Management of Cerebral Edema/Intracranial Pressure in Ischemic Stroke

Introduction

Stroke is the fifth leading cause of death in the United States, resulting in greater than 125,000 deaths annually . Large brain infarctions are associated with edema and, in severe cases, shift of intracranial contents and elevation of intracranial pressure (ICP). Depression of consciousness and other signs of brainstem compression represent symptoms concerning for severe cerebral edema and can be correlated to imaging findings of midline shift and herniation. High ICP from excessive cerebral edema, if untreated, may result in severe morbidity or mortality. In this chapter, we discuss the pathophysiology, assessment, and management of cerebral edema in ischemic stroke.

Pathophysiology

Ischemic infarction results in the accumulation of toxic metabolites in the setting of breakdown of neural tissue regulation and loss of structural integrity in the surrounding architecture due to depletion of energy sources. The inability to power ATP sodium-potassium pumps results in neuronal depolarization, increase in intracellular calcium levels, the generation of free radicals, and cell death. The failure to reduce intracellular sodium concentrations results in the osmotic accumulation of water. Apoptosis and necrosis ensue hours after ischemic onset and progress over the course of days, resulting in neuronal injury extending into the subacute period. Apoptosis occurs predominantly in the periphery of ischemia known as the penumbra through two major pathways, namely, the intrinsic and extrinsic apoptotic pathways, mediated by cellular and extracellular signals of irreversible injury, respectively. Both pathways serve to damage mitochondrial membranes and activate caspases, the proteins responsible for autolysis via promoting DNA cleavage . Irreversible ischemic injury in the core area of infarction is mediated by necrosis caused by the inability to maintain even the basic regulatory mechanisms necessary for apoptosis due to energy depletion. Depletion of oxygen, glucose, and other energy substrates results in rapid transition to anaerobic glycolysis and acidosis from lactate production. Acidosis enhances free radical development and intracellular protein injury crucial to cellular homeostasis and mitochondrial integrity. Mitochondrial membrane breakdown results in further free radical formation. Free radicals react with phospholipid membranes while simultaneously degrading DNA bonds and preventing cellular repair and regulation. High concentrations of free radicals result in a localized inflammatory response and the activation of the innate immune system through the release of adhesion molecules. Neutrophils, macrophages, and monocytes accumulate in the ischemic area, worsening local ischemia by simultaneously increasing local energy requirements and by obstructing blood flow. Cells not succumbing to necrosis are thus subjected to a proapoptotic environment beyond the hyperacute period .

In a process distinct from, but parallel to, neuronal cell death, blood–brain barrier (BBB) breakdown causes the accumulation of cellular and plasma proteins in the interstitial tissues. The basal membrane of the BBB, which is composed of collagen type IV, heparin sulfate proteoglycan, fibronectin, laminin, and other proteins, is cleaved by the matrix metalloproteinases . In the setting of postischemic reperfusion, hydrostatic pressure gradients further encourage water migration into the extravascular space, contributing to vasogenic edema in tissues already undergoing cytotoxic edema. As edema progresses, macroscopic swelling appears, compressing the adjacent structures until the volume of the brain tissue exceeds the intracranial volume, thus increasing ICP. Given the typically unilateral injury in acute stroke, this may additionally cause midline shift into the territory of the contralateral brain, herniation of critical tissues, compression of blood vessels, and ultimately additional infarction .

The most frequent occluded vessel that results in malignant intracranial hypertension is the middle cerebral artery (MCA). As the largest branch of the internal carotid artery (ICA), the MCA is frequently occluded by emboli from either carotid plaque or cardiac thromboembolism because of its higher rate of flow and ability to accommodate thrombi too large to enter the anterior cerebral artery (ACA). The MCA supplies the largest cerebral territory and thus its occlusion can result in a large infarction and the development of edema over a larger territory, which is directly related to the risk of progression to intracranial hypertension . ICA occlusion likewise poses an increased risk of malignant edema. ACA occlusion may also occur in isolation or in the setting of terminal ICA occlusion; however, contralateral blood supply from the contralateral ACA often preserves tissue from as great a risk of infarction .

Assessment of Cerebral Edema