Remote Ischemic Conditioning in Aneurysmal SAH

Aneurysmal subarachnoid hemorrhage (aSAH) is one of the most devastating types of stroke. Half of the patients die during the acute ictus, and those who survive have a poor prognosis as 20-30% are disabled or eventually die from the disease. In the acute phase after aSAH, the most devastating complication is rebleeding, whereas in the late phase, delayed cerebral ischemia (DCI) is another feared complication, associated with high morbidity and mortality. Symptoms of DCI occur in 30 % of patients and 15-20 % of patients will develop a disabling stroke due to DCI. DCI typically occurs between days 4 and 14 after the initial bleeding. The cause of DCI is not fully understood. Cerebral vasospasms (CVS) are commonly seen on angiography in the first 4-14 days after initial bleeding, and have been linked to late onset of symptoms of focal ischaemia since the 60s. Modern research suggests that the pathophysiology is multifactorial, but CVS is still thought to be a major contributor. Other contributing factors are thought to be microthrombosis, microvascular spasm, oxidative stress, cortically spreading depolarizations, cell death, breakdown of blood-brain barrier, among others. Treatment with nimodipine is standard-of-care and is the only pharmacological intervention that has been shown to improve outcome in aSAH patients, although it has no impact on large-vessel CVS\[.

The need for developing effective methods for prevention or treatment of DCI persists, and an effective prophylactic treatment may have a large impact on the general outcome of aSAH.

Ischemic conditioning is a potent activator of endogenous protection against ischemic injury. RIC can be applied as repeated short-lasting ischemia in a distant tissue that results in protection against subsequent long-lasting ischemic injury in the target organ. This protection can be applied prior to or during a prolonged ischemic event as remote ischemic preconditioning (RIPreC) and perconditioning (RIPerC), respectively.

RIC is commonly achieved by inflation of a blood pressure cuff to induce 5-minute cycles of limb ischemia alternating with 5 minutes of reperfusion. RIC activates several protective mechanisms, through humoral and neural pathways and shows promise in the setting of acute stroke.

Inflammation initiated by cerebral ischemia can contribute to secondary brain injury and is correlated with poor outcome. Following ischemia there is a harmful excess leukocyte infiltration in the brain parenchyma, and in experimental studies on aSAH, pharmacological inhibition of cytokines has been associated with improved outcome. RIC has been demonstrated to reduce inflammation and downregulate inflammatory markers. In addition, RIC has protective effects on cerebral endothelial function and induces vasodilation, increasing cerebral blood flow (CBF).

Angiogenesis, erythropoietin and nitric oxide (NO) are suggested to induce neuroprotection and stimulation of these strategies by conditioning including inhibition of inflammation has the potential to play an important part in treatment of patients after aSAH.

The effect of RIC on blood and cerebrospinal fluid biomarkers has never been explored in the setting of aSAH.

To-date, no serious adverse events have been documented in RIC. The procedure has been applied in numerous cardiovascular ischemic patients and in patients suffering from ischemic stroke and cerebral hemorrhage (ICH/SAH).

A recent smaller randomized trials of RIPreC after aSAH showed promising results with regards to functional outcomes and incidence of cerebral oxygen desaturation, likewise without adverse effects of RIC.

RIC is a non-pharmacologic and non-invasive treatment without noticeable discomfort that has neuroprotective potential worldwide.

Aneurysmal SAH and subsequent DCI represents a unique clinical opportunity to test RIC as DCI typically manifests within the first 14 days after ictus and is often a significant contributor to neurological injury. The treatment is feasible, safe, and rooted in well-explored physiological concepts. There is a clear scientific gap and opportunity to explore RIC in the setting of aSAH and DCI in larger randomized trials.

• Difference in Infarct growth [Time frame: MRI performed 4-6 weeks after initial hemorrhage.]
• Clinical outcome after 14 days measured by modified Rankin scale score (0-6, Higher score indicates worse outcome) [Time frame: 14 days after initial hemorrhage.]
• Occurrence of delayed cerebral ischemia [Time frame: Within first 14 days after initial hemorrhage.]
• Mortality after 3 months [Time frame: Assessed at 3 months post initial hemorrhage]
• Mortality after 12 months [Time frame: Assessed at 12 months post initial hemorrhage]
• Presence of angiographic vasospasm on CT angiography baseline vs 8-day scan [Time frame: 8-9 days post initial hemorrhage.]