eMedicine Specialties > Neurology > Neuro-vascular Diseases

Reperfusion Injury in Stroke

Author: Hoda Elzawahry, MD, Resident Physician, Department of Neurology, University of South Florida College of Medicine
Coauthor(s): Pedro E Hernandez-Frau, MD, Resident Physician, Department of Neurology, University South Florida and Tampa General Hospital; Reza Behrouz, DO, Assistant Professor of Vascular and Critical Care Neurology, Department of Neurology, University of South Florida College of Medicine; Co-Director, Neurosciences Intensive Care Unit, Tampa General Hospital; Wayne M Clark, MD, Director of Oregon Stroke Center, Professor, Department of Neurology, Oregon Health & Science University
Contributor Information and Disclosures

Updated: Jun 24, 2009

Definition

Cerebral hyperperfusion or reperfusion syndrome is a rare but a serious complication following revascularization. Hyperperfusion is defined as a major increase in ipsilateral cerebral blood flow (CBF) that is well above the metabolic demands of the brain tissue. Quantitatively, hyperperfusion is a 100% or greater increase in CBF compared to preexisting baseline.¹ This definition also extends to rapid restoration of normal perfusion pressure, for example thrombolytic therapy for acute ischemic stroke. Reperfusion syndrome can occur as a complication of carotid endarterectomy (CEA), intracranial stenting, and even bland cerebral infarction.

The terms hyperperfusion and reperfusion are often used interchangeably. The former implies excessive flow while the later suggests normalization of flow.^1,2 Both can result in cerebral injury with similar clinical pictures, hence the basis in substitution of terms. However, not all patients with hyperperfusion are symptomatic; conversely, patients with only moderate rises in CBF can have devastating outcomes. Therefore some authors prefer to address this subject as reperfusion syndrome.²

Clinical presentation

• Cerebral reperfusion syndrome presents as a triad of ipsilateral headache, contralateral neurological deficits, and seizure.¹
• The time frame in which symptoms arise can be immediately after restoration of blood flow and up to 1 month later. Patients are usually symptomatic within the first week.^1,3,4
• Headache is the most common symptom (62%).⁵  Typically, patients display migrainous features with severe, ipsilateral, pounding headache.
• Deficits are usually cortical (eg, hemiplegia, neglect, aphasia) or may be worsening of preexisting deficit. By the same token of cortical affection, seizures present as focal or generalized.^1,4

Pathophysiology

Several mechanisms have been proposed to the pathogenesis of cerebral reperfusion injury. These range from modifiable events such as postoperative hypertension to molecular modalities such as free oxygen radical release. Each theory is complex and none are widely accepted. For the time being, known risk factors include the following:⁶

• 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

Hypertension

Elevated blood pressure is the most common factor found in symptomatic patients.^5,7,8 During acute ischemic stroke, systemic blood pressure often rises as a physiologic compensation for cerebral ischemia.⁹  As a rule, elevated blood pressure is not treated so as not to compromise flow to the tenuous penumbra. The key to reperfusion injury in this scenario is ischemic disruption of the blood brain barrier (BBB). The offended BBB is comprised of abnormally permeable ischemic capillaries. Adding insult to injury, these small vessels do not have a substantial conduit to buffer systemic pressures. The injured endothelium is unable to maintain their structure against systemic vascular resistance, thus resulting in reperfusion injury or hemorrhagic transformation.¹⁰  

Dysautoregulation

Cerebral autoregulation protects the brain against changes in systemic blood pressure. A drop in blood pressure could lead to ischemia, while on the other hand a sudden rise could lead to edema or hemorrhage. In patients with high grade stenosis, CBF is maintained at the expense of maximal arteriolar vasodilatation.¹¹ Chronic cerebral hypoperfusion (eg, critical stenosis) leads to production of carbon dioxide and nitric oxide. These are vasodilatory substances causing endothelial dysfunction.¹² In the absence of cerebral autoregulation, CBF is directly dependent on the systemic blood pressure. Correction of a critical stenosis causes rapid and large changes in the CBF, which leads to edema or hemorrhage.¹³

Ischemia-reperfusion

Reperfusion Injury After Thrombolytic Therapy

Symptomatic hemorrhagic transformation rates within 24-36 hours of stroke are increased in the setting of revascularization therapy regardless of modality (intravenous lytics, intra-arterial lytics, antithrombotics, mechanical devices).¹⁵ In the absence of revascularization therapy, hemorrhagic transformation is a common and natural consequence of infarction.¹⁶

In the setting of revascularization, the fundamental question is if the increased rates of hemorrhagic transformation are caused by reperfusion and the biochemical pathways, or if they are specific consequences of the lytic state itself.

Rates of symptomatic intracerebral hemorrhage are generally higher in intra-arterial lytic trials¹⁷ (10% in PROACT-II) compared with intravenous lytic trials (6.4% in NINDS).¹⁸
 
Antithrombotic trials using heparins and heparinoids have shown lower hemorrhagic transformation rates compared with rt-PA. However, the relatively low hemorrhagic transformation rates remain in excess of their minimal benefit in the acute setting and often include less severely affected subjects.^19,20,21
 
Hemorrhagic transformation is now known to be a multifactorial process.  

• Stroke severity is likely to be a major predictor of symptomatic intracerebral hemorrhage because it is associated with volume of ischemic brain at risk for hemorrhagic transformation.
• Older patients may be at greater risk of symptomatic intracerebral hemorrhage.
• Higher lytic doses are associated with higher symptomatic intracerebral hemorrhage risk, but whether lower doses can achieve adequate benefit with less risk is not known.
• Delayed revascularization minimizes benefit and likely increases risk. The goal of acute revascularization should not just be to open occluded vessels, but to open them quickly. Patient selection based on physiological parameters is likely important to reduce late hemorrhage attributable to revascularization.

Prevention

Preoperative transcranial Doppler

Transcranial Doppler (TCD) 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.^13,14 Therefore, TCD can be used to select patients for aggressive post procedure observation and management. In a patient who is determined to be at risk, TCD can also be used during the postoperative period to assess for hyperperfusion.

Preoperative acetazolamide SPECT scan

Cerebrovascular reactivity (CVR) to carbon dioxide can test for cerebral hemodynamic reserve. Normally, administration of acetazolamide (a carbonic anhydrase inhibitor that causes a local increase in carbon dioxide) induces a rapid increase in CBF.²²  This iatrogenic CBF surge is measured using single-photon emission computed tomography (SPECT). In chronic cerebral ischemia, the vasculature is maximally dilated. Therefore, there is little change in CBF, which means decreased CVR. Patients with low preoperative CVR are at risk of developing hyperperfusion and thus parenchymal injury.^23,24

Blood pressure control

The most important factor in preventing reperfusion syndrome is early identification and control hypertension.^3,7,25 This is important even in normotensive patients since delayed hypertension can occur.⁴ The use of TCD pre- and postoperatively can aid in identifying patients with increased CBF and consequently risk of hyperperfusion.^23,24 Blood pressure should then be aggressively controlled CBF elevates.

Pressures can be gently reduced with antihypertensive that do not increase CBF or cause excessive vasodilatation. Examples include labetalol or nicardipine. Less favorable medications include intravenous ACE inhibitors, calcium channel blockers or vasodilators such as nitroprusside.^23,26

Unfortunately, no specific parameters or guidelines have yet been determined for optimal blood pressure during these circumstances. According to the American Stroke Association ICH guidelines, the blood pressure goal for an acute intracranial hemorrhage is MAP <110.^27,28  This modest pressure can also function in acute ischemic stroke with reperfusion issues because it does not hypoperfuse the tenuous surrounding tissues, nor does it further aggravate injury or hemorrhagic conversion. In any case, the consensus remains that patients should be observed postoperatively in an ICU setting. If blood pressure management is an issue, it should be managed in the ICU until stabilized.

Free-radical scavengers and anti-adhesion therapy

Free radicals produced during ischemia have been a purported culprit in reperfusion injury. Free-radical scavengers and antiadhesion therapy have shown promise in decreasing the incidence of endothelial injury.¹⁴

Animal studies using various methods of modulating the cytokine response have found beneficial effects for IL-1 and TNF. Various experimental studies using agents that block leukocyte endothelial adhesion (ie, monoclonal antibodies that block either the adhesion receptor on leukocytes [CD-18] or the corresponding adhesion receptor on the endothelial cell [ICAM-1]) have found beneficial effects in terms of reducing infarct size and improving functional outcome.

In general, these experimental studies have found benefit when a period of ischemia is followed by a return of blood flow (reperfusion) but not in studies in which ischemia is permanent. For this reason, these anti-adhesion therapies may prove to be most beneficial clinically when given in association with thrombolytic agents.

Although clinical studies using antibodies against ICAM-1 have failed to find a clinical benefit, further investigations of antiadhesion therapies with TPA are ongoing. Given the strong preclinical support for the usefulness of anti–reperfusion injury agents, they are likely to be used in future "stroke cocktail" therapeutic efforts.

Summary

When patients are identified and treated early the prognosis is better and incidence of intracranial hemorrhage is less.²³  Outcomes are dependent upon timely recognition and prevention of precipitating factors. Most important is the treatment of hypertension before it can inflict damages such as edema or hemorrhage. Prognosis following hemorrhagic transformation is poor. Mortality in such cases is 36–63% and morbidity is 80% in survivors.^3,7,25

Studies indicate that CNS 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 deleterious effects.

Multimedia

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Media file 1: A. Schematic representation of the process of endothelial-dependent leukocyte adhesion. Endothelial cells activated by histamine or thrombin rapidly translocate P-selectin to their surfaces (also E-selectin, not shown), tethering leukocytes to the endothelial cell. This tethering does not require an active response from the leukocyte. Once tethered, other factors, including platelet-activating factor and cytokines, are released to stimulate a leukocyte activation response. This response includes shape-changing and increased surface expression of CD-11/CD-18. The CD-11/CD-18 then binds to the corresponding intercellular adhesion molecule 1 (ICAM-1) receptor on the endothelial cell, leading to firm endothelial attachment. This attachment may produce either direct obstruction of the microcirculation or lead to infiltration into the surrounding brain parenchyma.B. Schematic representation showing that through the use of monoclonal antibodies directed against the anti-ICAM-1 receptor, the CD-11/CD-18 to ICAM-1 attachment is prevented. This, in turn, prevents subsequent microvessel obstruction and leukocyte infiltration.

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Media file 2: Postcontrast image 24 hours after a right middle cerebral artery stroke, which demonstrates contrast extravasation through a faulty blood brain barrier.

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Media file 3: T1 sagittal image without contrast demonstrating gyriform hyperintensities. These represent subacute petechial hemorrhage around an area of subacute infarction secondary to uncontrolled hypertension.

Keywords

hyperperfusion, reperfusion of ischemic brain tissue, inflammatory response, blood flow, leukocyte adhesion, leukocyte infiltration, free radical release, neuronal membrane breakdown, reperfusion injury in stroke, hemorrhagic transformation

The authors wish to thank Anne Tillinghast for her assistance in preparing this manuscript.

We would like to extend a special thanks to our esteemed colleague Reed Murtagh M.D. who provided the MRI images.

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