Ischemic Stroke

Transient hypertension is observed frequently following acute ischemic stroke and might be the result of a combination of factors, including anxiety, pain, neuroendocrine factors, stroke location, or a compensatory response to increased ICP (41-44). Acutely elevated BP is associated with increased early mortality after stroke, although whether this represents the consequence of stroke severity or its cause is presently unknown (1,2,45). Interestingly, low SBP and DBP, as well as elevated SBP, DBP, and MABP have been associated with poor stroke outcome, producing a U-shaped relationship between SBP and outcome (46-50). Analysis of a single SBP measurement prior to randomization in the International Stroke Trial in 17,398 patients with confirmed ischemic stroke also found a U-shaped relationship between baseline SBP and both early death and late death or dependency (50). In addition, patients with admission SBP greater than 200 mmHg had more than a 50% greater risk of recurrent stroke, compared to those with SBP of 130 mmHg. The relationship of low BP with poor outcome was associated with an excess of early deaths from coronary events and possible cerebral reinfarctions. It was not clear whether these associations were causal.

From a retrospective analysis of 1455 ischemic strokes from the Glycine Antagonist in Neuroprotection (GAIN) international trial, elevated pulse pressure during acute ischemic stroke was found to be independently associated with poor stroke outcome at three months, after correcting for baseline NIHSS, age, gender, treatment group (Gavestinel vs. placebo), heart rate, stroke risk factors, and stroke, type (51). Another issue is the potential compounding effect of BP on overall cardiovascular risk. A meta-analysis of approximately 1 million subjects by The Prospective Studies Collaboration found that stroke and other types of cardiovascular mortality increase exponentially with BP (52). A follow-up report stated a doubling of mortality for every 20/10 mmHg increase in BP, starting as low as 115/75 mmHg (53). However, BP reduction in the acute stages of stroke might not be beneficial and might be potentially harmful.

The Nimodipine West European Stroke Trial randomized 295 patients within 24 hr of stroke to placebo, low-dose nimodipine (1 mg/hr), or high-dose nimodipine (2 mg/hr) (54). For patients who had less than total anterior circulation strokes, lowering of DBP worsened neurologic outcome and high-dose nimodipine worsened both neurologic and functional outcome, compared to placebo-treated patients. However, nimodipine treatment and lowering of BP had no significant effect on outcome for patients with total anterior circulation infarcts (50 ).

Early BP elevations often decline spontaneously during the first minutes to hours of monitoring and may not require pharmacologic treatment (55). SBP and DBP decrease spontaneously by 12 and 7 mmHg within the first 24 hr after stroke, and by 22 and 12 mmHg within the first week (46). Because cerebral autoregulation is impaired in ischemic brain regions, CBF is pressure dependent, and further reduction may irreversibly injure the ischemic penumbra and increase stroke volume. A prospective study of 115 patients with acute ischemia, whose serial SBP was recorded for 24 hr, found on multivariate analysis, that poor outcome at 3 months was independently significantly associated with only initial NIHSS and the degree of reduction in SBP (56). An odds ratio (OR) of 1.89 for each 10% decrease in SBP was reported. Antihyper-tensive medication use was unrelated to initial BP levels and was not significantly associated with outcomes, suggesting that even spontaneous reductions in SBP may be detrimental in acute ischemia (57 ).

Further evidence for the effect of reduction in BP comes from a prospective study of 372 patients with acute ischemic stroke that evaluated the relationship between changes in SBP and DBP from hospital admission to 24 hr after admission with dichotomized Rankin Scale outcome (score < 2). Outcome assessment was performed at day 5 after admission (58). Mul-tivariate logistic regression analysis showed that a DBP reduction of more than 25% from admission to 24 hr after admission was associated with a 3.8-fold increase in adjusted odds for poor neurologic outcome on day 5. This result was independent of whether the reduction was spontaneous or induced by antihypertensive treatment. No significant association was found for SBP reduction and outcome.

It is probably safe to conclude that optimal BP management has not been established in ischemic stroke. The Stroke Council of the American Stroke Association has produced consensus guidelines that state that antihypertensive agents should be withheld unless DBP is greater than 120 mmHg or SBP is greater than 220 mmHg (59). This recommendation, however, is based on level V, or anecdotal evidence. Labetalol is a preferred drug, but intravenous infusion of nicar-dipine may be warranted when BP is difficult to control. Oral nicardipine and captopril are also suggested. Avoiding sublingual use of calcium antagonists, such as nifedipine, is recommended due to anecdotal evidence of rapid absorption, causing precipitous BP reduction (60 ).

I n patients who present with hypotension, the differential diagnosis includes aortic dissection, volume depletion, and decreased cardiac output secondary to myocardial ischemia or cardiac arrhythmias (59). Treatment should begin with volume replacement with normal saline and correction of underlying causes, such as arrhythmia, followed by vasopressor agents if initial management is unsuccessful.

Acute treatment of elevated BP should be considered for patients undergoing thromboly-sis and patients with severe hypertension, hemorrhagic transformation of the infarct, acute myocardial infarction, aortic dissection, acute pulmonary edema, hypertensive encephalopa-thy, or severe left ventricular failure (61). For patients receiving thrombolysis with recombinant tissue plasminogen activator (rtPA), the National Institute of Neurological Disorders and Stroke (NINDS) rtPA Stroke Study Group Guidelines recommend maintaining BP at less than 185/110 mmHg prior to thrombolysis and less than 180/105 mmHg during and after administration of rtPA (62). Intravenous labetalol is the agent of choice. The rate of BP control is also important, because rapid decreases in systemic pressure can worsen neurologic condition and responses to antihypertensives may be exaggerated in these patients (43,63,64)

Increasing BP in patients with small infarcts on diffusion-weighted imaging (DWI) and a large area of hypoperfusion on MRI perfusion-weighted imaging or CT perfusion scan might improve neurologic outcomes (65) . Patients with completed stroke without a large diffusion-perfusion mismatch might alternatively have worse outcomes with elevated BP due to exacerbation of edema or hemorrhage.

A few animal and patient studies have even provided preliminary data that suggest that raising BP with intravenous vasopressors might be effective in improving neurologic function in acute/subacute stroke, especially in patients with large diffusion-perfusion mismatch on MRI (10,66). For example, in patients with more than 20% diffusion-perfusion mismatch up to 7 days post onset of symptoms, 9 patients with induced hypertension showed significant improvement from day 1 to day 3 and at 3-month follow-up in NIHSS (3-day mean, 5.6 vs. 9.7; p < 0.02; 3-month NIHSS: p<0.04) and cognitive scores (mean 28% errors vs. 67% errors; p = 0.03) compared to "untreated" patients (64). Only treated patients demonstrated a significant reduction in the volume of hypoperfused tissue on perfusion weighted imaging (mean of 132-58 ml; p < 0.02). BP elevation involved increasing the MABP in 10% increments over 12 hr (achieved with a combination of intravenous saline and phenylephrine infusion) until motor/cognitive function improved or a MABP of 130 to 140 was reached. At 24 hr, patients were started on midodrine (up to 10 mg orally t.i.d.), fludrocortisone (up to 0.2 mg t.i.d.), and NaCl tablets, while weaning the phenylephrine to keep MABP in the goal range. Oral medications were tapered off at 4 weeks, as long as no clinical deterioration was observed. Two patients resumed oral medication for up to 3 months. No adverse effects of pharmacologic BP elevation with phenylephrine occurred. The authors concluded that patients in this study were highly selected, because all had severe stenosis or complete occlusion of the proximal middle cerebral artery (M1 segment) and/or internal carotid artery. These characteristics had shown the best response to BP elevation in earlier studies (67). Improvement in neurologic function, therefore, could be ascribed to recanalization of middle cerebral arterial branches, development of collateral blood supply, or reduction of edema. The risks of this treatment strategy have not been fully evaluated and include hemorrhagic conversion of infarct, cardiac ischemia, bradycardia, and congestive heart failure (68). Ideally, an ongoing NIH-sponsored clinical trial will assess this issue and fully evaluate efficacy of induced BP elevation in acute and subacute strokes.

In another study to evaluate the effect of dexamphetamine in acute ischemic stroke, 45 patients were randomized within 72 hr of symptom onset to 1 of 3 dose levels (2.5, 5, or 10 mg) orally b.i.d. or placebo for 5 days (69). At 7 days, dexamphetamine was associated with significant increases in SBP (mean increase 14 mmHg; p < 0.004) and DBP (mean increase 8 mmHg; p = 0.01) and significant improvement in Scandinavian Stroke Scale and functional outcome (based on motor function and Barthel index). The 1- and 3-month outcomes, however, were not different from those of placebo patients. The improvement in function may have been related to BP elevation or to other effects of amphetamine reported in experimental models (70 ).

Finally, evidence has been reported that lowering SBP at some point after stroke reduces the risk of recurrent stroke, both ischemic and hemorrhagic, as well as other vascular complications. The PROGRESS trial (perindopril protection against recurrent stroke) randomized 6105 patients who had had transient ischemic attack (TIA) or stroke in the previous five years to placebo or antihypertensive treatment with perindopril and, if no contraindication, to a diuretic, indapamide (71,72). A relative risk reduction of 43% (95% confidence interval (CI): 30-54) was realized in patients who received the combination regiment but not perindopril alone. The BP reduction in the combination therapy group was 12/5 mmHg, compared to 5/3 mmHg in the monotherapy group. The risk reduction was greatest in patients with baseline intracranial hemorrhage (49%; 95% CI: 18-68) and was significant in patients with baseline ischemic stroke (26%; 95% CI: 12-38) but not in patients with baseline TIA (23%; 95% CI: 23-52). Subgroup analysis showed no significant reduction for the stroke subtypes of lacunar stroke or cardio-embolic stroke (73 ).

BP reduction probably should not be the goal, however, in patients with bilateral carotid stenosis of 70% or greater or with unilateral carotid occlusion (57). This recommendation is based on a meta-analysis of data from the United Kingdom TIA (UK-TIA) trial, the European Carotid Surgery Trial, and the North American Symptomatic Carotid Surgery Trial, which showed a significant negative relationship between SBP reduction and stroke risk in patients, with greater than 70% stenosis in both carotid arteries, who did not receive endarterectomy, as well as a trend toward higher stroke risk in patients with carotid occlusion and lower diastolic pressure (74 ) . The 5-year stroke risk was significantly higher in patients with SBP below the median compared to those with SBP above the median (64% vs. 24%; p < 0.002). If endarterectomy was performed, the stroke risk was reversed to 13.5% in the high-SBP group and 18.3% in the low SBP group but was not significantly different ( p = 0.6). In the UK-TIA trial, patients with TIA had significantly reduced stroke risk with lower SBP.

In conclusion, based on the ASA consensus guidelines and studies evaluating outcomes in relation to BP, it is recommended that BP not be lowered in the first week after ischemic stroke, except for SBP greater than 220 mmHg, DBP greater than 120 mmHg, or medical conditions requiring urgent BP lowering (59,61). From the International Stroke Trial, patients with admission SBP between 140 and 179 mmHg had the most favorable outcomes. Early death occurred in patients with SBP both above and below this range (50). Induced hypertension may benefit certain patients, notably those with severe intracranial stenosis and a large diffusionperfusion mismatch on MRI (67). Considering the PROGRESS trial data, SBP should eventually be lowered in almost all stroke patients by 1 to 6 months after stroke onset by approximately 12/5 mmHg. Caveats include lesions that may reduce cerebral perfusion (intracranial large vessel stenosis, bilateral carotid stenosis, and carotid occlusion), which may require initial management prior to BP lowering (57 ).

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