Induced Hypertension in Acute PRogrESsive Perforating Artery Stroke Using Peripheral Dilute noREpinephrine

Perforating artery strokes represent 25% of all ischemic strokes and is a well-known cause of progressive symptoms : 12 to 36% of cases experience early neurological deterioration in hours or days after stroke onset. A possible mechanism is hypoperfusion due to lack of a rapid development of collateral flow because of the terminal distribution of perforating arteries. Moreover, arterioles are maximally dilated within penumbra region, resulting in a cerebral autoregulation failure and a passive dependence of cerebral blood flow on arterial pressure. Thus, induced-hypertension therapy by using vasopressive agents is an attractive therapy to increase the cerebral perfusion pressure and therefore restore blood flow in the ischemic penumbra.

Inclusion criteria

• Acute ischemic stroke < 72 h in a perforating artery territory on brain MRI
• Early neurological deterioration or fluctuation, attested by the neurologist in charge, defined by a ≥ 3-point increase in global NIHSS score OR a 2-point increase on motor or ataxia score, whether this deterioration is transient or permanent.
• Time between early neurological deterioration and randomization < 6 hours
• Age ≥ 18 years
• Contraception required in women of childbearing potential (Intra-uterine device, hormonal contraception associated with inhibition of ovulation (combined or progestogen-only; oral, intravaginal or transdermal), Female Sterilization, Vasectomised partner, sexual abstinence)
• Beneficiary of a health insurance system

Exclusion criteria

• - Pre-Stroke Modified Rankin Score > 3
• Contraindication to brain Magnetic Resonance Imaging (MRI)
• High risk of intracerebral hemorrhage:

• Cerebral microbleeds ≥ 10
• Non traumatic focal superficial siderosis
• Hemorrhagic transformation of the present ischemic stroke
• Previous history of intracerebral hemorrhage (symptomatic or asymptomatic identified on brain MRI)
• Intracranial vascular malformation or tumor with suspected risk of rupture or bleeding
• Prior intravenous thrombolysis < 24 hours
• Requirement for anticoagulation in the first 7 days after randomization
• Systolic blood pressure (SBP) > 180mmHG and/or mean arterial pressure (MAP) ≥ 110mmHG at inclusion
• Large artery atherosclerosis (ipsilateral atherosclerotic stenosis > 50%), intra and extracranial dissection, or cardio-embolic stroke mechanisms
• Drugs with important interactions with norepinephrine: monoamine oxidase inhibitors (including reversible, non-selective agents such as linezolid), tricyclic antidepressants, entacapone.
• Pregnancy or breastfeeding