Endovascular Treatment, Ischemic Stroke, Large Vessel Occlusion
Conditions
Keywords
hypothermia, neuroprotection
Brief summary
The goal of this clinical trial is to test the combination of hypothermia and endovascular treatment in acute stroke patients with large vessel occlusion. The main question it aims to answer is: does an additional cooling to 35°C result in a benefit on clinical outcome ? Participants receive immediate cooling using a noninvasive transnasal cooling technique (RhonoChill) and are maintained at 35°C for 6 hours after reopening of the vessel using surface cooling, and then slowly rewarmed. Researchers will compare the intervention group (hypothermia and endovascular treatment and best medical treatment including iv thrombolysis) and control group (only endovascular treatment and best medical treatment including iv thrombolysis) to see if additional hypothermia leads to a better outcome after 3 months without relevant complications.
Detailed description
Despite the well-established benefit of endovascular treatment (EVT) for acute ischemic stroke due to large vessel occlusion (LVO), more than half of patients treated with EVT remain functionally dependent despite high reperfusion rates. Thus, new strategies such as additional neuroprotection using hypothermia need to be explored, first to bridge time to reperfusion and second, to attenuate reperfusion injury. Although therapeutic hypothermia has consistently demonstrated robust neuroprotection in animal ischemic-reperfusion models, randomized trials in acute stroke patients have failed to demonstrate the efficacy of induced hypothermia. The reasons for this treatment failure are diverse and include treatment delay, the unfeasibility of inducing and maintaining hypothermia due to intolerance and shivering in awake patients, the missing recanalization in a large proportion of patients, the heterogeneity of patients included, and too deep (32-34°C) hypothermia associated with an increase in side effects. In the pilot study COTTIS-1, we could demonstrate the feasibility and safety of immediately induced intraischemic hypothermia to 35°C with non-invasive transnasal cooling by RhinoChill® (BrainCool) followed by surface cooling for 6h after recanalization in sedated and intubated patients with LVO undergoing EVT. By combining this cooling technique with thrombectomy we have tried to address the above mentioned reasons for hypothermia failure. In COTTIS-1, the target temperature of 35°C was reached within 30 min, corresponding to a cooling rate of 2.6°C/h. All patients reached the target temperature, and 86% of the patients had reached ≤35°C at recanalization by thrombectomy. 68% of patients had a good outcome (independency) after 3 months. There were only asymptomatic side effects during hypothermia. As a consequence, the present COTTIS-2 study is planned to evaluate the efficiency of this cooling protocol in a multicentric, randomized, controlled, end-point-blinded study in Germany.
Interventions
DEVICEhypothermia
hypothermia is started after intubation for endovascular treatment and induced by transnasal cooling (RhinoChill) to a target temperature of 35°C and hypothermia is then maintained at 35°C for 6 hours after recanalisation by surface cooling followed by slow rewarming by 0.2°C per hour to 36.5°C
Sponsors
European Union
E+E CRO consulting, Vienna, Austria
Center for Medical data science, University of Vienna, Austria
University of Freiburg
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pre-stroke modified Rankin Scale (mRS) 0-2 \[7-point scale rating from 0 (no symptoms) to 6 (dead)\] * Acute ischemic stroke with NIHSS \>5 * Intracranial occlusion of the M1 or M2 segment of the middle cerebral artery (MCA) or internal carotid artery (ICA) or tandem occlusion on CT-angiography or MR-angiography with indication for endovascular treatment: * Time window 0-24h: 1. Last seen normal to groin puncture \< 6h: native CT or MRI-DWI with ASPECTS \>5 2. Last seen normal to groin puncture 6-24h or unknown time window: significant mismatch imaging according to the eligibility criteria of the DEFUSE-3 trial * Infarct core \<70ml (DWI oder CBF\<30%) * Penumbra \> 15ml (Tmax \>6sec) * Ratio penumbra/core \>1.8 * with or without iv thrombolysis with rtPA
Exclusion criteria
* Patients with an intranasal obstruction that prevents complete insertion of the nasal cannula should not be treated with the RhinoChill system. * Known severe hemorrhagic diathesis (International Normalized Ratio (INR) \>3.0, partial thromboplastin time (PTT) \> 70s, platelet count \< 50.000/μl) * Brain trauma or neurovascular surgery/intervention \<3 months * Severe infection * Pregnant women or women of childbearing potential (women of childbearing potential with negative pregnancy test may be included) * Known cerebral vasculitis * Proof of bleeding in cerebral CT or MRI (cerebral microbleeds in MRI \[hypertensive or in the context of cerebral amyloid angiopathy\] is permitted). * Known life expectancy \< 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| functional outcome | 3 months | The presence of patients with good neurological outcome after 3 months as defined by modified Rankin Scale (mRS; on which scores range from 0 to 6, with 0 means no symptoms and 6 means death) of 0-2 or back to baseline before stroke |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| infarction volume | 24 hours | Infarction volume assessed in the standard CT 24 hours after thrombectomy |
| increase in infarction | 24 hours | increase of the infarct core based on imaging at the time of admission (DWI-MRI or CBF\<30% of contralateral side at CT-Perfusion) and CT after 24 hours |
| recanalization result | after thrombectomy and 24 hours | Recanalization result (by mTICI score: successful recanalization mTICI 2b-3) after thrombectomy (based on angiography during/after thrombectomy) and 24 hours after thrombectomy (based on ultrasound of the cerebral vessels) |
| neurological improvement | 48 hours | Change of at least 8 points on the National Institutes of Health Stroke Scale (NIHSS; on which scores range from 0 to 42, with higher scores indicating a greater deficit) at 48 hours after thrombectomy |
| outcome at discharge | up to 3 months | modified Rankin Score (mRS; on which scores range from 0 to 6, with 0 means no symptoms and 6 means death) upon discharge/transfer in rehabilitation |
| shift in functional outcome | 3 months | ordinal shift across the range of modified Rankin Score (mRS; on which scores range from 0 to 6, with 0 means no symptoms and 6 means death) |
| very good clinical outcome | 3 months | Presence of patients with very good clinical outcome after 3 months (mRS 0-1) |
| time to groin puncture | baseline, pre-intervention | Time from arrival until groin puncture |
| time to recanalization | periprocedurally | Time from arrival until recanalization |
| mortality | 3 months | Mortality during acute hospitalisation and after 3 months |
| Length of ventilation | 3 months | Length of mechanical ventilation |
| Length of stay | 3 months | Length of ICU stay and hospital stay |
| body temperature | 24 hours | Temperature at admission, at recanalization, and first 6 hours after recanalization, and at 24 hours |
Other
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of intracerebral haemorrhage (ICH) | 24 hours | * Any ICH (subarachnoid, intraparenchymal, intraventricular) on the CT after 24 hours * Symptomatic ICH (defined according to SITS-MOST criteria): Hematoma \>30% of initial infarction volume associated with a clinical deterioration in NIHSS score of at least 4 points within 24 hours after thrombectomy |
| Complications associated with hypothermia | 24hours | * Nosebleed and pailing of the nose * Periorbital emphysema * Pneumocephalus (in 24-hour control CT) * Blood pressure, heart rate, oxygen saturation SO2 * Episodes with severe hypotension with systolic blood pressure \<110mmHg * Incidence of pneumonia (defined as: any new pulmonary infiltrate on radiographic imaging occurring \<48hrs after admission combined with at least one of the subsequent findings: fever \>38°C, leukopenia/leucocytosis, purulent secretions with positive cultures) * Disturbances in electrolytes, renal function, coagulation (potassium, sodium, chloride, creatinine, INR, pTT, thrombocytes measured on admission before hypothermia and at 24 hours) |
Countries
Germany
Contacts
Primary ContactJuergen Bardutzky, Prof.
Backup ContactWolf-Dirk Niesen, PD Dr.
Outcome results
None listed