The Acute and Chronic Management of Large Cerebral Infarcts

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Cerebral Infarcts

E.M. Manno, A.R. Rabinstein, and E.F.M. Wijdicks

Introduction

Stroke remains a major source of morbidity and mortality throughout the world representing the third leading cause of death in North America and the second leading cause of death in Asia [1]. Large hemispheric strokes account for a majority of these deaths and represent a significant proportion of stroke patients treated in an intensive care unit (ICU). Our understanding of the secondary processes that occur after the initial stroke has changed our approach to the management of this popula- tion. We will review and discuss the new management strategies that have been developed to decrease the morbidity and mortality of patients with large hemispheric infarctions.

Definitions, Acute Presentation, and Clinical Course

Strokes that involve greater than 50% of a cerebral hemisphere are generally consid- ered large cerebral infarcts. These occur secondary to acute occlusions of the internal carotid (ICA) or middle cerebral artery (MCA). The most common pathological processes include acute carotid artery dissections, in situ thrombosis of a near occluded carotid artery, and cardiac or artery-to-artery emboli to the stem of the MCA. The extent and size of the resultant cerebral infarct depends upon a number of factors including the exact location of the occlusion, the extent of collateral circulation, core body temperature, blood pressure, and if and when recanalization occurs [2].

Patients with large hemispheric cerebral infarcts present with acute contralateral hemiparesis or hemiplegia, hemianesthesia, and hemianopsia. Involvement of the frontal eye fields leads to the development of a gaze deviation ipsilateral to the side of the stroke and contralateral to the hemiparesis. Patients with dominant hemispheric stroke will present with a global aphasia. Non-dominant hemispheric stroke will present with spatial neglect. Apraxia of eye opening leading to an inability to open the eyes is common and often misleads the examiner into believing the patient is unresponsive. A Horner’s syndrome suggests dissection or acute occlusion of the ipsilateral internal carotid artery.

Clinically, patients may be awake and agitated or alternatively may appear drowsy or stuporus. Hypertension is common and is worsened by agitation, and confusion.

Seizures can occur but are unusual.

Most patients will stabilize both neurologically and hemodynamically a few hours post ictus. Secondary neurological deterioration occurs due to the development of

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cerebral edema. The pathological time course of the development of cerebral edema was quantified by Ng and Nimmannitya [3] Typically maximal swelling peaks 3 – 5 days post infarct; however, it can occur up to 7 days post infarct. Neurological deterioration parallels the development and worsening of cerebral edema and is her- alded by decreasing levels of consciousness, pupillary abnormalities, flexor or exten- sor posturing, and Cheynes-Stokes or ataxic respirations. Neurological deterioration usually mandates endotracheal intubation, mechanical ventilation, and treatments designed to decrease cerebral edema and lower intracranial hypertension.

Despite maximal medical treatment, many patients will worsen and progress to brain death. The mortality rates for large hemispheric strokes are approximated to be between 40 – 60 % in many clinical studies. European studies have listed the mortality as high as 80 % after the development of ‘malignant’ cerebral edema. Survivors are severely disabled and usually unable to reintegrate into normal activities of daily life [4, 5].

Mechanisms of Neurological Deterioration

Early clinical studies attributed neurological deterioration to downward displacement of the brain caused by increased intracranial hypertension. A clinical syndrome of central herniation was proposed and codified by Plum [6]. Thus, the main management strategy was to use agents to reduce increased intracranial pressure (ICP) [6].

Ropper, however challenged this dogma [7]. In a series of patients with supraten- torial mass lesions Ropper was unable to correlate between downward displacement of brain structures and the patients’ level of consciousness. Level of consciousness, however, correlated strongly with horizontal displacement of the pineal imaged on sequential computed tomography (CT) scanning. Ropper thus demonstrated that expanding mass lesions inducing horizontal and not vertical displacement of the rostral diencephalon (using the pineal as a surrogate marker) were responsible for neurological deterioration [7]. Ropper postulated that ICP differentials and not total increases in ICP were responsible for this. Frank later verified this hypothesis by placing ICP monitors in 19 patients with large cerebral infarctions and subsequent neurological deterioration. A large majority of patients showed neurological deterioration without an increase in ICP. Patients with increases in ICP tended to be younger [8].

The above finding had significant implications for the treatment of patients with expanding hemispheric infarctions. In some patients intracranial hypertension may be problematic. However, lowering ICP may not be effective if global increases in ICP are not the source of neurological deterioration. In addition there was growing concern that traditional measures to decrease ICP (i.e., placement of a ventriculo- stomy, mannitol, hyperventilation) may actually worsen tissue shifts and cause neurological deterioration by shrinking of normal tissue disproportionately to damaged tissue. Kaufmann and Cardoso had similarly shown in a cat stroke model that repeated dosing of mannitol accumulated in damaged brain tissue and, thus, could theoretically worsen midline shift [9].

Manno and Videen directly addressed these issues in a series of studies [10, 11].

Eight patients with midline shift and neurological deterioration after a large hemispheric stroke were given a 2 g/kg dose of mannitol. Sequential magnetic resonance imaging (MRI) was obtained during and for up to 30 minutes after the infusion. A

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volumetric analysis revealed that the non-infarcted tissue decreased in size by 8 % compared to no change in the infarcted tissue. However, this was not a large enough change to affect either vertical or horizontal shifts of midline structures [10, 11].

Initial Management of Large Hemispheric Cerebral Infarcts

The acute management of large ischemic strokes includes the basic assessments of assessing the airway breathing and circulation. Most patients with large strokes will not require endotracheal intubation unless they have aspirated. However, patients with a depressed level of consciousness may lose pharyngeal tone and develop airway obstruction. Under these circumstances a nasal or oral airway can be used to maintain airway patency. Adequate intravenous fluid replacement to maintain euvo- lemia is necessary to avoid periods of hypotension. Normal saline solutions are pre- ferred to avoid decreases in serum sodium levels, and dextrose solutions are generally not used to prevent hyperglycemia. Emergent head CT scanning is required [2].

In North America, intravenous tissue plasminogen activator (t-Pa) can be used within 3 hours of stroke onset if patients meet a set of radiologic, hemodynamic, and laboratory criteria [12]. Patients outside of the 3-hour window may be eligible for intra-arterial t-Pa or mechanical clot retrieval through endovascular methods [13].

Hypertension is common after large hemispheric strokes and may represent a normal physiological response to maintain adequate cerebral perfusion or could be secondary to an acute stress response, agitation, pain, or noncompliance with anti- hypertensive medication. Control of hypertension in an acute stroke should be judi- cious and used only if there are concerns of cardiopulmonary deterioration. Over- zealous control or attempts to normalize blood pressure can theoretically extend the infarct by decreasing cerebral perfusion [14].

Anticoagulation is controversial. Larger strokes are at risk for hemorrhagic con- version and enthusiasm for the use of heparin in acute strokes has waned in recent years. Indications for anticoagulation include atrial fibrillation, suspected myocar- dial infarction, or a visualized thrombus or large akinetic segment of the myocar- dium detected on echocardiography. Re-embolization has been reported to be as high as 21% within the first 3 weeks under these circumstances. Goal anticoagulation should be between 1.5 – 2.0 times above baseline control activated partial thromboplastin time (aPTT) [2].

Management of Neurological Deterioration

Neurological deterioration after large strokes may be multifactorial but most commonly accompanies the development of cerebral edema and its resultant tissue shifts. Neurological deterioration usually occurs within 96 hours of ictus but there is wide variation ranging from a few hours to a week post ictus [13]. A unilateral head- ache or vomiting may precede drowsiness. Cheynes-Stokes respiration progresses to hyperventilation and irregular respiratory patterns. Endotracheal intubation is usually required if a patient progresses to stupor. Unilateral anisocoria and bilateral ptosis are evidence of parahippocampal gyrus compression of the ipsilateral third nerve and warrant immediate intervention [2]. Mechanical ventilation for ischemic stroke is in itself a poor prognostic sign. Prospective series have reported 66 – 76%

mortality. Mortality, however, can be improved with acute interventions [15 – 17].

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ICP monitoring can be used but, as noted, brain tissue shifts may occur due to variations in pressure gradients that do not manifest as elevated ICP [7]. Hyperven- tilation is commonly employed to decrease ICP. Arteriolar vasoconstriction in response to a decrease in cerebrospinal hydrogen ion concentration subsequently decreases cerebral blood flow (CBF) and volume. Hyperventilation can be used acutely to lower ICP and should be utilized if neurological deterioration develops rapidly. The effect of hyperventilation on ICP, however, is short lived and ICP will return to baseline in a few hours [18]. Hyperventilation, therefore, does not represent a long-term treatment.

The mainstay of treatment for neurological deterioration is osmotic therapy.

Mannitol is the most commonly used agent. In Europe, intravenous or enteric glyc- erol are also used to lower ICP [19]. There are several potential mechanisms which may explain how mannitol can lower ICP. As an osmotic diuretic, mannitol can cre- ate an osmotic gradient favoring movement of water into the intravascular space, which can subsequently be excreted. Paczynski et al. [20] were able to demonstrate dehydration of an ischemic cerebral hemisphere in a rat stroke model using progres- sively increasing doses of mannitol. This process, however, took several hours to develop [20]. More commonly, the rheological effect of mannitol is advocated to account for the effect on ICP. According to this theory, mannitol lowers ICP by decreasing cerebral venous engorgement. A bolus of mannitol will lead to an influx of fluid into the intravascular space. The subsequent hemodilution leads to a decrease in serum viscosity. If flow remains constant, passive vasoconstriction should occur leading to a decrease in CBF and cerebral blood volume. This effect takes approximately 30 minutes to occur and closely matches the clinical effect of mannitol on ICP [21].

More recently, hypertonic saline has been advocated as a potential substitute for mannitol. Theoretically, by inducing acute changes in serum osmolality, hypertonic saline should operate under the same mechanisms as mannitol. The advantages of hypertonic saline would include fewer electrolyte abnormalities, nephrotoxicity, and volume depletion [22]. Suarez et al. have also used hypertonic saline successfully in head trauma patients as salvage treatment for patients with recalcitrant intracranial hypertension [23]. Implementation in acute stroke, however, has been limited due to a lack of standardization of both timing and dosage.

Osmotic therapy is typically initiated at first evidence of neurological worsening (i.e., worsening level of consciousness, cerebral ptosis, or anisocoria). Mannitol is given in large doses, up to 1 g/kg, which can be repeated in approximately 30 minutes if needed. Scheduled dosing may be given. Neurological and critical care text- books suggest that serum osmolality should not be increased beyond 320 mOsm/l due to concerns about nephrotoxicity [2]. A recent review, however, suggested that nephrotoxicity with mannitol use is probably overstated [24]. All the proposed mechanisms of action of mannitol require the development of an osmotic gradient for mannitol to be effective. Thus, at higher osmolality mannitol may be less effective. The osmolal gap (i.e., the difference between measured and calculated osmolality) appears more useful then serum concentrations of mannitol [25].

Previously stated concerns about mannitol becoming trapped inside the tissue and worsening cerebral edema may be overstated [8]. Maioriello et al. [26] described a patient with end stage renal disease and a large stroke who was given radiolabeled mannitol for treatment of cerebral edema before and after dialysis. The labeled mannitol seen inside the infarcted tissue was excreted uniformly after dialysis suggesting that trapping of mannitol inside these tissues does not occur [26].

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Hypothermia has been advocated as a potential treatment for large cerebral infarctions. Animal models strongly support that acute and delayed elevations in brain temperature worsen focal and global ischemia after cerebral infarction [27].

Both retrospective and prospective studies have revealed a strong relationship between hyperthermia and poor outcome after ischemic stroke [27]. Schwab et al.

were able to demonstrate that brain temperature exceeded core body temperature by approximately 1 – 2 °C after stroke [28]. Hypothermia has been shown to be effective in improving neurological outcome after cardiac arrest in two large studies [29, 30].

Hypothermia has been studied in large strokes. Moderate hypothermia to 33 °C was induced initially in 25 patients after large cerebral infarcts. The overall mortality was 47 % compared to 80 % of historical controls. Follow up work in 50 patients suggested that hypothermia is feasible but is associated with several medical complica- tions including coagulopathies, pneumonia, and bradycardia. Rebound increases in intracranial hypertension also proved to be problematic [31].

The optimal method for providing temperature control in acute neurological con- ditions is under study. Mayer et al. demonstrated that ‘traditional’ methods to cool neurological patients (i.e., acetaminophen, air cooling blankets) were largely ineffective [32]. Newer non-invasive surface cooling devices applied directly to the skin, accompanied by pharmacologic and non-pharmacologic measures to control shiver- ing, have proved superior for controlling fever and inducing hypothermia. Tempera- ture regulated invasive catheters attached to central line catheters have similarly been shown to be effective in temperature modulation [33]. A large company-spon- sored safety and feasibility trial studying external cooling devices in ischemic stroke is currently enrolling patients.

Barbiturates have been found to be ineffective in the treatment of large cerebral infarcts. Schwab et al. induced barbiturate coma in 60 patients with large hemispheric strokes and recalcitrant intracranial hypertension. The effect of barbiturate coma on ICP, however, proved to be transient, with 50 patients returning to baseline ICP elevation within 3 hours. The remaining non-responders did not survive [34].

Decompressive hemicraniectomy has recently been used for treatment of large cerebral infarcts. This strategy has largely taken introduced because of our new understanding of the horizontal tissues shifts involved with cerebral herniation syn- dromes and the failure of medical therapies to significantly impact morbidity and mortality. In this procedure, a large bone flap (almost half of the skull) over the involved hemisphere is removed. An incision is made in the underlying dura and a dural sac is added to allow edematous brain to swell outside the cranial cavity. The bone and dura are usually replaced several weeks later [2] (Fig. 1).

Several successful hemicraniotomy procedures were reported in the 1980s [35].

Decompressive hemicraniectomy began to gain favor as a series of uncontrolled trials reported improvements in morbidity and mortality [35]. Rieke et al. [36] in an open non-randomized trial compared the results of 32 patients with large hemispheric infarctions treated with hemicraniectomy to 21 patients managed medically.

Approximately two-thirds of the surgery group had either a good outcome or were moderately disabled compared to only 24 % of the medical group who were moderately disabled. Mortality was 11 % for the surgical group compared to 76 % for the medical group [36].

The Hemicraniectomy and Duratomy upon Deterioration From Infarction Related Swelling Trial (HeADDFIRST) was a 3-year multicenter, randomized, prospective pilot study. Patients with large hemispheric infarcts who displayed evidence of neurological deterioration were randomized to standard medical therapy or stan-

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Fig. 1. Schematic representation of a hemicraniectomy with the bone flap removed, incision of the dura, and placement of a dural sac to accommodate for the expanding brain tissue outside of the cranial cavity (with permission of the Mayo foundation for Medical Education and Research)

dard medical therapy plus hemicraniectomy at the first sign of neurological deterioration. Sixty-six patients screened from almost 5000 met enrollment criteria; 41 developed neurological deterioration and were randomized. The results showed a trend (p ‹ 0.10) for improvement in the surgical group (Frank JI, unpublished data, presented at the American Academy of Neurology, Honolulu, April 2003). The Hemicraniectomy After MCA Infarction with Life-Threatening Edema Trial (HAM- LET) is an ongoing European open multicenter trial comparing standard medical therapy to standard medical therapy plus hemicraniectomy. One year measures of outcome and disability will be evaluated.

Standardization of clinical trials has been difficult due to considerations about the timing, method, and location of surgery. Some advocate the use of early surgery prior to neurological deterioration. The theoretical basis for this was provided by Doerfler et al. [37], who performed a series of hemicraniectomies at various time periods post-infarction in a MCA occlusion rat model. The infarcted brain volume was markedly smaller with early surgery. Infarct size was unchanged compared to control rats if surgery was delayed for 36 hours. Improved surface collateral blood flow and perhaps local hypothermia were postulated to account for the difference [37]. Schwab et al. [38] reported a trend for improved mortality in patients who had decompressive surgery within the first day of ictus compared to delayed surgery.

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Fig. 2. Computed tomography images of brain herniation outside a craniotomy used for decompression.

Note the hyperdense right MCA sign.

Evidence of uncal herniation prior to surgery was postulated to represent a poor prognostic sign for recovery [38]. Most authors, however, recommend delaying surgery. The rationale is that in some cases surgery can be avoided and, in the case of progressive neurological deterioration, medical therapy can at least provide some temporizing measures until surgery can be arranged.

Some surgeons have recommended removal of the uncus or a temporal lobectomy in addition to hemicraniectomy [38]. Kalia and Yonas reported good outcomes in 4 patients who had necrotic cerebral tissue, as identified by Xenon CT, removed [39].

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There has also been considerable debate about long-term outcomes after surgery.

A systematic review of 138 patients followed for at least 4 months after hemicraniectomy revealed that 7 % of patients were independent, 35 % moderately disabled, and 58 % dead or severely disabled [40]. Older patients (8 50 years) fared much worse (80 % dead or severely disabled). The timing of surgery, hemisphere infarcted, or signs of herniation did not affect outcome [40].

The growing consensus that hemicraniectomy improves mortality has lead to attempts to identify early markers of neurological deterioration. Radiological markers extracted from the large National Institute of Neurological Disorders and Stroke (NINDS) t-PA trial suggested that a hyperdense MCA sign, signifying clot in the MCA, and greater than 50 % involvement of the MCA territory were predictors of neurological deterioration [41]. Manno et al., however, reported that only the hyperdense MCA sign had significant predictive power [42]. Large areas of infarction were only predictive of neurological deterioration if they were found on the initial CT scan [42] (Fig. 2). Newer studies using CT perfusion suggest that infarcted tissue may be able to be identified early in the clinical assessment of patients [43]. A recent paper has identified cellular-fibronectin, a component of the cerebral endothelium, as a potential marker for the amount of cerebral tissue at risk of developing cerebral edema [44]. Elevation of 8 16.6 µg/ml was a powerful predictive index for subsequent neurological deterioration.

Conclusion

Large hemispheric cerebral infarcts are common strokes admitted to both neuro and general ICUs. The morbidity and mortality associated with these infarcts is significant and is related to the development of cerebral edema. Medical management designed to decrease cerebral edema has been disappointing. Our understanding of the mechanics of the subsequent tissue shifts involved has led to the development of surgical procedures to allow swelling to occur outside of the cranial cavity. A large series of studies has uniformly reported improvements in mortality with these procedures. Morbidity may also be improved in younger patients. Significant questions remain as to the timing and location of surgery and the predictive power of early clinical, radiographic markers of neurological deterioration. The results of large randomized trials are awaited.

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