Acute Stroke Management in the Era of Thrombectomy

© Springer Nature Switzerland AG 2019

Edgar A. Samaniego and David Hasan (eds.)Acute Stroke Management in the Era of Thrombectomyhttps://doi.org/10.1007/978-3-030-17535-1_1

1. Best Medical Management for Acute Ischemic Stroke

Amir Shaban¹ and Enrique C. Leira², ³  

(1)

Department of Neurology, Carver College of Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA, USA

(2)

Department of Neurology and Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA

(3)

Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA, USA

Enrique C. Leira

Email: enrique-leira@uiowa.edu

Keywords

Acute ischemic strokeTissue plasminogen activatorComplicationsSeizureHemorrhagic transformationAngioedemaCerebral edemaHydrocephalusInfectionsDeep venous thrombosisDepressionSleep apnea

Background

Stroke is the first cause of disability and fifth cause of death in the United States [1]. The overall prevalence of stroke ranges between 2% and 15%, with higher prevalence in older patients. In the Western world, about 85% of all strokes are ischemic, and the rest are hemorrhagic, but brain hemorrhages are more common in other ethnicities such as Asians. Disparities in acute ischemic stroke (AIS) rates and outcomes based on gender, race, and geographic location have been identified. Women have higher life-time risk of AIS and poorer outcome. Black men have higher incidence of AIS, a disparity that is more obvious in young patients. Overall, mortality related to AIS has been in constant decline; this may be related to the advancement in acute stroke care. In this chapter we discuss the principles of medical acute stroke care from arrival to the emergency department to the initiation of secondary prevention and rehabilitation (Fig. 1.1).

Fig. 1.1

Overview of acute stroke management

Stabilization and Initial Evaluation

Acute ischemic stroke is a time-sensitive condition. On average, 1.9 million neurons die per minute in the hypo-perfused ischemic penumbra that surrounds the core of the infarction. This sense of urgency should guide all the aspects of the patient evaluation and management. The first step, obviously, is to stabilize the patient. In patients with AIS, the most immediate threats are related to the airway and circulation. The airway is primarily assessed by inspection. While most patients with AIS are able to maintain their airway, that might not be the case for those presenting with a decreased level of consciousness (e.g., large hemispheric infarctions, top of the basilar artery syndrome, secondary seizures, large intracerebral hemorrhages) or for those experiencing severe lower cranial nerve dysfunction and secretions (e.g., lower brainstem infarction, basilar artery occlusions). Oxygenation parameters (pulse oximeter or arterial blood gas) can be misleading and should not be used to endorse airway stability in AIS patients. Beside clinical features, operational factors (e.g., the need to transport to another facility or to obtain MRI) might influence the decision to intubate a patient. If the airway appears to be potentially compromised, a prophylactic endotracheal intubation might be necessary. In those cases, the provider should perform a quick neurological examination prior to intubation, since the neurological assessment will be clouded by the pharmacological sedation.

The circulatory assessment should include blood pressure (BP) measurements and heart rhythm assessment by a 12-lead EKG or telemetry. Most patients with AIS present with elevated BP values. Many of them are chronically hypertensive individuals, but even patients without a history of hypertension can have reactive elevated values on presentation. This acute hypertension can help perfuse a hemodynamically vulnerable ischemic penumbra. On the other hand, an excessive BP can increase the chances of reperfusion injury and hemorrhagic transformation, as well as systemic end-organ damage. In practice, AIS patients are more often harmed by aggressive BP lowering than by untreated hypertension. As a result, the American Stroke Association recommends permissive hypertension of no more than 220/110 during the initial AIS evaluation, unless IV-tPA is being considered in which case 185/110 is recommended [2]. Often, just waiting for a few minutes without any intervention is enough to achieve more acceptable BP values. If treatment is needed, low-dose intravenous beta blocker such as labetalol (10 mg) is preferred due to the moderate and predictable response. This treatment should be avoided in patients that consumed sympatheticomimetic drugs as it could result in an unopposed alpha effect. If that is the case, or the patient has bradycardia, hydralazine (10 mg) is a reasonable alternative given its tendency to raise the heart rate. Less commonly, a continuous drip is required, and in those cases nicardipine is the first choice. In other parts of the world where these drugs may not be available or are too expensive, alternative agents such as nimodipine may be used to lower the BP.

Highlight

The American Stroke Association recommends permissive hypertension of no more than 220/110 during the initial AIS evaluation, unless IV-tPA is being considered in which case 185/110 is recommended.

The next step is establishing diagnosis, which is done clinically. The history should aim to detect any acute, focal, negative neurological symptoms that follow a vascular territory compatible with AIS. We should rapidly establish the last known normal (LKN) time. People tend to think events happen at the time they notice them, so rather than asking about the stroke onset, the evaluator should establish the most recent time when patients were at their usual baseline. Sometimes that can be challenging, for example, in patients with language barriers or anosognosia who do not recognize their own symptoms. In these situations, the provider should seek collateral information from family or friends. For wake-up strokes, the time when patient went to bed the night before is usually accepted as the LKN time. Despite all efforts, sometimes the LKN time remains unknown. In those cases, the neuroimaging findings might be used as a surrogate to establish the time of the infarction. A clear hypodensity on non-contrast CT scan, for instance, would be consistent with a subacute infarction that is several hours or days old. Similarly, a CT perfusion or perfusion MRI may help estimate the age of the infarction and the presence of viable penumbra.

A quick review of patient’s past medical history should be done in order to identify vascular risk factors such as previous strokes, hypertension, atrial fibrillation, diabetes, smoking, and drug abuse. Identifying these risk factors may increase the likelihood that stroke is the correct diagnosis and may provide clues to the possible stroke mechanism. The most important information for treatment purposes is whether the patient is taking any anticoagulants or not.

The optimal head position of the patient during the acute phase is controversial. Should the patient be kept flat to improve the collateral cerebral blood flow in the ischemic penumbra, or should the bed be raised to prevent aspiration pneumonia/pneumonitis? The HeadPoST trial randomized patients with acute stroke (85% ischemic) to flat vs. at least 30 degrees head elevation. The functional outcomes and rates of pneumonia did not differ between the two groups [3]. The study had limitations, including the delay between the symptom onset and randomization. We have to recognize that a small subset of AIS patients, often with a vessel occlusion or stenosis, is very sensitive to position changes in the hyperacute stage. We recommend flat for the first 24 hours unless there is a clinical concern for increased risk for aspiration, in which case the patient can be challenged with head elevation.

For the initial neurological examination, one should use the National Institute of Health Stroke Scale (NIHSS) as a standardized scoring system for patients with suspected stroke [4]. The baseline NIHSS score is a valuable tool as it predicts outcomes at 3 months, which is useful for providers and families to decide about interventions [5]. The NIHSS has limitations, as it tends to underestimate lesions in the non-dominant hemisphere and in the posterior circulation.

The history and physical exam can help differentiate AIS from other mimics including brain hemorrhage. But this distinction is not good enough for making treatment decisions, so neuroimaging is needed. A non-contrast CT is preferred given the availability and speed of that technique. Because a CT will not typically detect a hyperacute AIS, the diagnosis remains largely clinical.

Decision Regarding Intravenous IV-tPA Treatment

Intravenous tissue plasminogen activator (IV-tPA) is effective and a standard of care treatment for adult patients with AIS. While the US Food and Drug Administration (FDA) has approved IV-tPA for use only within 3 hours of LKN, the American Heart Association in addition to other agencies around the world recommends its use up to 4.5 hours of LKN based on the ECASS-III trial [6].

IV-tPA therapy generally doubles the odds of having a favorable outcome (no symptoms, or non-disabling symptoms) at 3 months. Those odds vary depending how soon the treatment is administered [7]. Furthermore, patients treated within the first hour (golden hour) of LKN time had substantially higher odds of neurological recovery [8]. Treatment with IV-tPA is not recommended if LKN time is >4.5 hours or unknown.

IV-tPA therapy has known complications, which should be discussed with patient and family prior to treatment. Symptomatic intracerebral hemorrhage (sICH) is the most feared complication. About 6% of patients treated with IV-tPA had sICH (associated with worsening of at least 4 points on NIHSS) compared to 1–2% in patients who did not receive IV-tPA. The risk for fatal hemorrhage is about 3% in patients treated with IV-tPA compared to less than 1% in controls [9]. Patients with severe stroke and higher NIHSS on presentation are more likely to have hemorrhagic transformation. However, it is important to recognize that, despite the increased ICH risk, IV-tPA increases the odds of a favorable outcome without an increase in mortality. Moreover, IV-tPA is considered standard of care and most emergency rooms in the US have waived the need for informed consent before administering IV-tPA.

Contraindications and cautions for IV-tPA therapy are reviewed in Table 1.1 [2, 10]. Please note that minor non-disabling strokes should be judged on a case-by-case basis. Observational studies have shown that one-third of patients who did not receive IV-tPA for minor or rapidly improving symptoms but were otherwise eligible were disabled at 3 months. On the other hand, a recent trial in mild non-disabled strokes did not show benefit of IV-tPA [11]. In clinical practice, the relative contraindications for IV-tPA have been widely questioned. In a recent review, Fugate et al. argue that 80 years of age should not be a contraindication [12].

Table 1.1

Contraindications for IV-tPAa

INR International Normalized Ratio, aPTT activated partial thromboplastin time, PT prothrombin time, NIHSS National Institutes of Health Stroke Scale, AVM arteriovenous malformation

aData from Demaerschalk et al. [10]

To be eligible for IV-tPA, blood pressure must be below 185 mmHg systolic and 110 mmHg diastolic. Patients with higher blood pressure must be treated with intravenous blood pressure-lowering agents prior to the administration of IV-tPA. Blood can be drawn and sent to the laboratory, but the results are usually not needed to make the decision regarding IV-tPA unless the patient is taking warfarin, in which case the INR is needed. Hypoglycemia can closely mimic stroke symptoms and should be rapidly ruled out with an Accu-Check determination.

The recommended dose of IV-tPA is 0.9 mg/kg (maximum dose 90 mg) with 10% given as bolus over 1 minute and the rest given as infusion over 60 minutes. Patients should be closely monitored during the infusion for signs of hemorrhagic transformation or angioedema.

Patients with clinical suspicion for large vessel occlusion should be evaluated for mechanical thrombectomy. Evaluation includes vessel imaging, preferably CT angiography, to identify the location of the clot. CT or MR perfusion is also commonly performed to calculate the size of the stroke core in comparison with the potentially salvageable penumbra. Current guidelines extend the window for mechanical thrombectomy treatment up to 24 hours in selected patients [13, 14].

As an effort to decrease time delay from symptoms onset to endovascular intervention, several scales have been developed for prehospital stroke recognition, severity grading, and LVO identification. These scales are intended to provide an easy and simple stroke prediction tool that can be scored by emergency and rescue personnel. Some of the most notable scales are briefly discussed in Table 1.2 [15].

Table 1.2

Prehospital stroke scalesa

CPSS Cincinnati Prehospital Stroke Severity Scale, FAST-ED Field Assessment Stroke Triage for Emergency Destination, G-FAST Gaze, Face, Arm and Speech Test scores, LAMS Los Angeles Motor Scale, PASS Prehospital Acute Stroke Severity scale, RACE Rapid Arterial Occlusion Evaluation scale, ROSIER Recognition Of Stroke In the Emergency Room score, sNIHSS-EMS shortened NIH Stroke Scale for emergency medical services, PPV positive predictive value, NPV negative predictive value

aData from Vidale et al. [15]

Post-IV-tPA Care

Once IV-tPA has been initiated, blood pressure should be closely monitored and maintained below 180 mmHg for systolic and 105 mmHg for diastolic blood pressure for the first 24 hours. Frequent neurological examinations are necessary during the following IV-tPA infusion to readily diagnose any adverse effects.

Angioedema is an acute complication that occurs in about 1% of the patients, with higher rates in patients taking angiotensin-converting enzyme inhibitors. It is typically asymmetric, worse on the side of the hemiparesis. Depending on the severity, the treatment may range from antihistamines or corticosteroids for mild and moderate angioedema to intubation in extreme life-threatening cases.

Illustrative Cases

Case #1

A 55-year-old right-handed man with past medical history of diabetes and hypertension taking aspirin and lisinopril presented with a mild right hemiparesis and dysarthria that started 2 hours earlier and had an NIHSS score of 4. Head CT scan without contrast was unremarkable. Patient had no contraindications for IV-tPA and treatment was started. His deficit improved significantly in the first 30 minutes. Close to the end of the infusion, he was noted to have worsening dysarthria for labial and lingual sounds only, not for guttural. Initially, there was concern for a hemorrhagic transformation, but he denied any headache and his blood pressure was stable. His level of consciousness was intact and his hemiparesis had actually resolved. Physical examination noted angioedema on his right lip and tongue. His airway was not compromised. Patient was given a dose of diphenhydramine and methylprednisolone and the angioedema rapidly improved.

Hemorrhagic transformation following IV-tPA typically manifests with the combination of sudden headache, acute blood pressure elevation, and worsening of the neurological exam and/or level of consciousness. If hemorrhagic transformation is suspected based on the presence of those symptoms, the infusion should be discontinued immediately and an emergent head CT scan should be obtained after re-evaluating the need for airway protection. Labs including coagulation labs, platelet count, and fibrinogen should be obtained. A rapid reversal of IV-tPA is typically achieved by administrating an initial dose of 10 units of cryoprecipitate. Fibrinogen levels should be rechecked following the reversal with a target goal of >150. Cryoprecipitate infusions should be repeated to achieve that goal. Platelets should be administered for counts lower than 100,000. Neurosurgical consultation should be considered to evaluate the patient for a decompressive hemicraniectomy.

Radiographically hemorrhagic transformation can be classified (based on the ECASS I trial) into hemorrhagic infarction 1 (HI1), hemorrhagic infarction 2 (HI2), parenchymal hematoma 1 (PH1), and parenchymal hematoma 2 (PH2) (Fig. 1.2). This classification is useful for prediction of outcomes, as only PH2 was associated with increased risk of early deterioration and 3-month mortality [16].

Fig. 1.2

Radiological classification of hemorrhagic transformation per ECASS I trial. (a) Hemorrhagic infarction 1 (HI1): small petechia; (b) hemorrhagic infarction 2 (HI2): confluent petechia; (c) parenchymal hematoma 1(PH1): ≤30% of the infarcted area with some mild space-occupying effect; (d) parenchymal hematoma 2 (PH2): >30% of the infarcted area with significant space-occupying effect, or clot remote from infarcted area

Case #2

A 74-year-old man with past medical history of coronary artery disease and diabetes developed sudden onset of right-sided weakness and aphasia 2 hours and 45 minutes earlier. On arrival he was fully alert but not able to respond to questions. He could follow simple commands. He was constantly repeating I’m alright. He scored 6 on the NIHSS. Head CT scan did not show any hemorrhage and had an ASPECTS score of 8 for ischemic changes seen in the M5 and M6 territories (Fig. 1.3). He had no contraindications for IV-tPA and treatment was started at 3:15 hours. A CT angiography did not reveal a large artery occlusion so thrombectomy was not indicated. Two hours later, he developed headache, nausea, vomiting, and tachypnea and became drowsy and mute. His BP rose to 210/130 mm Hg. A repeated CT revealed hemorrhagic transformation with vasogenic edema and midline shift (Fig. 1.4). IV-tPA was reversed by administration of 10 units of cryoprecipitate. Fibrinogen levels were checked after administration and were 261 mg/dL and platelets levels were 256.000/mm³. His blood pressure was closely monitored with a systolic blood pressure goal of less than 160 mmHg. Later at night, neurological examination deteriorated further and repeated head CT showed expansion of the intraparenchymal hematoma. Decompressive hemicraniectomy was recommended. However, patient’s family declined the procedure and requested patient comfort care measures only.

Fig. 1.3

Head CT scan without contrast showing no hemorrhage. Alberta Stroke Program Early CT Score (ASPECTS) of 8 for ischemic changes in M5 and M6 territories (arrows)

Fig. 1.4

A repeated head CT scan without contrast revealed hemorrhagic transformation (black arrow) with vasogenic edema, midline shift and compression of the lateral ventricle (white arrow)

Patients with AIS should be admitted to a dedicated stroke unit, as that has been shown to improve mortality and decreased disability independently of any specific acute intervention [17]. The mechanism of how stroke units improve outcome is uncertain, but probably the result of better prevention and treatment of complications through organized nursing care. The American Heart Association, European, and UK guidelines all recommended early stroke unit admission and care.

Blood glucose levels should be closely monitored in AIS patients. Hyperglycemia is noted in 50% of AIS patients on presentation and could be related to the stress response. Hyperglycemia has been associated with poor outcomes. The GIST-UK trial showed no benefit for intravenous insulin treatment on outcomes in AIS, although it was probably underpowered [18]. Patient’s temperature should also be checked frequently. Hyperthermia is associated with worse outcomes in AIS patients, so normothermia should be maintained.

Management of Stroke Complications

Several complications can occur in the initial days to weeks, commonly during the initial hospitalization following the AIS. Neurological complications usually precede the medical, and both worsen patient outcomes, survival, and disability and prolong length of hospital stay.

Neurological Complications

Intracranial Edema

Cerebral edema is an expected complication following AIS, particularly in large MCA and posterior fossa strokes. It can cause injury by several mechanisms, including mass effect and decreased blood flow. Neurological deterioration resulting from cerebral edema typically peaks within 3–4 days from the onset of stroke in supratentorial strokes and 24–48 hours in the posterior fossa.

The larger the stroke, the more worrisome its edema is going to be. Malignant MCA cerebral infarction (defined as infarct volume of >145 cc on MRI DWI or infarction of at least 50% of MCA territory on CT scan) is associated with increased risk of herniation and death. Medical management aimed to reduce cerebral edema with osmotic therapy is an option, either with hypertonic saline with goal serum sodium of around 150 mEq/L or mannitol therapy with goal serum osmolarity of 310 mOsm/L. However, the evidence of efficacy is stronger for decompression. Several clinical trials (DESTINY, DECIMAL, HAMLET) investigated the benefit of early decompressive hemicraniectomy compared to conservative medical management in patients with large hemispheric strokes [2, 19]. Decompressive hemicraniectomy performed in the first 48 hours in patients <60 years old improved survival with number needed to treat (NNT) of 2 and improved survival with mRS ≤ 3 with NNT of 4 [2, 19]. That benefit still exists for patients older than 60 years old, but with lesser magnitude according to the DESTINY II trial [20]. It is important to note that hemicraniectomy improves survival and disability, but returning back to normal was not possible. As such, hemicraniectomy should only be offered to patients willing to accept some degree of disability [20].

Highlight

Decompressive hemicraniectomy should be offered early—first 48 hours—in patients with a stroke volume > 145 cc or at least 50% of MCA territory.

Large posterior circulation strokes can also cause several complications including swelling, herniation, and hydrocephalus. These complications can also lead to worsening outcome and death. Decompressive suboccipital craniectomy with dural expansion is recommended in large posterior fossa strokes with mass effect and neurological deterioration (Fig. 1.5) [2, 21, 22]. Ventriculostomy is the recommended treatment for obstructive hydrocephalus [2, 21, 22]. The risk of upward herniation associated with ventriculostomy can be minimized by conservative fluid drainage or performing subsequent decompression [2, 21, 22].

Fig. 1.5

Sagittal (a) and axial (b) CT scans showings a decompressive suboccipital craniectomy (white arrows) performed in a patient with a large posterior circulation stroke (black arrowheads) to prevent herniation and hydrocephalus secondary to cerebral edema. (Courtesy of Samaniego/Roa)

Dysphagia

A swallowing evaluation is recommended for all stroke patients before initiating oral diet due to the high rate of dysphagia in the acute settings. Intravenous hydration should be started for patients who fail swallowing evaluation. A nasogastric tube should be placed early in patients with high risk for aspiration. Percutaneous endoscopic gastrostomy (PEG) tube should be placed if more prolonged tube feeding is needed. Overall goals of care should be taken into consideration when making the decision for PEG tube placement. The FOOD trial compared these two modalities and found equipoise [23]. It is important to recognize that these devices decrease but do not eliminate the risk of aspiration.

Highlight

Every patient with a stroke should be NPO until a swallow evaluation is performed.

Seizures

Less than 10% of all AIS develop seizures. Hemorrhagic strokes or patient with AIS with hemorrhagic transformation have a higher risk for seizures. Routine prophylactic treatment with antiepileptic has shown no benefit. Once seizure is noted, then antiepileptic medication should be started.

Highlight

Routine administration of antiepileptics in patients with stroke—ischemic or hemorrhagic—is not advised.

Sleep Apnea

Patient with stroke have higher prevalence of both obstructive and central sleep apneas. Routine screening with polysomnography is currently experimental and not recommended unless sleep apnea is suspected.

Non-Neurological Complications

Venous Thromboembolism

Stroke patients have increased risk for DVT/PE due to impaired mobility. In patients with restricted mobility, pharmacological prophylaxis is recommended. Pharmacological prophylaxis should be held for 24 hours if IV-tPA was administered.

Low molecular weight heparin at 40 mg/day might be superior to unfractionated heparin without a significant difference in the incidence of intracranial hemorrhage [24]. Pneumatic compression devices are effective for DVT prevention in immobilized patient with contraindications for heparin use. For patients with contraindication to both heparin and pneumatic compression, aspirin can be used. Inferior vena cava filter is an option for high-risk patients with contraindication to all pharmacological and mechanical means of prophylaxis.

Infections

Aspiration pneumonia and urinary tract infections are the most common infections following AIS. Prophylactic treatment with antibiotics is not recommended [25]. Early mobilization and avoiding dwelling catheters are useful preventative measures.

Depression

Poststroke depression is a common complication that delays recovery. It affects more than one-third of patients within the first year after stroke. Fluoxetine use in patients with motor deficit has shown to enhance motor recovery and decrease poststroke depression [26].

Etiology and Secondary Prevention

Antiplatelet therapy for secondary stroke prevention should be held during the first 24 hours after IV-tPA administration. Traditionally, a 24-hour head CT is used to rule out hemorrhagic conversion prior to initiating the antiplatelet therapy.

Stroke etiology should be thoroughly investigated to determine the optimal secondary prevention strategy. Stroke etiologies are classified based on the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) as cardioembolic, large-artery atherosclerosis, small vessel, stroke of indeterminate etiology, and stroke of other determinate etiology [27]. The extent of investigations needed following an AIS varies case to case. Head and neck vessel imaging are usually obtained in the acute settings to evaluate for large vessel disease including extra and intracranial atherosclerosis. In patients with non-disabling AIS (mRS 0–2) in the carotid