The purpose of this research study is to better understand when to start rehabilitation therapies after acute ischemic stroke to prevent further harm to the brain and to improve outcomes for stroke survivors.

Stroke is the second leading cause of death and reduced quality of life worldwide, with one Canadian diagnosed with stroke every five minutes. The most common subtype, ischemic stroke, occurs when a blood vessel in the brain is blocked. Hyperacute treatments aim to remove these blockages to restore blood flow and improve deficits, but in some cases, this is not achieved and leads to persistent large or medium intracranial vessel occlusion.

After stroke, early medical and physical care can reduce physical and cognitive impairment and improve long-term functional outcomes. Prolonged immobilization can cause secondary complications and make recovery more difficult. Other research studies have demonstrated varying results with both benefit and no difference in the long-term level of functional independence when starting physical activity between 24 to 48 hours after acute ischemic stroke. The optimal timing for mobilization is unclear especially for patients with persistent vessel occlusion large stroke size, or intracranial hemorrhage, where starting active therapy too soon can cause additional harm by damaging the brain further.

In this research study, the investigators aim to evaluate the feasibility and effect of delayed mobilization (DeM), defined as physical therapy starting on or after day 3 from stroke symptom onset, on stroke volume growth and functional outcomes in patients with persistent vessel occlusion. The investigators think that individuals who still have evidence of persistent blockage in their arteries may benefit from waiting until day 3 after stroke to begin rehabilitation.

Improving care strategies for stroke survivors will ultimately benefit individuals, their families, and healthcare systems. This study may guide the optimal timing of initiating stroke rehabilitation in patients with persistent vessel occlusion and ischemia to improve recovery times and reduce long-term disabilities.

While stroke remains the world's second leading cause of death and reduced quality of life in adults, mortality and disability have decreased over the years with advances in acute care and improvements in risk stratification (1). Ischemic stroke is the most common stroke subtype, caused by a blockage of blood flow in an artery in the brain. Revascularization interventions aiming to restore blood flow include intravenous thrombolysis and endovascular thrombectomy and have evidence in reducing the likelihood of long-term disability when performed rapidly in patients presenting early and without contraindications (2-4). Traditionally, functional independence is measured at 90 days after stroke using the modified Rankin scale (mRS) (5), where a score of 0 to 2 indicates limited impairment.

Early multidisciplinary care is essential for reducing physical and cognitive impairment following stroke, and in improving the chances of functional independence in the long-term. Immobilization for prolonged periods of time can result in secondary complications that further negatively impact recovery, including pneumonia, deep venous thrombosis, delirium, reduced muscle mass, and joint contractures (6). These secondary complications not only limit recovery, but increase the risk of mortality after stroke. Physical rehabilitation after stroke includes sitting, standing, supported ambulation, and repetitive body strength training with registered physiotherapists and occupational therapists. Early mobilization after stroke has been defined as starting physical rehabilitation between 24 to 48 hours after stroke onset, while some have proposed that very early (7) mobilization occurring within 12 hours of stroke onset has benefit.

Evidence for early or very early mobilization suggest that proteins associated with endogenous neural repair and growth-promoting factors are altered within the first few weeks after ischemic stroke (8-10). As a result, the upregulation in these processes may provide greater neuroplasticity for the injured brain to greater enhance its responsiveness to rehabilitation (11-13), and subsequently improve outcomes for stroke survivors. However, animal studies have also observed that starting exercise 6 hours after infarction raises pro-inflammatory cytokines and pro-apoptotic proteins leading to aggravated brain injury (14-15). The best timing for mobilization remains unclear when considering individual stroke factors such as persistent vessel occlusion (PVO), size of the ischemic core, or presence of intracranial hemorrhage, where active therapy can cause harm by increasing ischemic depolarization and reducing cerebral blood flow.

Clinically, the evidence regarding the timing of mobilization is additionally controversial. Studies have demonstrated both benefit (7,11,16-17) and no difference (18-22) in the level of functional independence following early mobilization between 24 to 48 hours after acute stroke when compared to individuals who received active therapy starting at 72 to 96 hours after stroke onset. More recently, the AVERT trial found a decrease in the odds of good outcomes (mRS score 0-2) at 3 months when mobilizing survivors within 24 hours of acute ischemic stroke (21). These findings are likely explained by their heterogenous sample including patients with PVO of large or medium caliber. Despite advances in stroke care and prevention, determining the optimal time to start physical activity after stroke to balance the risks of increasing stroke growth versus providing stroke survivors the best chance for greater independence is unknown.

Rehabilitation is crucial for reducing post-stroke disability and improving functional independence (23). The exact timing, however, on when to initiate rehabilitation after stroke is unclear. In some cases, starting rehabilitation immediately and very early after stroke (i.e., within 24 hours) can result in growth of the infarcted brain tissue due to cerebral hypoperfusion, resulting in worse clinical outcomes (21). In the present study, the investigators aim to determine the optimal timing of when to start active therapy after ischemic stroke by comparing a model of delayed mobilization (active therapy starting on or after day 3 post-stroke) to standardize care (active therapy starting by day 2 post-stroke). The investigators aim to determine the impacts of delayed mobilization on stroke volume growth, secondary brain injuries including hemorrhagic transformation and tissue hypoperfusion, and clinical measures of independence.

References

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Inclusion Criteria:

• Participants with acute ischemic stroke presenting to Foothills Medical Centre meeting eligibility for intravenous thrombolysis (Tenecteplase, TNK) - ≥18 years of age presenting within 4.5 hours of symptom onset with a diagnosis of suspected acute ischemic stroke causing significant neurological disability - and/or endovascular thrombectomy (EVT).

• Age ≥18 years.

• Persistent vessel occlusion will be defined as any of the following:

  • EVT treatment of medium or large intracranial vessel occlusion with a thrombolysis in cerebral infarction (TICI) score of ≤2b.
  • A moderate infarct core (ASPECTS ≤5) despite TICI 3.
  • 24-hour CT with evidence of hyperdense sign appropriate to clinical deficits.

Exclusion Criteria:

• Comorbid conditions limiting recovery or life expectancy (e.g., significant cognitive impairment, stage IV cancer, end-stage renal disease).
• Low pre-stroke baseline functional status (mRS ≥4).
• Symptoms due to another acute neurological condition (e.g., migraine with aura, seizure) or neurological deficits secondary to metabolic/toxic derangements (e.g., hyponatremia, hypoglycemia).

Participants will be assigned to the control or experimental group using a 1:1 computer-generated randomized dynamic allocation procedure. All members of the research team will be blinded to group allocation. Participants and allied health team members (physiotherapist, occupational therapist, nursing) will not be blinded but will be asked not to tell the assessor or other participants which group they have been allocated to, in order to preserve blinding of the assessments. The study statistician and the rest of the Data Safety Monitoring Board will have access to the assignment if necessary.