(1)
Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
Keywords
Acute ischemic strokeCerebral edemaThrombolysisDecompressive surgeryRaised intracerebral pressure (ICP)MannitolHypertonic salineStroke causes 9 % of all deaths worldwide and is the second most common cause of death after ischemic heart disease. In over 75 % of cases the stroke is ischemic in nature. However, unlike acute myocardial infarction, therapeutic interventions which attempt to limit infarct size have been of limited success. Only two interventions in a small subset of patients (less than 5 % of patients) have been demonstrated to improve the outcome of patients suffering an acute ischemic stroke (AIS). The single most important intervention to alter the natural history of AIS and improve the patients’ functional outcome is the administration of a thrombolytic agent (intravenous rt-PA) in the appropriate patient within the narrow 3–4.5 h window [1]. Endovascular therapy represents an alternative therapy to intravenous rt-PA in patients who are not candidates for intravenous rt-PA, but has no advantage over intravenous rt-PA [2]. Hemispheric decompression in patients less than 60 years of age with malignant middle-cerebral-artery-territory infarction and space occupying brain edema has been demonstrated to improve outcome. An individual patient meta-analysis demonstrated a marked improvement in neurological recovery and survival with decompressive craniectomy [3]. Despite initial enthusiasm, neuroprotective agents have failed to show a benefit in the management of AIS [4, 5], as has tight glycemic control [6], high dose albumin [7], and the use of anti-hypertensive agents [8–11]. Considering this data, the rationale for admitting patients to an ICU needs to be evaluated. Furthermore, aspects of medical care which maximize the potential for recovery and limit complications need to be explored. In most instances such treatment is best provided by specialized “low-technology” Stroke Units.
Stroke ICU’s, Medical ICU’s or Stroke Units
Stroke Intensive Care Units were abandoned in the 1970s after it was demonstrated that such units had very little impact on the outcome of patients following a stroke. The situation is not much different today; for the overwhelming majority of patients suffering a stroke acute medical intervention in an ICU have not been established to improve outcome, and in fact, certain interventions may be harmful [12]. Admission to and aggressive management in an ICU may only serve to prolong the dying process of a patient who has suffered a catastrophic neurological event. In patients who have had an AIS the requirement for mechanical ventilation appears to be associated with both a high short- and long-term mortality. Using a large administrative database covering 93 counties in the eastern half of the United States, Golestanian and coworkers evaluated the outcomes of 31,301 patients suffering an AIS [13]. The 30-day and 1-year mortality was 64 and 81 % respectively in those patients who required mechanical ventilation compared to 16 % and 35 % in those patients who did not require mechanical ventilation. Similarly, Burtin and colleagues evaluated 199 stroke patients who underwent mechanical ventilation in an ICU [14]. The 1 year survival rate was just 8 %. These data suggest that patients intubated and ventilated for coma (or neurologic deterioration) may not benefit from mechanical ventilation. A small group of patients who suffer a stroke may benefit from admission to the ICU if they develop a reversible/treatable medical complication. Endotracheal intubation should be reserved for patients with reversible respiratory failure or comatose patients who are likely to have a good prognosis for a functional recovery. Furthermore, it is arguable that endotracheal intubation and mechanical ventilation will reduce the risk of atelectasis and pneumonia in patients with an impaired level of consciousness, when compared to good nursing and respiratory care without endotracheal intubation. The notion that intubation “protects the airway” is not true; intubation alters the normal airway protective mechanisms and likely “unprotects the airway.”
Profiles Predictive of Futility After Devastating Stroke [15]
Aneurysmal SAH
Persistent coma after attempts to lower ICP
Massive intraventricular hemorrhage with hydrocephalus
Presence of delayed global edema on CT
Lobar intracerebral hemorrhage
Coma with extensor posturing and absent pontomesencephalic reflexes
Coma with septum pellucidum shift >6 mm on CT
Ganglionic intracerebral hemorrhage
Coma with hydrocephalus and hematoma size >60 cm3
Pontine hemorrhage
Coma with hyperthermia and tachycardia
Coma with acute hydrocephalus and hemorrhage extension into thalamus
Cerebellar hemorrhage
Absent corneal reflexes
Absent oculocephalic response with hydrocephalus
Hemispheric ischemic infarction
Clinical deterioration with coma and loss of pontomesencephalic reflexes
Shift of pineal gland >4 mm on CT scan performed within 48 h
Cerebellar ischemic infarction
Persistent coma after decompressive surgery
The failure of specific intervention to improve the outcome of patients suffering a stroke should not imply that physicians should adopt a fatalistic approach when managing these patients [12]. A number of well conducted clinical trials have demonstrated that the mortality and functional recovery of patients following a stroke is significantly improved when these patients are cared for in a specialized stroke unit as compared to a general medical ward. These units provide specialized nursing care and a well-organized multidisciplinary rehabilitation program. Stroke unit care reduces the medical complications in stroke patients and allows for earlier and more intense rehabilitation. The Stroke Council of the American Heart Association (AHA/ASA) recommends “rapid transfer of a patient to a hospital that has a specialized stroke care unit” [16].
Acute Ischemic Stroke (AIS)
Ischemic stokes may be conveniently classified as:
large vessel atherosclerotic
cardioembolic
small artery (lacuna)
stroke of other identified cause (e.g. vasculitis)
stroke of undetermined cause (likely cardioembolic).
Imaging
Non-contrast enhanced CT scans (NECT) are recommended in all patients suffering AIS. NECT excludes parenchymal hemorrhage and can assess for other exclusion criteria for rt-TPA such as widespread hypoattenuation [16]. NECT is however insensitive in detecting acute and small infarctions, especially in the posterior fossa. A “subtle” sign of cerebral ischemia within the first few hours of symptom onset on NECT is loss of gray-white differentiation. This sign may be manifest as a loss of distinction among the basal ganglia or as a blending of the densities of the cortex and underlying white matter [16]. Another sign of cerebral ischemia is swelling of the gyri that produce sulcal effacement. Another useful CT sign is that of increased density within the occluded artery, such as the hyperdense middle artery (MCA) sign. Diffusion-weighted MRI imaging (DWI) is currently the most sensitive and specific technique for the diagnosis of AIS. DWI imaging has a sensitivity of 88–100 % in the diagnosis of AIS within minutes of symptom onset. CT perfusion and MRI perfusion and diffusion imaging allow measurement of the size of the infarct core and the penumbra. However, reperfusion therapy based on the mismatch between infarct size and penumbra has not been proven to improve outcome [17].
Thrombolytic Therapy
The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial demonstrated that rt-PA given to patients within 3 h of the onset of stroke resulted in an 11–13 % absolute increase in the chance of minimum or no disability at 3 months [18]. Studies with a longer time window for enrollment have demonstrated a higher mortality in the treatment group, largely due to an increased incidence of intracerebral hemorrhage. In the European Cooperative Acute Stroke Study (ECASS) patients with moderate to severe acute ischemic strokes were randomized (<6 h) to placebo or rt-PA. Patients with infarction involving more than one third of the middle cerebral artery territory on CT scan were excluded. At 30 days there was a higher mortality in the rt-PA group (17.9 % vs. 12.7 %) [19]. Large parenchymal hemorrhages were increased threefold in the rt-PA group. In the second European Cooperative Acute Stroke Study (ECASS II) no benefit for rt-PA was demonstrated; furthermore, treatment differences were similar whether patients were treated within 3 h or 3–6 h [20]. ECASS III reported the results of a study in which alteplase (0.9 mg/kg) or placebo was administered between 3 and 4.5 h after the onset of acute ischemic stroke [21]. Patients with severe stroke were excluded from this trial. Although mortality did not differ between groups, more patients has a favorable outcome with alteplase than with placebo (52.4 vs. 45.2 %; OR 1.34 95 % CI 1.02–1.76, p = 0.04). The Third International Stroke Trial (IST-3) randomized 3,035 patients to 0.9 mg/kg rt-TPA or placebo within 6 h of suffering an AIS; this study had no exclusion criteria based on age [22]. Patients who had a clear indication for rt-TPA were commonly treated with rt-TPA; hence this study included patients with clinical equipoise. In this study, 53 % of the patients were older than 80 years (an exclusion criteria in previous studies). Furthermore, 38 % of patients received rt-TPA after a delay of 3.0–4.5 h while 33 % received therapy after a delay of 4.5–6.0 h. At 6 months, 37 % of patients in the rt-TPA group as compared to 35 % in the control group were alive and independent (primary outcome variable; NS). However, an ordinal analysis demonstrated a significant shift in the Oxford Handicap Score (OHS) towards a favorable outcome with thrombolytic therapy (OR 1.27; 95 % CI 1.10–1.47). It is noteworthy that patients over the age of 80 years appeared to benefit the most from rt-TPA, emphasizing that age alone should not be used as a “contraindication” to treatment with rt-TPA. Furthermore, only patients treated within 3 h of the onset of the ictus benefited from treatment with rt-TPA. Wardlaw performed an updated meta-analysis which included data from the IST-3 trial [23]. This meta-analysis included 12 trials (7,012 patients) of rt-TPA given within 6 h of the onset of stroke symptoms. rt-TPA significantly increased the odds of being alive and independent at final follow up (46.3 % vs. 42.1 %, OR 1.17, 95 % CI 1.06–1.29, p = 0.001). However, the benefit of rt-TPA was noted only in patients given rt-TPA within 3 h. There was a trend towards an increased risk of death for patients treated between 3 and 6 h (OR 1.16; 95 % CI 1.00–1.35; p = 0.06). Symptomatic ICH occurred in 7.7 % of patients receiving rt-TPA as compared to 1.8 % in the placebo group. These data suggest that suitable patients with AIS treated within 3 h of the onset of symptoms benefit from treatment with rt-TPA (see contraindications below). The use of rt-TPA beyond this narrow window is controversial. To help resolve the time to treatment issue, Lees et al. performed a pooled analysis investigation time to treatment and outcome [1]. This meta-analysis predated the publication of the IST-3 study. The adjusted odds for a favorable 3 months outcome were 2.55 (95 % CI 1.44–4.52) for 0–90 min, 1.64 (1.12–2.40) for 91–180 min, 1.34 (1.06–1.68) for 181–270 min (4.5 h) and 1.22 (0.92–1.61) for 271–360 min in favor of rt-TPA. This data would suggest that “selected” patients (low risk of bleeding) may benefit from TPA up to 4.5 h and that the risks outweigh the benefits beyond 4.5 h. Drug regulatory authorities have taken contradictory actions with regards to the extended treatment window for rt-TPA, with the European Medicines Agency expanding the approval to 4.5 h while the US FDA have declined to do so [16]. The most recent guidelines (January 2013) published by the AHA/ASA state “Intravenous rt-TPA is recommended for administration to eligible patients who can be treated in the time period of 3–4.5 h after stroke onset (Class 1; Level of evidence B) [16]. In addition to the exclusion criteria for patients treated within 3 h (listed below), the AHA/ASA include the following additional exclusion criteria for treatment between 3 and 4.5 h: Age > 80 years, those taking an oral anticoagulant regardless of the INR, those with an NIHSS score > 25, >1/3 MCA territory stroke and those with a history of both stroke and diabetes.
The most recent guidelines from the AHA/ASA suggest the following inclusion and exclusion criteria for thrombolytic therapy [16]:
Inclusion Criteria
Diagnosis of ischemic stroke causing measurable neurological deficit
Onset of symptoms <3 h before beginning treatment
Age >18 years
Exclusion criteria
Significant head trauma or prior stroke in previous 3 months
Symptoms suggestive of subarachnoid hemorrhage
Arterial puncture at a noncompressible site in previous 7 days
History of previous intracranial hemorrhage
Intracranial neoplasm, AV malformation, or aneurysm
Recent intracranial or intraspinal surgery
Elevated BP (SBP > 185 or DBP > 110 mmHg)
Active internal bleeding
Acute bleeding diathesis, including but not limited to
Platelet count <100,000/mm3
Heparin received within 48 h, resulting in abnormally elevated aPTT greater than the upper limit of normal
Current use of anticoagulant with INR > 1.7
Current use of a direct thrombin inhibitor or direct factor Xa inhibitor with elevated sensitive laboratory tests (such as aPTT, INR, platelet count, ECT, TT or factor Xa activity assay)
Relative exclusion criteria (risk and benefits must be carefully considered on a case by case basis)
Only minor or rapidly improving stroke symptoms
Pregnancy
Seizure at onset with postictal residual neurological impairment
Major surgery or serious trauma in 14 days
Recent GI or urinary tract hemorrhage (within 21 days)
Recent acute myocardial infarction (within 3 months)
Treatment of Acute Ischemic Stroke With Intravenous rtPA [16]
Infuse 0.9 mg/kg (maximum dose 90 mg) over 60 min with 10 % of the dose given as a bolus over 1 min
Admit the patient to an ICU or stroke unit for monitoring
Perform neurological assessments every 15 min during the infusion and every 30 min thereafter for the next 6 h, then hourly until 24 h after treatment
If the patient develops severe headache, acute hypertension, nausea or vomiting discontinue the infusion (if rtPA being administered) and obtain emergency CT scan
Measure blood pressure every 15 min for the first 2 h and subsequently every 30 min for the next 6 h, then hourly until 24 h after treatment
Increase the frequency of BP measurements if SBP > 180 or if DBP > 105; administer antihypertensive medication to maintain BP below these levels
Delay placement of NG tubes, CVC’c, bladder catheters or intra-arterial catheters
Obtain a follow-up CT scan at 24 h before starting anticoagulants or antiplatelet drugs
Angioedema is estimated to occur in between 1 and 5 % of patients who receive rt-TPA. The angioedema is usually mild, transient and contralateral to the ischemic hemisphere. Empiric treatment with H2RA’s, anti-histamines and corticosteroids are recommended [16].
Endovascular Interventions
Intravenous thrombolytic therapy has a number of limitations, most notably the low recanalization rate which is reported to be about 6 % for the internal carotid artery, 30 % for the proximal segment of the middle cerebral artery and 33 % for the basilar artery. In contrast to rt-TPA endovascular treatment offers the potential for significantly higher rates of recanalization which may limit secondary brain injury [24]. Furthermore, emergency endovascular treatments could be prescribed for those patients who do not improve following rt-TPA and those who have contraindications for rt-TPA. Consequently, a number of endovascular treatment options for AIS have been developed over the past decade, including intra-arterial fibrinolysis, mechanical clot retrieval, mechanical clot aspiration angioplasty and stenting and a combination of these approaches. Despite initial encouraging results, three RCT’s published in 2013 failed to demonstrate a benefit from acute endovascular interventions [2, 17, 25]. These trials are summarized in Table 42.1. The MR RESCUE trial compared endovascular therapy with standard care in patients within 8 h of stroke onset. Patients were sub grouped according to the presence of an ischemic penumbra. In this study patients with an ischemic penumbra had better outcomes than patients without a penumbral pattern, but endovascular therapy provided no advantage in either group. Currently endovascular interventions for AIS are of unproven benefit and should only be performed within the setting of a RCT. Endovascular therapies can be considered otherwise suitable candidates who have clear cut contraindications to rt-TPA.
Table 42.1
Pivotal trials of endovascular therapy for acute ischemic stroke
Trial | n | Test Rx | Control Rx | Window to randomization | Rate of disability free survival at 90 days |
|---|---|---|---|---|---|
IMSI III [25] | 656 | IV-TPA followed by EVT | IV rt-TPA | IV rt-TPA within 3 h | EVT = 40.8 % |
IV rt-TPA = 38.7 % | |||||
Synthesis | 362 | EVT | IV rt-TPA | 4 h | EVT 42 % |
Expansion [2] | IV rt-TPA 46.4 % | ||||
MR RESCUE [17] | 127 | EVT | Standard care | 8 h | EVT 14 % penumbral group |
9 % non-penumbral group | |||||
SC 23 % penumbral group | |||||
10 % penumbral group |
Antiplatelet Therapy and Anti-Coagulation
The International Stroke Trial (IST) randomized (using a factorial design) over 19,000 patients within 48 h of an AIS to 14 days of treatment with placebo, heparin (5,000 or 12,500 U q 12 hourly) or aspirin 300 mg daily [26]. Aspirin resulted in a 1.1 % absolute reduction in recurrent ischemic strokes at 14 days; both heparin regimens had no effect on outcome. Additional studies have demonstrated that heparin, low-molecular-weight heparin (LMWH) and heparinoids do not improve outcome following a stroke [27, 28].
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