Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Hypertensive Emergencies in Acute Ischemic Stroke: Pathophysiology and Management Robert A. Felberg, MD Stroke Program Director Department of Neurology Geisinger Medical Center Danville, Pennsylvania Objectives • To define hypertensive emergencies and identify the major risk factors involved • To explain key principles of cerebrovascular pathophysiology in the stroke patient, reinforcing the importance of gradual downward titration of elevated blood pressure to prevent complications • To examine current guidelines and treatment options for managing hypertensive emergencies in patients with acute ischemic stroke, focusing on the role of intravenously administered vasoactive agents • To discuss the specific management of a hypertensive emergency in acute ischemic stroke using a case study that follows a patient from presentation to posttreatment Defining Hypertensive Crises and Understanding the Scope of the Problem Hypertensive Crisis: Emergency vs Urgency • Hypertensive emergency1,2 – Evidence of end-organ damage • Kidney • Retina • Heart • Brain – About 500,000 cases annually in US due to high prevalence of HTN • Hypertensive urgency1,2 – No evidence of end-organ damage – BP reduction over several hours to days – Usually treated with oral antihypertensives 1. Mansoor GA, Frishman WH. Heart Dis. 2002;4:358-371. 2. Varon J, Marik PE. Chest. 2000;118:214-227. End-Organ Damage Characterizes Hypertensive Emergencies Brain Hypertensive encephalopathy Stroke Retina Hemorrhages Exudates Papilledema Cardiovascular System Unstable angina Acute heart failure Acute myocardial infarction Acute aortic dissection Dissecting aortic aneurysm Adapted from Varon J, Marik PE. Chest. 2000;118:214-227. Kidney Hematuria Proteinuria Decreasing renal function Major Risk Factors for Hypertensive Emergencies • Antihypertensive therapy failing to provide adequate blood pressure control • Failure to adhere to prescribed antihypertensive regimens • Lack of a primary care physician • Illicit drug use Varon J, Marik PE. Critical Care. 2003;7:374-384. Current State of Hypertensive Emergency Management • Accelerated hypertension is among the most misunderstood and mismanaged of acute medical problems seen in clinical practice1 • Delays in initiating therapy can cause severe complications in target end organs2 • Overzealous therapy resulting in a too-rapid reduction in blood pressure is equally damaging2 • Many clinicians fail to consider the pathophysiologic principles involved in managing hypertensive emergencies1 1. Varon J, Marik PE. Chest. 2000;118:214-227. 2. Epstein M. Clin Cornerstone. 1999;2:41-54. Pathophysiologic Principles at Work in the Hypertensive Milieu Pathophysiology of the Hypertensive Emergency1-4 Hypertensive Emergency Circulating vasoconstrictors End organ ischemia Abrupt Loss of autoregulatory function Abrupt Endothelial damage SVR BP Vasoconstriction, often with intravascular hypovolemia – Increased circulating catecholamines – Activation of reninangiotensin-aldosterone system – Altered autoregulatory function SVR = systemic vascular resistance. 1. Ault NJ, et al. Am J Emerg Med. 1985;3(6 suppl):10-15. 2. Wallach R, et al. Am J Cardiol. 1980;46:559-565. 3. Varon J, et al. Chest. 2000;118:214-227. 4. Kincaid-Smith P. J Hypertens. 1991;9:893-899. Endothelial/Vascular Smooth Muscle Interactions • Triggers of acute changes in vascular resistance – – – – – – – Excess catecholamines (CAT) Angiotensin II (ATII) Vasopressin (ADH) Aldosterone Thromboxane (TxA2) Endothelin (ET1) Low nitric oxide (NO) or prostaglandin (PGI2) • Abrupt rise in BP – Promotes expression of cellular adhesion molecules (CAMs) Vaughan CJ, Delanty N. Lancet. 2000;356:411-417. Endothelium NO ATII ADH PGI2 CAT CAMs PGI2 ET1 TxA2 CAMs Endothelium NO Vascular Smooth Muscle Vascular Smooth Muscle Contraction Is Calcium Dependent Ca++ Ca++ plus calmodulin Myosin kinase Calcium influx into vascular smooth muscle may occur via opening of L-type calcium channels Release of intracellular stores may also be a source of Ca++ Actin-myosin interaction Contraction Ca++ Adapted with permission from Frishman WH, et al. Curr Probl Cardiol. 1987;12:285-346. Cerebral Autoregulation Is Central to Treatment of Hypertensive Crises Patients with chronic hypertension autoregulate cerebral blood flow around higher set points Cerebral Blood Flow Patients with cerebral ischemia lose their ability to autoregulate Increasing risk of hypertensive encephalopathy Ischemia Normotensive Chronic hypertensive Increasing risk of ischemia 0 50 100 150 MAP (mm Hg) Adapted with permission from Varon J, Marik PE. Chest. 2000;118:214-227. 200 250 Hypertension Can Drive Elevated Intracranial Pressure 75 Autoregulation Maximum Breakthrough Zone Constriction Zone of Normal Autoregulation 50 50 25 25 0 0 0 25 50 75 100 Cerebral Perfusion Pressure (mm Hg) Courtesy of Stephan A. Mayer, MD. 125 150 Intracranial Pressure (mm Hg) Cerebral Blood Flow (mL/100 g/min) Passive Collapse Vasodilatory Maximum Cascade Zone Dilatation Cerebral Blood Flow Is Controlled by Arterioles Veins Arteries Hypertensive Emergencies in Acute Ischemic Stroke: Treatment Principles and Guidelines Stroke Epidemiology and Outcomes Incidence of Stroke by Type 9% ICH 3% SAH 88% IS ICH = intracerebral hemorrhage; IS = ischemic stroke; SAH = subarachnoid hemorrhage. American Heart Association. Heart Disease and Stroke Statistics—2005 Update. Dallas, Tex: American Heart Association; 2005. High or Low Admission SBP in IS Patients Correlates With Increased Early and Late Mortality 1 month Mortality Rate (%) 80 12 months * † 70 60 50 40 30 20 10 0 N=930 <101 101-120 121-140 n=23 n=87 n=268 SBP = systolic blood pressure; IS = ischemic stroke. *P<0.001 vs SBP 121-140 mm Hg on admission. †P<0.05 vs SBP 121-140 mm Hg on admission. 141-160 161-180 n=248 n=162 SBP (mm Hg) Adapted from Vemmos KN, et al. J Intern Med. 2004;255:257-265. 181-200 201-220 >220 n=82 n=43 n=17 Ischemic Penumbra: Hypoperfused Area of Focal Ischemia Can Be Salvaged by Timely Intervention Infarct <8 mL/100 g/min Normal 50 mL/100 g/min Penumbra 8-23 mL/100 g/min Ahmed SH, et al. In: Fisher M, ed. Stroke Therapy. 2nd ed. Woburn, Mass: Butterworth-Heinemann; 2001:25-57. Ullman JS. In: Andrews BT, ed. Intensive Care in Neurosurgery. New York, NY: Thieme; 2003:29-46. Treatment of Hypertension in Acute Ischemic Stroke: Concerns • Without treatment – Formation of brain edema – Hemorrhagic transformation – Further vascular damage • Overly aggressive treatment – Secondary reduction in perfusion to ischemic area Adams HP, et al. Stroke. 2005;36:916-923. Hypertensive Crisis: Goals of Therapy • Immediate and controlled BP reduction1 – Reduce BP 25% within minutes to 1 hour – If BP is then stable, target toward 160/100-110 mm Hg over the next 2-6 hours – If this level of BP is well tolerated and the patient is clinically stable, further gradual reductions toward normal BP can be targeted over the next 24-48 hours • Increased caution in acute ischemic stroke patients2 – Not indicated if DBP ≤120 mm Hg or SBP ≤220 mm Hg – Lower cutoffs in certain circumstances 1. The 7th Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. US Dept of HHS; NIH publication No. 03-5233; 2003:54. 2. Adams HP, et al. Stroke. 2005;36:916-923. Should Acute Hypertension Be Treated in Ischemic Stroke? No Increased BP necessary Yes Increased BP harmful ↑ BP ↓ BP Maintain CBF to ischemic penumbra1 Hemorrhagic transformation2,3 Brain edema2 HTN post–rt-PA ↑ ICH risk4 CBF = cerebral blood flow; rt-PA = recombinant tissue plasminogen activator; ICH = intracerebral hemorrhage. 1. Powers WJ. Neurology. 1993;43:461-467. 2. Adams HP, et al. Stroke. 2005;36:916-923. 3. Hornig CR, et al. Stroke. 1986;17:179-185. 4. NINDS t-PA Stroke Study Group. Stroke. 1997;28:2109-2118. AHA/ASA 2007 Treatment Guidelines for Arterial Hypertension: Ischemic Stroke Not Eligible for Thrombolytic Therapy BP Level (mm Hg) Treatment SBP ≤220 or DBP ≤120 Emergency administration of antihypertensive agents to be withheld SBP >230 or DBP 121-140 Nicardipine or labetalol to 15% -25% ↓ in BP within the first day DBP >140 Nitroprusside to 15% -25% ↓ in BP within the first day ASA = American Stroke Association; IS = ischemic stroke; SBP = systolic blood pressure; DBP = diastolic blood pressure. Adapted from Adams HP, et al. Stroke. 2007;38:1655-1711. Odds Ratio for Favorable Outcome at 3 Months Time Is Brain 8 7 6 5 4 3 2 1 Benefit for rt-PA No benefit for rt-PA μ 0 60 70 80 90 100 110 120 130 140 150 160 Minutes From Stroke Onset to Start of Treatment rt-PA = recombinant tissue plasminogen activator. Marler JR, et al. Neurology. 2000;55:1649-1655. 170 180 AHA/ASA 2007 Treatment Guidelines for Arterial Hypertension: Ischemic Stroke Eligible for Thrombolytic Therapy BP Level (mm Hg) Pretreatment SBP >185 or DBP >110 Treatment Labetalol (may repeat once) or nitropaste or nicardipine If BP not reduced and maintained, do not administer rtPA During and after rt-PA SBP 180-230 OR DBP 105-120 Labetalol SBP >230 OR DBP 121-140 Nicardipine or labetalol If BP not controlled, consider nitroprusside DBP >140 Nitroprusside Adapted from Adams HP, et al. Stroke. 2005;36:916-923. JNC 7: Special Considerations in Hypertensive Emergencies • Patients with marked BP elevations and acute target-organ damage – Should be admitted to an ICU for continuous monitoring of BP – Should receive parenteral antihypertensive therapy with an agent appropriate for the individual patient • Patients with ischemic stroke in which no clear evidence from clinical trials exists to support the use of immediate antihypertensive therapy are an exception The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. US Dept of HHS; NIH publication No. 04-5230; 2004:54. Pharmacologic Profile of Commonly Administered IV Agents to Treat Hypertensive Emergencies Properties of an Ideal Parenteral Antihypertensive Agent • Rapid onset of action • Predictable dose response • Titratable to desired BP • Minimal dosage adjustments • Minimal adverse effects • Not associated with coronary steal Oparil S, et al. Am J Hypertens. 1999;12:653-664. Antihypertensive Agents Used in Hypertensive Crises* • • • • • • • Clonidine Diazoxide Enalaprilat Esmolol Fenoldopam Hydralazine Labetalol • • • • • • Nicardipine Nifedipine Nitroglycerin Nitroprusside Phentolamine Trimethaphan *Highlights denote more commonly used intravenous agents for hypertensive emergencies that are discussed in this presentation. Enalaprilat • • • • ACE inhibitor1 Onset of action: 15-30 minutes2 Duration: 6-12 hours2 Adverse effects: precipitous fall in pressure in high-renin states; variable response2 • Special indications/contraindications – Appropriate in acute left ventricular failure2 – Contraindicated in acute myocardial infarction2 or a history of angioedema1 – Also contraindicated in MAP insufficient for renal perfusion, low cardiac output, volume depletion, renal vascular disease, and therapy with vasoconstrictor agents (eg, NSAIDs, cyclosporine A) 1. Vasotec® I.V. injection (enalaprilat). Physician’s Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005:2170-2172. Enalaprit IV prescribing information. 2. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. US Dept of HHS; NIH publication No. 04-5230; 2004:55. Esmolol • Beta1-blocker1 • Onset of action: 1-2 minutes2 • Duration: 10-30 minutes per bolus—may necessitate use of multiple boluses2 • Adverse effects: hypotension, nausea, asthma, first-degree heart block, and heart failure2 • Special indications/contraindications – Appropriate in aortic dissection and perioperative management2; supraventricular tachycardia, intraoperative and postoperative tachycardia and/or hypertension1 – Contraindicated in sinus bradycardia, heart block greater than first degree, and cardiogenic shock or overt heart failure1 – Use with caution in bronchospastic diseases, since beta1 selectivity is not absolute1 1. Brevibloc injection (esmolol hydrochloride). Physician’s Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005:804808. 2. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. US Dept of HHS; NIH publication No. 04-5230; 2004:55. Labetalol • Combined nonselective beta-blocker and alpha1-blocker1 – Beta-blockade is 7 times greater than alpha1-blockade with IV administration1 – Not associated with decreased cardiac output seen with pure beta-blockers2 • Onset of action: 5-10 minutes per bolus—may necessitate use of multiple boluses2,3 • Duration: 3-6 hours3 • Adverse effects: vomiting, scalp tingling, brochoconstriction, dizziness, nausea, heart block, and orthostatic hypotension3 • Special indications/contraindications – Appropriate in most hypertensive emergencies except acute heart failure3 – Contraindicated in bronchial asthma, severe bradycardia, heart block greater than first degree, overt cardiac failure, and cardiogenic shock1 1. Labetalol hydrochloride injection. Prescribing information. Corona, Calif: Watson Laboratories, Inc. 2. Varon J, et al. Chest. 2000;118:214-227. 3. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. US Dept of HHS; NIH publication No. 04-5230; 2004:55. Nitroprusside • • • • Vasodilator―venous and arterial Onset of action: immediate Duration: 1-2 minutes Adverse effects: nausea, vomiting, muscle twitching, sweating, thiocyanate and cyanide toxicity – Doses >10 μg/kg/min for >10 minutes increase the risk of cyanide toxicity • Special indications/contraindications – Appropriate for most hypertensive emergencies – Use with caution with high ICP or azotemia • Requires special delivery system • Usually requires direct artery pressure monitoring The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. US Dept of HHS; NIH publication No. 04-5230; 2004:55. Nicardipine • Selective arteriolar vasodilator1,2 • Calcium ion channel inhibitor2 • Onset of action: 5-10 minutes3 • Duration: 15-30 minutes; may exceed 4 hours3 • Adverse effects: tachycardia, headache, flushing, and local phlebitis3 – No significant effect on ICP4 • Special indications/contraindications – Appropriate in most hypertensive emergencies except acute heart failure1-3 – Use with caution in coronary ischemia3 • Other considerations: more selective for vascular smooth muscle than cardiac muscle2; only IV CCB indicated for short-term treatment of HTN2; maintains or increases cardiac output2; as effective as sodium nitroprusside with fewer dose adjustments5; not associated with coronary steal2 1. Rose JC, et al. Neurocrit Care. 2004;1:287-299. 2. Cardene I.V. (nicardipine hydrochloride). Prescribing information. Fremont, Calif: PDL BioPharma Inc; 2006. 3.The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. US Dept of HHS; NIH publication No. 04-5230; 2004:55. 4. Nishiyama T, et al. Can J Anesth. 2000;47:1196-1201. 5. Neutel JM, et al. Am J Hypertens. 1994;7:623-628. Case Study in Acute Ischemic Stroke Patient Presentation • A 78-year-old woman presents with acute-onset aphasia and right hemiparesis • CT scan did not reveal any intracranial hemorrhage • The patient presented 4 hours after symptom onset and was eligible for intra-arterial thrombolysis • An emergent cerebral angiogram revealed 2 occlusions in distal branches of the superior and inferior divisions of the left middle cerebral artery • Initial blood pressure was 162/80 mm Hg but rose to 256/77 mm Hg prior to treatment 2 Sites of Occlusion (Arrows) on the Initial Angiogram (Qureshi Grade 1) Treatment • Intra-arterial thrombolysis was contemplated but required lowering of blood pressure to reduce the risk of intracranial hemorrhage • Intravenous nicardipine was initiated at 5 mg/h to achieve and maintain SBP <185 mm Hg and DBP <110 mm Hg consistent with AHA guidelines • Subsequently, a total of 1.5 units of reteplase* was administered through a microcatheter placed in the right middle cerebral artery • Intravenous eptifibatide* also was initiated after the procedure to prevent reocclusion *Use of reteplase and eptifibatide in stroke patients is still investigational. Blood Pressure Recordings After Administration of IV Nicardipine Blood Pressure (mm Hg) 300 250 200 SBP (mm Hg) DBP (mm Hg) HR (min) 150 100 50 0 0 5 10 Minutes 15 Partial Recanalization After Administration of Intra-arterial Reteplase (Arrows) Postthrombolysis and Acute Hypertension Treatment • CT scan at 24 hours revealed a small infarction without any intracranial hemorrhage Baseline 24 Hours Clinical Recap Algorithm for Managing Blood Pressure in the ED Following Ischemic or Hemorrhagic Stroke • In the first 24 hours post stroke – Stop oral medications – Do not treat hypertension unless • SBP >220 mm Hg and DBP >120 mm Hg on repeated readings • ICH • Need for TPA • Myocardial ischemia – If you treat hypertension in ICH • Go to MAP 130 mm Hg, SBP 185 mm Hg, DBP 110 mm Hg • Maybe go a little lower if the situation warrants • Use titratable drugs: IV labetalol or nicardipine • After the first 24 hours post stroke – Do not reduce MAP by more than 15 mm Hg/day – Start ACE inhibitor Key Points to Remember • Patients who experience an acute ischemic stroke are at risk of an acute hypertensive emergency in the aftermath • A patient’s eligibility to undergo thrombolysis must be assessed before an appropriate course of therapy can be selected • Selection of a therapy must consider the clinical idiosyncrasies of the individual patient as well as the cerebrovascular and cardiovascular pathophysiology involved • Antihypertensive therapy with an IV vasodilator may be essential to countering a hypertensive emergency