J. David Spence, MD. Opinion statement. Introduction

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1 New Treatment Options for Hypertension During Acute Ischemic or Hemorrhagic Stroke J. David Spence, MD Corresponding author J. David Spence, MD Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, 1400 Western Road, London, ON N6G 2V2, Canada. Current Treatment Options in Cardiovascular Medicine 2007, 9: Current Medicine Group LLC ISSN Copyright 2007 by Current Medicine Group LLC Opinion statement Widespread reluctance to treat hypertension during acute stroke is based on historical accounts of unfavorable outcomes of treatment that were badly done: therapies that cannot be controlled, such as sublingual nifedipine, oral or intramuscular antihypertensive drugs may drop blood pressure precipitously, leading to worsening of ischemia. Case fatality in stroke obeys a U-shaped relationship: blood pressures that are either too low or too high are associated with worse outcomes both in ischemic stroke and in intracerebral hemorrhage. Very high blood pressures should be lowered in acute stroke, and there are some circumstances in which high blood pressure must be treated despite the presence of stroke. To avoid worsening of ischemia by reduction in cerebral blood flow, it is necessary to treat high blood pressure in acute stroke with drugs that can be controlled; this usually means giving drugs by intravenous infusion; however, there is recent evidence that transdermal administration of nitrates, which can be removed if pressure is too low, is a convenient alternative that does not reduce cerebral blood flow in acute stroke. Introduction The risk of high blood pressure in stroke is U-shaped [1]; blood pressure during acute stroke should be neither too low nor too high, either in ischemic [2] or in hemorrhagic stroke [3,4 ]. However, the treatment of hypertension during acute stroke remains controversial. Most hypertension experts and stroke physicians are steeped in lore to the effect that it is normal and desirable for blood pressure to increase in the setting of acute stroke, and that lowering blood pressure during acute stroke is likely to be harmful. Those views were reviewed in 1985 by Yatsu and Zivin [5] in the do not treat side of a Controversies debate in Archives of Neurology. In the same issue, Spence and Del Maestro [6] responded in the treat piece. It seems they were not very persuasive. Since then the controversy persists [7,8], but clinical trials are finally under way [9,10]. In spite of the controversy, the evidence that blood pressure in acute stroke should be treated when it is very high, must be treated in some cases, and can be treated safely, is mounting. The change that has made the greatest difference is the advent of intravenous thrombolytics for acute stroke; lowering blood pressure in patients with acute stroke eligible for tissue plasminogen activator to achieve blood pressure below 185 mm Hg systolic and below 110 mm Hg diastolic so that tissue plasminogen activator can be given has become standard therapy [4 ]. In rare cases, strategically located infarctions can cause severe hypertension that mimics pheochromocytoma. Studies showed that lesions in the brain stem involve the nucleus of the tractus solitarii [11] or in the anterior hypothalamus [12]. In both of these animal models, there were marked elevations of plasma

2 New Treatment Options for Hypertension During Acute Ischemic or Hemorrhagic Stroke Spence 243 CBF Acute stroke Normal carotid artery, producing a stroke, is one example: it is not acceptable to leave blood pressure uncontrolled in a patient with aortic dissection on account of a stroke. Similarly, patients with acute congestive heart failure and/or myocardial ischemia cannot have severe hypertension untreated. The presence of a known berry aneurysm is another situation that mandates control of blood pressure. The real issues are the following: to what target levels should blood pressure be lowered, and by what means? Mean arterial pressure, mm Hg Figure 1. During acute stroke, autoregulation is lost and cerebral blood flow (CBF) becomes pressure passive in the ischemic zone. Compartmentalization of the brain by structures such as the falx and corpus callosum (in the carotid territory) or tentorium cerebelli (in the vertebrobasilar territory) result in local reduction of perfusion pressure as the result of high tissue pressure from worsening of cerebral edema by severe hypertension. catecholamines and plasma renin. Mazey et al. [13] reported a syndrome resembling pheochromocytoma secondary to stroke, and I have seen three such patients; two with brain stem and one with large carotid territory infarction. In such cases, and in patients with true pheochromocytoma, it may be necessary to use α blockade with phentolamine and/or phenoxybenzamine before giving intravenous β blockers because of the problem of increased blood pressure with unopposed α blockade. Similarly, patients with severe hypertension following bilateral neck dissection for cancer, or following a second endarterectomy contralateral to an earlier endarterectomy, may have a severe form of hypertension driven by sympathetic activation resulting from deafferentation of baroreceptors, which may require α blockade. Evidence that higher blood pressures in acute stroke are associated with worse outcomes was summarized by Willmot et al. [14 ] in a systematic review. Evidence from over 10,000 cases of acute stroke in which admission pressures and outcomes were reported showed that higher blood pressures were associated with higher mortality, and among survivors of stroke, with worse outcomes. Recent results from the Tinzaparin in Acute Ischaemic Stroke Trial replicate that finding [15 ]. Reasons why high pressure may be harmful in acute stroke include 1) increased cerebral edema in ischemic tissue [16 18], raising tissue pressure in compartments of the brain and thereby reducing cerebral blood flow (CBF); and 2) expansion of hematomas [14 ] in cases of intracerebral hemorrhage. In some patients with acute stroke, blood pressure cannot be left untreated. Aortic dissection that occludes both a renal artery, producing an acute severe hypertension, and at the same time occludes a subclavian or To what target level should the blood pressure be lowered? Concern about lowering pressure in acute stroke is based on reduction of CBF as pressure drops too low. This problem is aggravated in acute stroke because in the ischemic zone the autoregulation of CBF, which normally preserves CBF through a wide range of perfusion pressures, is lost [19]. CBF thus becomes pressure passive (Fig. 1), so maintenance of adequate perfusion pressure is critical. This problem is more complex than it may seem because patients with pre-existing severe hypertension and consequent thickening of cerebral arterioles have their CBF autoregulation shifted to the right [20]; therefore, they tolerate much higher pressures. For most patients, a mean arterial pressure approximately 120 mm Hg (representing pressures of ~ 160/100 or 180/90) would be on the autoregulation plateau; such pressure levels would therefore represent a reasonable target for initial lowering of blood pressure in most patients with acute stroke. The American Heart Association guidelines recommend a reduction of blood pressure by 10% to 15% [4 ]. Evidence of longstanding severe hypertension from the history, or the presence of left ventricular hypertrophy, would suggest that the patient s autoregulation curve is shifted to higher pressures. How should the blood pressure be lowered? In order to avoid a precipitous drop in pressure that could worsen cerebral ischemia, it is necessary to use treatments that can be controlled. Sublingual nifedipine, thankfully, is disappearing from emergency rooms. It should never be used because it can cause precipitous drops in blood pressure and cannot be retrieved. Sublingual is a misnomer; it is absorbed after swallowing [21]. Similarly, intramuscular drugs and oral drugs carry the risk of precipitous drops in blood pressure. Although candesartan appeared to be beneficial in acute stroke in the ACCESS (Acute Candesartan Cilexetil Therapy in Stroke Survivors) trial [22], there was no reduction in blood pressure in that study. Similar to inhibitors of angiotensinconverting enzyme, antagonists of angiotensin II receptors carry the risk of precipitous blood pressure

3 244 Cerebrovascular Disease and Stroke drop in patients with renovascular hypertension. The mechanism has been called kicking the back door out of the glomerulus [23]. I have reported that among patients with carotid stenosis and resistant hypertension, 25% have renovascular hypertension [24]. Therefore, oral angiotensin-converting enzyme inhibitors or angiotensin II receptors are not safe in patients with stroke. Thus, the management of hypertension in acute stroke requires administration of intravenous drugs by infusion. Diagnostic considerations When a patient with acute stroke has severe hypertension, it is important that the therapy initiated in the emergency room not interfere with diagnosis. Patients with resistant hypertension are much more likely to have an underlying cause of hypertension, the cause of which should be identified in order to optimize therapy. Among African-American patients with resistant hypertension, low renin hypertension is much more common [25,26]. Both primary hyperaldosteronism (usually due to bilateral hyperplasia of the adrenal cortex) [27] or a renal tubular sodium channel mutation (Liddle s syndrome and variants) [28] causing retention of salt and water are much more common in patients with African ancestors (and probably in Africans) [26]. Because β blockers suppress plasma renin, it is important to draw plasma renin and aldosterone before initiating Treatment Pharmacologic treatment Intravenous β blockers therapy with intravenous β blockers. Administration of a diuretic such as intravenous furosemide before drawing the blood samples for plasma renin and aldosterone will help, both with blood pressure control and with diagnosis [29]. Treatment of hypertension in acute stroke Current guidelines recommend treatment with intravenous β blockers, intravenous nicardipine, nitroglycerine paste, and/or sodium nitroprusside [4,30]. However, although nitroprusside apparently spares CBF [30], it is rather difficult to use. Blood pressure control is very brief, requiring minute-to-minute adjustment of dose, and both tolerance and cyanide toxicity [31,32] are problems. My own preference is for infusion of a β-adrenergic blocker, and if necessary addition of nitrate paste or patches. In more severe hypertension intravenous nitroprusside, or intravenous hydralazine (which is easier to manage because blood pressure fluctuations are not so chaotic), may be necessary. If the hypertension is very severe and difficult to control, unusual causes such as pheochromocytoma or distention of the urinary tract (eg, from ureteric stricture or inadvertent ligation of a ureter in the course of hysterectomy or other abdominal surgery) should be suspected, detected, and treated specifically. β-adrenergic blockers can be given by intravenous infusion; because their half-lives are usually hours in duration, there is a long lead time to anticipate excessive dosing and reduce the dose; heart rate can be used to guide dosing. Contraindications: Asthma, congestive heart failure. Main adverse effects: Aggravation of asthma, bradycardia, congestive heart failure. Labetalol Initial dose of 10 to 20 mg intravenously over 1 to 2 minutes, followed by an intravenous infusion at 2 to 8 mg/min [4 ]; aim for a 10% to 15% reduction in blood pressure [4 ]. Intravenous sodium nitroprusside Sodium nitroprusside is very potent but difficult to use because blood pressure lability requires constant monitoring (best by arterial line) with frequent dose adjustments. This is best reserved for very severe hypertension; American Heart Association guidelines recommend greater than 140 mm Hg for diastolic blood pressure [4 ].

4 New Treatment Options for Hypertension During Acute Ischemic or Hemorrhagic Stroke Spence 245 Contraindications: Severe aortic stenosis requires special caution [33,34]. Main drug interactions: Low serum albumin may increase toxicity. Main adverse effects: Cyanide toxicity. Sodium nitroprusside Initially, 0.5 μg/kg/min by intravenous infusion, with constant monitoring of blood pressure [4 ]; titrate dose to achieve target blood pressure (up to 8 μg/kg/min [35]); aim for a 10% to 15% reduction in blood pressure [4 ]. Intravenous hydralazine Intravenous infusion achieves smoother blood pressure control compared with nitroprusside; it is best used with intravenous β blockers, which prevent tachycardia and worsening of angina pectoris. Contraindications: Caution required in patients with angina. Main adverse effects: Tachycardia, aggravation of angina. Hydralazine 5 to 10 mg/h by intravenous infusion; titrate dose to target blood pressure; aim for a 10% to 15% reduction in blood pressure [4 ]. Intravenous calcium channel antagonists Intravenous infusion achieves smoother blood pressure control compared with nitroprusside; it is best used with intravenous β blockers, which prevent tachycardia and worsening of angina pectoris. Contraindications: Caution required in patients with angina. Main adverse effects: Tachycardia, aggravation of angina. Nicardipine 5 to 10 mg/h by infusion initially; titrate dose to target blood pressure by increasing 2.5 mg/h every 5 minutes to a maximum of 15 mg/h [4 ]; aim for a 10% to 15% reduction in blood pressure [4 ]. Emerging therapies Recently, Willmot et al. [9 ] have shown that transdermal glyceryl trinitrate (GTN) lowers blood pressure in patients with acute stroke, while maintaining CBF. Patients were randomized to receive GTN, 5-mg patch, versus control. GTN lowered peripheral systolic blood pressure by 14% systolic and 3% diastolic, with no change in heart rate, and without any reduction of CBF in either hemisphere, or in the area of stroke oligemia, penumbra, or core. Nitrate patch is convenient to use and has the important advantage that it can be removed when pressure reaches target levels [36]. Therefore, this form of therapy is likely to become more prevalent. The efficacy results of the ENOS (Efficacy of Nitric Oxide in Stroke) trial are eagerly anticipated.

5 246 Cerebrovascular Disease and Stroke References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock PA: Blood pressure and clinical outcomes in the International Stroke Trial. Stroke 2002, 33: Okumura K, Ohya Y, Maehara A, et al.: Effects of blood pressure levels on case fatality after acute stroke. J Hypertens 2005, 23: Dandapani BK, Suzuki S, Kelley RE, et al.: Relation between blood pressure and outcome in intracerebral hemorrhage. Stroke 1995, 26: Adams H, Adams R, Del ZG, Goldstein LB: Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke 2005, 36: Consensus guidelines of the American Heart Association Stroke Council, with specific recommendations on blood pressure lowering, including targets and recommended treatments in acute stroke. 5. Yatsu FM, Zivin J: Hypertension in acute ischemic strokes. Not to treat. Arch Neurol 1985, 42: Spence JD, Del Maestro RF: Hypertension in acute ischemic strokes. Treat. Arch Neurol 1985, 42: Bath P, Chalmers J, Powers W, et al.: International Society of Hypertension (ISH): statement on the management of blood pressure in acute stroke. J Hypertens 2003, 21: Chalmers J: Blood pressure and stroke: a continuing debate. J Hypertens 2006, 24: Willmot M, Ghadami A, Whysall B, et al.: Transdermal glyceryl trinitrate lowers blood pressure and maintains cerebral blood flow in recent stroke. Hypertension 2006, 47: A randomized trial showing that transdermal GTN patches lower blood pressure in acute stroke while preserving CBF. 10. Bath PM: Major ongoing stroke trials. Efficacy of Nitric Oxide in Stroke (ENOS) trial [abstract]. Stroke 2001, 32: Doba N, Reis DJ: Acute fulminating neurogenic hypertension produced by brainstem lesions in the rat. Circ Res 1973, 32: Nathan MA, Reis DJ: Fulminating arterial hypertension with pulmonary edema from release of adrenomedullary catecholamines after lesions of the anterior hypothalamus in the rat. Circ Res 1975, 37: Mazey RM, Kotchen TA, Ernst CB: A syndrome resembling pheochromocytoma following a stroke. Report of a case. JAMA 1974, 230: Willmot M, Leonardi-Bee J, Bath PM: High blood pressure in acute stroke and subsequent outcome: a systematic review. Hypertension 2004, 43: A systematic review of the consequences of high blood pressure in acute stroke. 15. Sprigg N, Gray LJ, Bath PM, et al.: Relationship between outcome and baseline blood pressure and other haemodynamic measures in acute ischaemic stroke: data from the TAIST trial. J Hypertens 2006, 24: A large clinical trial with useful evidence regarding the effects of high blood pressure on the outcome of acute stroke. 16. Halsey JH Jr, O Brien MD: Role of hypertension in pathogenesis of cerebral infarction edema. Adv Neurol 1980, 28: Hayakawa T, Waltz AG, Jacobson RL: Hypertension and acute focal cerebral ischemia. Infarction and edema after occlusion of a middle cerebral artery in cats. Stroke 1979, 10: Karki A, Westergren I, Widner H, et al.: Tirilazad reduces brain edema after middle cerebral artery ligation in hypertensive rats. Acta Neurochir Suppl (Wien) 1994, 60: Paulson OB, Lassen NA, Skinhoj E: Regional cerebral blood flow in apoplexy without arterial occlusion. Neurology 1970, 20: Strandgaard S: Autoregulation of cerebral blood flow in hypertensive patients. The modifying influence of prolonged antihypertensive treatment on the tolerance to acute, druginduced hypotension. Circulation 1976, 53: van HJ, Burggraaf K, Danhof M, et al.: Negligible sublingual absorption of nifedipine. Lancet 1987, 2: Schrader J, Luders S, Kulschewski A, et al.: The ACCESS Study: evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors. Stroke 2003, 34: Hackam DG, Thain LM, Abassakoor A, et al.: Trapped renal arteries: functional renal artery stenosis due to occlusion of the aorta in the arch and below the kidneys. Can J Cardiol 2001, 17: Spence JD: Management of resistant hypertension in patients with carotid stenosis: high prevalence of renovascular hypertension. Cerebrovasc Dis 2000, 10: Spence JD: Individualized therapy for hypertension. Hypertension 2006, 47:e Spence JD: Physiologic tailoring of therapy for resistant hypertension: 20 years experience with stimulated renin profiling. Am J Hypertens 1999, 12(11 Pt 1): Biglieri EG, Kater CE, Arteaga EE: Primary aldosteronism is comprised of primary adrenal hyperplasia and adenoma. J Hypertens Suppl 1984, 2:S259 S Baker EH, Duggal A, Dong Y, et al.: Amiloride, a specific drug for hypertension in black people with T594M variant? Hypertension 2002, 40: Wallach L, Nyarai I, Dawson KG: Stimulated renin: a screening test for hypertension. Ann Intern Med 1975, 82: Butterworth RJ, Cluckie A, Jackson SH, et al.: Pathophysiological assessment of nitric oxide (given as sodium nitroprusside) in acute ischaemic stroke. Cerebrovasc Dis 1998, 8: Rindone JP, Sloane EP: Cyanide toxicity from sodium nitroprusside: risks and management. Ann Pharmacother 1992, 26: Alaniz C, Watts B: Monitoring cyanide toxicity in patients receiving nitroprusside therapy. Ann Pharmacother 2005, 39: Gogbashian A: Nitroprusside in critically ill patients with aortic stenosis. N Engl J Med 2003, 349: Khot UN, Novaro GM, Popovic ZB, et al.: Nitroprusside in critically ill patients with left ventricular dysfunction and aortic stenosis. N Engl J Med 2003, 348: Sinaiko AR: Hypertension in children. N Engl J Med 1996, 335: Spence JD: Treating hypertension in acute stroke: a better arrow for the quiver. Hypertension 2006, 47:1051.

BLOOD PRESSURE MANAGEMENT IN THE ACUTE PHASE

BLOOD PRESSURE MANAGEMENT IN THE ACUTE PHASE Ελένη Κορομπόκη, MD, PhD, FESO Α Νευρολογική Κλινική, ΕΚΠΑ, Αιγινήτειο Νοσοκομείο Κλινική Ερευνήτρια, Department of Stroke Medicine, Imperial College London,