Reperfusion Injury in Stroke Thanapon Songthammawat,MD Outlines • Overview • Symptoms of cerebral reperfusion syndrome • Causes of cerebral reperfusion injury • Reperfusion Injury After Thrombolytic Therapy • Reperfusion Injury After Endovascular Mechanical Thrombectomy • Assessment of Risk for Reperfusion Injury in Carotid Endarterectomy and Stenting • Prevention of Reperfusion Injury Reperfusion syndrome • Cerebral hyperperfusion, or reperfusion syndrome • Rare, but serious • Complication following revascularization • Rapid restoration of normal perfusion pressure • Reperfusion syndrome can occur as a complication of thrombolytic therapy for AIS, carotid endarterectomy (CEA), intracranial stenting, and even bland cerebral infarction. • However, not all patients with hyperperfusion are symptomatic • Patients with only moderate rises in CBF can have severe outcomes • Outcomes are dependent on timely recognition and prevention of precipitating factors • Most important is the treatment of hypertension • Reperfusion injury is involved directly in the potentiation of stroke damage • Components of the inflammatory response, including cytokine release and leukocyte adhesion, appear to play key roles in these effects. • Damage to the blood-brain barrier (BBB), an important factor in reperfusion injury • Postcontrast image 24 hours after a right middle cerebral artery stroke, demonstrating contrast extravasation through a faulty blood-brain barrier. Causes of Cerebral Reperfusion Injury • Several mechanisms • As time passes following arterial occlusion or partial occlusion • Eventually compensation for hypoperfusion will lead to increased vascular resistance and venous collapse • The extent of reperfusion injury will depend on the individuals time since collateral collapse and irreversibly damaged tissues • Known risk factors include the following – Postoperative hypertension – High-grade stenosis with poor collateral flow – Decreased cerebral vasoreactivity – Increased peak pressure, such as in contralateral carotid occlusion – Recent contralateral CEA (< 3 mo) – Intraoperative distal carotid pressure of less than 40 mm Hg – Intraoperative ischemia peak flow velocity Cerebral hyperperfusion syndrome following carotid endarterectomy. QJM. 2007; 100(4):239-44 FUNCTIONAL ANATOMY OF THE BLOOD– BRAIN BARRIER • BBB is composed of endothelial cells, pericytes, astrocytes, neurons, and the Neurovascular unit (NVU) extracellular matrix (ECM) - For the energy-dependent processes, nutrient support and protection of the brain - Astrocytes play a very important role not only in BBB support and its maintenance but also in neuron–NVU interactions • Ischemia is a disruption of the bidirectional communication between microvessels and neurons with the participation of the intervening astrocytes • Microglial cells are basically the macrophages of the CNS and have the potential to release immunoregulatory, inflammatory, and cytotoxic mediators and thereby influence the BBB • Insult to the brain causes the “resting” microglia to change from small bodies with long– thin processes to a phagocytic form with stubby processes. • The ECM is composed of structural proteins, which are susceptible to enzymatic degradation. Endothelial cells, pericytes, and astrocytes express the integrin and dystroglycan families of matrix adhesion receptors, which adhere to the ECM and serve to mediate NVU function • Proinflammatory cytokines such as interleukin-1 and tissue necrosis factor are induced and are followed by chemokines • This leads to leukocyte recruitment and extravasation • Enhancing inflammatory activity and toxic free radical production • Therefore, the various previously discussed mechanisms initiated during the ischemic cascade have a significant impact on the BBB Impact of reperfusion • Proposed that there are 3 stages of reperfusion (animal models) • Stage 1 is reactive hyperemia; loss of cerebral autoregulation, increased BBB permeability, and acute elevation in regional cerebral blood flow • Stage 2 is hypoperfusion which occurs immediately after the stage of hyperemia • Continued cerebral metabolic depression, microvascular obstruction, occlusion via swelling of endothelial cells and astrocytic end-feet, and formation of endothelial microvilli • This causes nutritional deficiency in brain tissue and enhances neutrophil adhesion, with subsequent inflammatory activity • Stage 3, increased paracellular permeability, which occurs as a biphasic response. • Usually occur > 72-96 hr • Associated with vasogenic edema, resulting in increased permeability to macromolecules Key factors in the pathophysiology of cerebral hyperperfusion syndrome Reperfusion Injury After Thrombolytic Therapy • Symptomatic hemorrhagic transformation rates may occur in 24-36 hours • Rates of symptomatic intracerebral hemorrhage are generally higher in intra-arterial lytic trials (eg, 10% in PROACT-II) than in intravenous lytic trials (eg, 6.4% in NINDS). • The rates of symptomatic ICH following revascularization with a device are even lower and range from 4%-2% with the Trevo and Solitaire stent systems Risk factors for hemorrhagic transformation • Stroke severity • Older patients • Comorbidity • Time Reperfusion Injury After Endovascular Mechanical Thrombectomy • Proximal cerebral artery occlusions often result in large areas of penumbra • Vulnerable to reperfusion injury following revascularization • Therapeutic treatment window has extended beyond 6 hours in patients with favorable perfusion imaging • Two studies have demonstrated that higher blood pressure goals following thrombectomy, correlated with worse clinical outcomes. Post-CEA CHS 4 criteria to define post-CEA CHS : • Occurrence within 30 days post-CEA • Clinic features such as new onset headache, seizure, hemiparesis, and glasgow coma scale (GCS) <15 or radiological features including cerebral edema or intracerebral hemorrhage (ICH); • Evidence of hyperperfusion (defined as a cerebral blood flow [CBF] >100 % or perioperative values) on imaging studies [e.g., transcranial doppler, single photon emission computerized tomography (SPECT) or magnetic resonance perfusion (MRP)] or systolic blood pressure >180 mmHg and • No evidence of new cerebral ischemia, postoperative carotid occlusion and metabolic or pharmacologic cause. Assessment of Risk for Reperfusion Injury in Carotid Endarterectomy and Stenting • Preoperative transcranial Doppler ultrasonography – Measures cerebral blood flow in major cerebral arteries. – Low preoperative distal carotid artery pressure (< 40 mm Hg) and an increased peak blood flow velocity have been found to be predictive of postoperative hyperperfusion. – Therefore, TCD can be used to select patients for aggressive postprocedure observation and management. – In a patient who is determined at risk, TCD can also be used during the postoperative period to assess for hyperperfusion. T. Yoshimoto et al. / Surgical Neurology 63 (2005) 554 –558 # Preoperative acetazolamide SPECT scanning • Cerebrovascular reactivity (CVR) and carbon dioxide can be used to test cerebral hemodynamic reserve. • Administration of acetazolamide induces a rapid increase in CBF. • This iatrogenic CBF surge is measured using single-photon emission computed tomography (SPECT) scanning. • In chronic cerebral ischemia, the vasculature is maximally dilated. Therefore, there is little change in CBF. • Patients with low preoperative CVR are at risk for developing hyperperfusion and parenchymal injury. Prevention of Reperfusion Injury • Blood pressure control – The most important factor in preventing reperfusion syndrome is early identification and control of hypertension – The use of TCD ultrasonography preoperatively and postoperatively can aid in identifying patients with increased CBF • Cleveland Clinic has implemented an effective protocol for identifying risk factors of reperfusion syndrome and post-op hemorrhage – Stenosis of >80% – Pre-morbid hypertension – Poor collaterals • Antihypertensives that do not increase CBF or cause excessive vasodilatation. Examples include labetalol and nicardipine • No specific parameters or guidelines for optimal blood pressure • ASA/AHA and intracerebral hemorrhage guidelines, the blood pressure goal for ICH is a mean arterial pressure (MAP) of less than 110 mm Hg , BP < 140/90 mmHg. • Maybe can also be applied in acute ischemic stroke with reperfusion issues. • NVUs are also niches for neural stem/progenitor cells in the adult brain. • Preclinical studies have revealed that brain injury induces neurogenesis and angiogenesis • Agents and manipulations that boost angiogenesis or neurogenesis may promote functional recovery after brain injuries. • Therefore future experimental studies need to explore the BBB as a potential target for such therapies. MMP inhibitors(matrix metalloproteinases Take home message • CHS is rare but a potentially life-threatening complication • Aware of the main risks for CHS such as high-grade carotid artery stenosis, poor collateral blood flow, post- operative hypertension, intra-operative distal carotid pressure of <40 mmHg, intraoperative ischemia. • Can occur within a few days postoperatively, but presentation can be delayed for weeks. • TCD is the most commonly and widely available technique used in the perioperative period to monitor for cerebral hyperperfusion • Labetalol and clonidine may be useful for the prevention and control BP for treatment of CHS • So, understanding of these BBB changes in acute ischemic stroke could lead to better patient selection as well as safer and potentially improved clinical outcomes with thrombolysis and mechanical thrombectomy. • Thank you .