PROMISE (Somatosensory Evoked POtEntials MonItoring During Acute Ischemic StrokE) Study

PROMISE (somatosensory evoked PotEntials MonItoring during the acute ischemic StrokE) is a prospective, observational, single center study of somatosensory evoked potentials (SEPs) monitoring with blinded clinical and neuroimaging evaluation of a cohort of patients with acute ischemic stroke undergoing endovascular mechanical thrombectomy (MT). The study is conducted under clinical routine protocols following the ESO and ASA guidelines (29). All patients, or their surrogates, provide written informed consent for using their clinical data for the research purposes.

The study has been designed to confirm in a large cohort a diagnostic hypothesis previously tested in a pilot academic study. The invention, as a solution to a specific technological problem, novelty, usefulness, and non-obviousness, has been protected by an European patent. The pilot study was founded by our academic Institution. This confirmatory study aims to validate the presence of the N20 response on SEPs monitoring prior to- and during the mechanical thrombectomy (MT) as a non-invasive and useful biomarker of functional recovery after MT.

Patients Recruitment period has started in February 2018 and will be open until June 2020 since the project end is expected for December 2020. Eligible patients are older than 18 years with an score equal or less of 2 in the modified Rankin Scale, and an occlusion in the anterior circulation (M1 or M2 segment of middle cerebral artery with or without ipsilateral internal carotid artery (ICA) significant stenosis or occlusion diagnosed by CT angiography (CTA) or angio-MRI) The study site is a certified comprehensive stroke center (CSC) that treats more than 500 patients with acute stroke and performs more than 100 mechanical stroke thrombectomy procedures annually and is staffed by trained neurointerventional technique.

A sample of 228 patients has been estimated to be necessary to demonstrate the utility of SEPs. They are going to be recruited from acute stroke patients gone under urgent thrombectomy in our center. Data of the patient is going to be register manually on paper and electronically with a statistical program (SPSS).

Medical treatment and mechanical thrombectomy workflow. Intravenous alteplase is given within 4.5 hours in eligible patients following a model ship or drip and ship model with a DTN target median time of less than 35 min. The target time from hospital arrival at the CSC to groin puncture is 80 minutes or less and from study baseline neuroimaging to first reperfusion is 90 minutes or less. MT is performed with stent retrievers or thrombus aspiration. The use of general anesthesia or conscious sedation is left at the discretion of the neurointerventional staff, but conscious sedation is preferred over intubation (30,31). BP and vital signs are continuously monitored during the procedure. Patients are admitted at acute stroke units (or ICU if needed) and treated following the European Stroke Organization ESO guidelines(32)

Clinical and neuroimaging assessments All participants have standard assessments of demographic characteristics, medical history, laboratory values and stroke severity by means of NIHSS score at the moment of the admission. Time metrics from stroke onset to different diagnostic and treatment interventions will be recorded during the acute phase. Basal neuroimaging may be indistinctly noncontrast head computed tomography (NCCT) plus CTA, multiparametric MR or perfusion CT (CTP) if MR is not available. In patients whose vascular occlusion study confirming qualifying occlusion is performed beyond 4.5 hours of last seen well or when the neurointerventional team is not immediately available in-hospital, multiparametric MR or CTP are recommended prior to the endovascular treatment, although treatment decision is only made following the ASPECTS score criteria. Follow-up NCCT or MR scans are performed within 24 hours for assessment of infarct volume and to rule out intracranial hemorrhage or malignant edema. CTA, MRA or TCD are used to confirm persisting vessel revascularization at 24 hours.

CTP protocol is carried out on a 64 detector scanner (APV General Electrics, GE Medical Systems; Milwaukee, Wisconsin, USA) and includes CBF, CBV, MTT and TMax perfusion maps. MR protocol is carried out on a 3 Tesla Siemens Magneton Verio with a 32-Channel Head Coil. MR images include axial brain SWI/EPI-gradient recalled echo (GRE), DWI, fluid attenuation inversion recovery imaging (FLAIR), Angio MR TOF, dMRA (dynamic postcontrast MR angiography) and perfusion study, which is performed immediately after dynamic study. All images are anonymised and stored in DICOM format. Blinded investigators to clinical outcome and SEPs monitoring adjudicate all neuroimaging studies. Imaging investigators perform a visual analysis of qualitative variables and quantitative analysis of post-processed variables: firstpass permeability and perfusion maps. Post-process of DWI and perfusion sequences are done by using Olea Sphere platform. In addition, RAPID software (iSchemaView, Redwood City, CA) is used for emergent baseline and follow-up ischemic lesion volume calculation on MR-DWI or CTP-rCBF maps and for the automatic evaluation os ASPECTS score on NCCT and DWI-MR.

Pre-procedural imaging variables include volume and location of ischemic core and hypoperfused tissue at baseline, severity of hypoperfusion, site of occlusion and degree of collaterals according to the Arterial Collateral Grading Scale (ACG) if CTA or by using the ASITN/SIR Collateral Grading System scale if dMRA is performed. Follow-up images include volume and location of ischemic lesion, hemorrhagic transformation and arterial status.

Testing: SEPs monitoring Evoked potentials recordings are performed by the intraoperative monitoring system OSIRIS (Inomed Medizintechnik GmbH). SEPs recording are initiated in the emergency room or the angiosuit before the groin puncture and endovascular treatment, and continuous during the procedure. Because there may also be neurological damage during reperfusion (33), SEPs recordings are prolonged until patient leaves the angiography room and is transferred to the Acute Stroke Unit.

Both median nerves will be stimulated at wrist by means of surface adhesive electrodes. The investigators use supramaximal stimulation defined as the intensity that causes visually perceptible movement of the stimulated limb. The investigators apply square wave electrical pulses of 0.2 ms duration at a frequency of 5.7Hz. The investigators used a rate of 6.7 Hz if it is required according to the signal-to-noise ratio. SEPs are recorded in a referential fashion from the C3' (right median nerve stimulation) and C4' (left median nerve stimulation) positions and from a reference electrode at Fpz (international 10-20 system) or Cz' electrodes (2 cm behind Cz). The investigators use needle electrodes in conscious patients or "cork screw" electrodes in patients under general anesthesia during the thrombectomy procedure (Figure 1). The signal was digitally filtered (5-200 Hz bandpass) and analyzed within 80 msec time window poststimulus. Twenty to one hundred fifty trials were averaged depending on the signal-to-noise ratio.

The target signal is the presence of N20 response ipsilateral to the stroke site. Secondarily, the investigators also measure the amplitude and latency of N20 response both ipsilateral and contralateral to the stroke site. SEPs traces were analyzed at the moment of their recording by the examinators. Later, they also were analyzed by another blinded investigator to clinical outcome and SEPs monitoring.

Motor evoked potentials can not be performed because patients are awoke during the endovascular procedure according to the current standard of care

Primary Outcome The primary outcome is the functional independence at 7 days or discharge, defined by the modified Rankin scale score 0- 2. This early and more feasible outcome has a very high correlation with functional dependence at 90 days (Davalos A et al. Lancet Neurol 2017). Local certified assessors who are unaware of the SEPs monitoring findings evaluate the primary outcome variable in each patient by means of a structured interview.

Secondary outcomes Secondary clinical outcomes are the primary outcome evaluated at 90 days, the severity of disability at 7 days and 90 days, according to the distribution of scores on the modified Rankin scale (shift analysis), severe disability (score of 5) and death (score of 6) are combined into a single, worst category; early dramatic response to treatment (defined as a decrease in the NIHSS score of 8 or more points from baseline or an NIHSS score of 0 to 2 at 24 hours); and neurologic improvement at 24 hours defined as a decrease in the NIHSS score of 4 or more points from baseline).

Secondary neuroimaging variables are adjudicated infarct volume on CT or MRI at 24 hours; postprocedural revascularization classified as modified TICI scale 2b or 3 (indicating reperfusion of more than 50% of the affected territory); degree of vessel revascularization on CT angiography (CTA) or MR angiography (MRA) at 24 hours by using AOL scale or TCD by using TIMI score. In a subgroup of patients with pre- and post-MT multimodal MR or CTP, it will be calculated tissue perfusion recovery as the reperfusion index (TMax6s pre-MT x TMax6s post-MT)/TMax6s pre-MT). Lately, baseline imaging variables are also studied as potential predictors of recovery

Safety variables Safety outcomes are the rates of death and symptomatic intracranial hemorrhage at 90 days, as confirmed on neuroimaging (CT or MRI) evaluated by blinded investigators, according to the definition used in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST). Evaluators also use the definition of symptomatic intracranial hemorrhage that was used in the second European-Australasian Acute Stroke Study (ECASS II) An independent investigator adjudicates procedure-related complications. Blood pressure variations during the procedure are also recorded.

Statistical Analysis All analyses will be performed in the total monitored patients (feasibility analysis). The primary measure of the effect size will be the unadjusted sensitivity and specificity (and their 95%CI) of the N20 response on SEPs prior to MT in predicting functional independence at 7 days or at discharge if earlier after treatment in patients with acute stroke and anterior large vessel occlusion.

According to our preliminary results, preestablished effect size is a true-positive rate of positive detection (functional independence) of > 92% (sensitivity) retaining a good rate of true-negative of negative detection (functional dependence) >90% (negative predictive value). In order to maintain the 95% low confidence intervals over 85% in both proportions, and considering a rate of negative detection of 28.6%, 228 patients are needed, 65 without N20 response and 163 with positive detection of N20 response. The adjusted predictive value of the N20 biomarker on functional independence after MT will be analyzed by binary logistic regression and its predictive value on the full range of disability (shift analysis) by ordinal logistic regression. The investigators will construct different regression models with other clinical predictors available at the prehospital setting and with those determined after hospital admission, including clinical and easy assessable imaging predictors. This analysis will give the independent predictive power of the N20 response for a potential treatment decision-making. The investigators will also evaluate the predictive binary effect of the N20 as a function of time from onset of symptoms to the first SEP stimulation and as a function of time from onset of symptoms to revascularization. Secondary analyses will include unadjusted association of N20 response with secondary clinical and neuroimaging outcomes and safety variables.