ketamine for thrombolysis in acute ischemic stroke

Conditions: Stroke

Summary: keta trial is a nonprofit, double-blind, randomized, controlled pilot trial with aiming to determine if co-administration of ketamine with recombinant of tissue type plasminogen activator (tpa) for thrombolysis in acute ischemic stroke compared with tpa co-administered with placebo, decreases cerebral infarction growth in diffusion weighted imaging between admission and day 1. eligibility applies to patients with symptomatic ischemic stroke seen within 4.5 h of onset with middle cerebral artery or distal internal carotid artery occlusion, no contraindication to intravenous tpa-mediated thrombolysis and eligible to endovascular treatment of stroke (i.e. thrombectomy). the study has been designed to have 80% power to detect a 80% decrease of infarct volume growth in the tpa-ketamine group at a two-sided type i error rate of 5%. for this purpose, at least 25 patients per arm should be enrolled.

rationale - tissue-type plasminogen activator (tpa) is a double-sided molecule, with beneficial effect in acute ischemic stroke due to its intravascular fibrinolytic activity but with potential deleterious effect due to its ability to potentiate neuronal n-methyl-d-aspartate (nmda) receptor signalling (nicole et al., 2001). co-administration of sub-anesthetic dose of ketamine - a non-competitive inhibitor of nmda receptor - was shown to improve efficacy of tpa-mediated thrombolysis following stroke in rodents (gakuba et al, 2011). aims - to assess efficacy and safety of co-administration of ketamine with tpa compared with tpa-placebo infusion in patients with acute ischemic stroke. sample size estimates -with 25 patients per group, the trial has a 80% probability of detecting a 80% decrease of infarct volume growth in the tpa-ketamine group compared with the tpa-placebo group on day 1 after admission at a two-sided type i error rate of 5%. study outcomes - the primary efficacy outcome is cerebral infarction growth on diffusion weighted imaging between admission and day 1. the primary safety measure is mortality and/or symptomatic intracerebral hemorrhage rate at 3 months.

Eligibility criteria:
inclusion criteria: * sudden focal neurological deficit attributable to acute ischemic stroke. * age between 18 and 85. * time from symptom onset less than 4.5 hours. * nihss score between 7 and 20. * informed consent for participation. * ketamine can be administered within 15 minutes after onset of tpa infusion. * mri-based ais diagnosis. * middle cerebral (m1 or m2 segment) and/or distal internal carotid artery occlusion. * no intracranial hemorrhage on mri. * patient eligible for thrombectomy. exclusion criteria: * contraindication to iv tpa treatment. * contraindication to ketamine. * contraindication to mri. * contraindication to intravascular iodinated contrast media. * consciousness level \>1 on question 1a of nihss. * pre-stroke mrs ≥3. * concomitant medical illness that would interfere with outcome assessments and follow-up (e.g. advanced cancer or respiratory disease). * previous participation in this trial or current participation in another investigational drug trial. * infarct volume on diffusion weighted mri more than 100 ml.

Keywords: cerebral infarct thrombolysis tissue-type plasminogen activator neuroprotection anesthetic agent magnetic resonance imaging