clin Neurophysiol. 2016 Jul;127(7):2661-7. doi: 10.1016/j.clinph.2016.04.026. Epub 2016 May 4. — View Citation

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. — View Citation

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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. — View Citation

Sakowitz OW, Kiening KL, Krajewski KL, Sarrafzadeh AS, Fabricius M, Strong AJ, Unterberg AW, Dreier JP. Preliminary evidence that ketamine inhibits spreading depolarizations in acute human brain injury. Stroke. 2009 Aug;40(8):e519-22. doi: 10.1161/STROKEAHA.109.549303. Epub 2009 Jun 11. — View Citation

Schiefecker AJ, Beer R, Pfausler B, Lackner P, Broessner G, Unterberger I, Sohm F, Mulino M, Thome C, Humpel C, Schmutzhard E, Helbok R. Clusters of cortical spreading depolarizations in a patient with intracerebral hemorrhage: a multimodal neuromonitoring study. Neurocrit Care. 2015 Apr;22(2):293-8. doi: 10.1007/s12028-014-0050-4. — View Citation

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Welling L, Welling MS, Teixeira MJ, Figueiredo EG. Cortical spread depolarization and ketamine: a revival of an old drug or a new era of neuroprotective drugs? World Neurosurg. 2015 Apr;83(4):396-7. doi: 10.1016/j.wneu.2015.01.006. Epub 2015 Jan 31. No abstract available. — View Citation

Zhou YT, Tong DM, Wang SD, Ye S, Xu BW, Yang CX. Acute spontaneous intracerebral hemorrhage and traumatic brain injury are the most common causes of critical illness in the ICU and have high early mortality. BMC Neurol. 2018 Aug 27;18(1):127. doi: 10.1186/s12883-018-1127-z. — View Citation

* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	All-cause mortality		assessed at 6 months after randomisation
Other	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	Before discharge from NICU or the semi-intentisive care unit, expected up to be no later than day 21 postrandomisation
Other	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
Other	Occurrence of local cerebral hypoxia (PbtO2 <20 mmHg for more than 20 minutes)		Postrandomisation period, expected up to 21 days
Other	Dosage of standard sedatives and analgesics		Postrandomisation period, expected up to 21 days
Other	Number of imaging procedures (CT of the brain, CT-angiography, digital subtraction angiography, MRI)		Postrandomisation period, expected up to 21 days
Other	Number of episodes of neurological worsening		Postrandomisation period, expected up to 21 days
Other	Occurrence of delayed cerebral ischemia (DCI) in participants with aSAH		Postrandomisation period, expected up to 21 days
Other	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
Other	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
Primary	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
Secondary	Rate of adverse events and adverse reactions		During treatment with S-ketamine or placebo, a maximum of 14 days
Secondary	Functional outcome at 6 months after randomisation	assessed using modified Rankin Scale	6 months after randomisation