How to Handle Hypertension Crisis

Learning Objectives

1. Define hypertensive crises: Hypertension urgency and hypertension emergency

2. Outline the pathophysiology of hypertensive urgencies and emergencies

3. Identify treatment goals and treatment options for hypertensive crises

Faculty

Karol E. Watson, MD, PhD, FACC Professor of Medicine/Cardiology, Co-director UCLA Program in Preventive Cardiology Director, UCLA Barbra Streisand Women’s Heart Health Program Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California

Slides are current as of the time of printing and may differ from the live presentation due to copyright issues. Please reference www.pri-med.com/west for the most up-to-date version of slide sets. West Annual Conference Anaheim, California April 27-30, 2016

Current State of Hypertensive Crisis Hypertension Emergencies in context Management

• Hypertensive crises are among the most misunderstood and mismanaged acute medical problems seen in clinical practice Chronic Hypertension • Delays in initiating therapy can cause severe complications in target end organs Hypertension Urgencies • Overzealous therapy or too-rapid reduction in blood pressure may be equally damaging

• Consideration of the pathophysiologic principles involved in hypertensive crises is of utmost importance Hypertension Emergencies Varon J, Marik PE. Chest. 2000;118:214-227. Epstein M. Clin Cornerstone. 1999;2:41-54.

Hypertensive Urgencies / Terminology and Definitions Emergencies: (JNC 7) Urgency Emergency • Classification / Definition SevereThe Hypertension diagnosisplus of hypertensiveEnd-organ Damage • Etiology / Pathophysiology ► BPemergencies > 180/110 mm Hg depends► CHF on the • Evaluation clinical manifestations► ACS/AMI rather ► Renal failure • Management than only on the absolute level of ► Stroke and ICH • Follow up the blood pressure.► Encephalopathy

► Aortic dissection

► Pre-eclampsia

► Other?

Hypertensive crisis Hypertensive Urgencies / Emergencies: • You will almost certainly see a hypertensive urgency in your career • Classification / Definition • You will also likely see a hypertensive • Etiology / Pathophysiology emergency - Only occur in 1-2% of the hypertensive population • Evaluation - But, there are 50 million hypertensive Americans • Management - 500,000 hypertensive emergencies/year • Follow up • Higher in the elderly and African Americans

• Incidence is twice as high in men as compared to women Most Hypertensive Crises are Pathophysiology of Hypertensive caused by: Emergencies: a Vicious Cycle

• Sodium excess Hypertensive Emergency Vasoconstriction, often • Extracellular volume expansion Circulating with intravascular vasoconstrictors • Sympathetic overactivation hypovolemia causes: End organ - Increased circulating ischemia Abrupt SVR catecholamines Too Much Sodium (Salt) - Activation of renin- Loss of angiotensin-aldosterone Abrupt BP system Too Much Water Autoregulatory - Altered autoregulatory function Too Much Sympathetic Activity Endothelial function damage

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. Varon J, et al. Chest. 2000;118:214-227. 4. Kincaid-Smith P. J Hypertens. 1991;9:893-899.

Signs and Symptoms Signs and HTN Urgency (%) HTN Emergency (%) Symptoms

Headache 22 3 How do patients with hypertensive Epistaxis 17 0 crises present? Chest Pain 927 Dyspnea 922

Faintness 10 10

Agitation 10 2

Neurologic Deficit 321

Vomiting 23

Arrhythmia 60 Zampaglione B, et al. Hypertension 1996;27:144-147.

Signs and Symptoms Hypertensive Urgencies / Signs and HTN Urgency (%) HTN Emergency (%) Symptoms Emergencies:

Headache 22 3 • Classification / Definition Epistaxis 17 0 • Etiology / Pathophysiology Chest Pain 927 Dyspnea • Evaluation 922 Goals of evaluation Faintness 10 10 • Management are to determine Agitation 10 2 • Outcomes etiology, and rapidly

Neurologic Deficit 321 assess for end organ damage Vomiting 23

Arrhythmia 60 Zampaglione B, et al. Hypertension 1996;27:144-147. End-Organ Damage Characterizes Initial Evaluation Hypertensive Emergencies • Symptoms Brain Retina • Medical History Hypertensive Hemorrhages - Episodic palpitations and perspiration? encephalopathy Exudates Stroke Papilledema • Medications - MAO inhibitors Cardiovascular Kidney - Clonidine System Hematuria Unstable angina Proteinuria • Social History Acute heart failure Decreasing renal function - Recreational Drugs Acute myocardial infarction Amphetamines Acute aortic dissection Cocaine Dissecting aortic aneurysm Phencyclidine

Adapted from Varon J, Marik PE. Chest. 2000;118:214-227.

Physical Exam Hypertensive Retinopathy

• Blood pressures must be taken in both arms Grade 1 – mild narrowing or sclerosis of retinal - If the cuff is too small, the BP will be falsely elevated arteries (arteriolar narrowing) - If the cuff is too low (below the level of the heart), the BP will be falsely elevated Grade 2 – moderate to marked arteriolar • Pulses should be checked in upper and lower narrowing with A-V crossing changes (AV extremities nicking)

• Neuro exam Grade 3 – All the above + hemorrhages or • Cardiac exam cotton-wool spots • Pulmonary exam Grade 4 – All the above + additional swelling of • Ocular exam: only happens in 13% of pts the optic disk (papilledema)

Labs / Imaging to consider Hypertensive Urgencies / Emergencies:

• Comprehensive Metabolic Panel • Classification / Definition • CBC with peripheral smear (which may suggest microangiopathic hemolytic anemia). • Etiology / Pathophysiology

• Urinalysis • Evaluation • EKG • Management • Chest X-ray • Outcomes • Head CT

• Echocardiogram Elderly woman with hypertension

• 78 year old woman with long- standing hypertension Management of Hypertensive • During a routine follow up Urgencies visit BP = 205 / 75

• No complaints except “not (BP > 180/110 mm Hg with NO end organ damage) feeling right”; fundi no visualized due to cataracts but otherwise normal exam

• Admits to running out of her BP medications

Goals of Therapy of Hypertensive Crises Elderly woman with hypertension

• Hypertensive urgencies can generally be • 78 year old woman with managed with oral medications as an outpatient. chronic hypertension; BP = BP should be lowered over 24-48 hours 205 / 75; exam - normal - Important to prevent too-rapid lowering • Admitted to running out of her BP medications • Hypertensive emergencies must be treated as an • Placed in a quiet room and inpatient, usually in the ICU with intravenous administered usual meds medications. Goal is to reduce MAP by ~ 20% • 2 hours later BP 165/70; she within first hour felt well; normal exam - Some conditions, such as aortic dissection or hemorrhagic stroke require even more rapid reduction • Sent home on usual meds with home health JNC 7, JAMA 2003; 289:2560-2572

39 year old man with chest pain and shortness of breath

• 39 year old male with chronic Management of Hypertensive substance abuse, renal failure Emergencies (on hemodialysis), and hypertension (BP > 180/110 mm Hg WITH end organ damage) • Missed last dialysis appointment and admits to current methamphetamine use

• Presents to ED with severe chest pain and shortness of breath

• BP 250/140 mm Hg 39 year old man with chest pain Presenting Symptoms and shortness of breath • Hypertensive Urgencies • CxR – CHF with pulmonary - vascular congestion Epistaxis - Headache • ECG – TW inversions inferiorly - Psychomotor agitation • Tn I – 0.11 (ULN 0.04)

• DIAGNOSES: Hypertensive • Hypertensive Emergencies EMERGENCY due to: - Neurologic deficits - Missed HD, methamphetamine use, - Chest pain medication nonadherence - Dyspnea • Myocardial ischemia (NSTEMI)

• Congestive heart failure Zampaglione et al, Hypertension 1996;27:144

How Low Should You Go? Hypertensive Encephalopathy

• Simple answer - 20-25% reduction in MAP within 1st hour PRES: Posterior reversible encephalopathy syndrome • Better answer - It really depends on clinical condition Typically symmetrical white Less aggressive with ischemic stroke matter edema in the More aggressive with hemorrhagic stroke, posterior cerebral acute HF and aortic dissection hemispheres

Marik and Varon. Critical Care 2003, 7:374-84.

Cerebral Autoregulation Is Central to Autoregulation Treatment of Hypertensive Crises • In the uninjured, normotensive brain, autoregulation is Normal Regulatory effective over mean arterial pressure (MAP) of ~ 50 – (BP ~ 120/70 to 240/150) Cerebral Blood Flow Range 150 (that’s a BP ~ 80/40 to 190/130)

(BP ~ 80/40 to 190/130) Increasing risk of • In chronic hypertension, this range isshifted upwards to hypertensive MAP 80 – 180 (BP ~ 120/70 to 240/150) encephalopathy Normotensive

Chronic hypertensive • So, in the patients with out of control hypertension, if BP Increasing risk falls too rapidly to below ~120/70 cerebral perfusion can of ischemia be compromised

0 50 100 150200 250 MAP (mm Hg) All blood pressure sensitive organs have some degree of autoregulation Adapted from Varon J, Marik PE. Chest. 2000;118:214-227. Hypertensive Emergency: Goals of Other Important Points Therapy • • Immediate and controlled BP reduction ***ICU, ICU, ICU*** - Reduce BP 20-25% within minutes to 1 hour - Some studies suggest that only 15% of pts are admitted 1st line to an ICU - If BP is then stable, target toward 160/100-110 mm Hg over the next 2-6 hours • Once BP is stable, oral medications should be started as parenteral (IV) medications are titrated off - If this level of BP is well tolerated and the patient is clinically stable, further gradual reductions toward • Do not use sublingual nifedipine or other therapies that normal BP over the next 24-48 hours lower BP too quickly • • More immediate BP reduction in certain cases in Be cautious with nitroprusside (except with aortic dissection) because it can decrease BP too quickly, - e.g. Aortic dissection, hemorrhagic stroke and may increases intracranial pressure • Increased caution in acute ischemic stroke patients • Many patients are volume depleted from pressure - In general, BP should not be lowered too naturesis so use caution with diuretics  BP may drop aggressively too quickly JMC 7. US Dept of HHS; NIH publication No. 03-5233; 2003:54. Adams HP, et al. Stroke. 2005;36:916-923.

Treatment Typically Parenteral (IV) IV Antihypertensive Agents

Onset/ Elimination Agent Adverse Events Cautions/Concerns Duration Half-Life

• Adrenergic receptor • Nitric Oxide (NO) donors Tachycardia, headache, nausea, Contraindicated in patients with allergies Clevidipine 2-4 mins 5-15 mins dizziness, hypotension and vomiting. to soybeans, soy products, eggs, or egg blockers – Nitroprusside products. Cautious use in heart failure Precipitous fall in BP in high-renin Enalaprilat <15 min/ 11 h states, headache, cough, renal Avoid in acute MI, long duration of action - Esmolol (β1) – Nitroglycerin 12–24 h failure, hyperkalemia, angioedema Heart block, hypotension, nausea, - Labetalol (α1 and β) • Dopamine agonist Esmolol 1–2 min/ 2–9 min bronchospasm, overt heart failure, Reduces cardiac output, which may 10–30 min cardiogenic shock impair organ perfusion - Phentolamine (α1) Tachycardia, headache, nausea, – Fenoldopam Fenoldopam 5–15 min/ 5 min dizziness, flushing, hypotension, Caution with glaucoma mesylate 30 min–4 h increased intraocular pressure - Urapidil (α1) • Direct vasodilator 10–20 min/ Marked hypotension, tachycardia, Avoid in aortic dissection, MI, severe 2+ Hydralazine 1–4 h 1 h flushing renal disease; prolonged and • Ca channel blockers unpredictable effects; difficult to titrate –Hydralazine Bradycardia (heart block), overt Labetalol <5 min/ 5.5 h heart failure, cardiogenic shock, Avoid in acute heart failure; severe - Nicardipine 3–6 h edema, nausea, vomiting bradycardia; heart block, asthma Tachycardia, headache, nausea, Avoid in acute heart failure; caution with - Clevidipine Nicardipine 5–15 min/ 44.8 min flushing, thrombophlebitis, coronary ischemia; long duration of 15 min–6 h hypotension, vomiting action Flushing, headache, vomiting, Reduction in preload and cardiac output • ACE inhibitors 2–5 min/ hypotension, methemoglobinemia, undesirable in patients with Nitroglycerin 5–10 min 1–4 min decreased arterial resistance, reflex compromised renal and cerebral - Enalaprilat tachycardia perfusion Nausea, muscle twitching, sweating, Increases intracranial pressure; may Sodium Immediate/ 2–3 min thiocyanate and cyanide intoxication, reduce coronary perfusion pressure nitroprusside 2–3 min hypotension (coronary “steal”); cyanide toxicity

39 year old man with chest pain Conditions requiring special and shortness of breath management

• Admitted to ICU, treated with IV Nitroglycerine and IV Nicardipine 1. Ischemic stroke for BP control • Given emergent hemodialysis for 2. Aortic dissection volume reduction and BP control • Over next 2 hours BP decreased 3. Sympathetic crises to 160/100 mm Hg

• Chest pain, SOB resolved; ECG normalized BP Management in Acute Stroke BP Management in Aortic Dissection

• If aortic dissection is suspected, treatment of HTN 1 month 12 months • Most acute stroke patients 80 should begin immediately present with hypertension * † 70 150 – 180 • Goal of therapy is to ↓ aortic stress by rapidly • There is a U-shaped mm Hg 60 lowering BP and controlling pulse rate relationship between BP 50 • Target is to reduce MAP by 10-15%, or reduce and neurologic outcomes 40 SBP to ~110 mm Hg, in 5-30 minutes • Thus, SBP should be 30 • Usual drugs are vasodilator + beta blocker, usually

maintained ~ 150 - 180 mm (%) Rate Mortality 20 Nitroprusside + Esmolol Hg during acute stroke and 10 • ***NB all vasodilators cause a reflex tachycardia, not “normalized” 0 <101 101-120121-140141-160161-180181-200201-220 >220 so they MUST be used in combination with a beta SBP (mm Hg) blocker in dissection

Adapted from Vemmos KN, et al. J Intern Med. 2004;255:257-265. Varon J, Chest 2000;118:214-227

BP Management in Sympathetic Crisis Examples of sympathetic crises

• In a sympathetic crisis, Beta-blockers will result in • Pheochromocytoma unopposed alpha-adrenergic stimulation • • Thus, in this situation, Beta blocker use can Cocaine/amphetamines/OTC herbals (ephedra) - Paradoxically INCREASE blood pressure • Clonidine withdrawal - Worsen coronary artery vasoconstriction • Monoamine oxidase inhibitor + tyramine - Decrease survival - Tyramine is found in many foods, and is a • In a sympathetic crisis, Avoid beta blockers (including sympathomimetic (like amphetamine non selective agents such as labetolol) - Patients on MAOIs experience an exaggerated • Recommended Drugs in a sympathetic crisis response to tyramine, resulting in prolonged and - Nicardipine, Fenoldopam, Verapamil, Benzodiazepines severe hypertension - If pheochromocytoma is suspected use phentolamine

Foods containing Medications that Clonidine withdrawal tyramine interact w/ MAOI • Occurs in patients on clonidine who abruptly • Beer • Meperidine discontinue therapy • Wine • Ephedrine • Symptoms are similar to pheochromocytoma • Aged cheeses • TCAs symptoms (but usually lesser severity)

• Chocolate • Reserpine • Occur 16-48 hours after last dose • • Coffee Dopamine • Treatment is to re-start clonidine • Pickled herring • Methyldopa

• Citrus fruites • Guanethidine

• Broad beans

• Chicken livers IV Antihypertensive Utilization Caution with Nitroprusside Nitroglycerin 1,400,000 • Disadvantages of sodium nitroprusside 1,200,444 2004 2005 2006 1,200,000 1,133,717Labetalol - Decrease cerebral blood flow and increases

1,000,000 intracranial pressure - Can reduce regional blood flow in coronary artery 800,000 735,647 disease 600,000 502,518 - Risk of cyanide toxicity Nitroprusside 400,000 312,432 • Use when other agents not effective 240,785

200,000 139,104 - Monitor thiocyanate levels 8,288 - Avoid in renal or hepatic dysfunction 0 Nitroglycerin Labetalol Hydralazine Enalaprilat Esmolol SNP Nicardipine Fenoldopam

Thomson Patient Level Data. 2006

Hypertensive Urgencies / Follow-up care in hypertensive Emergencies: emergencies

• Goal: Transition to oral therapy as soon as • Classification / Definition patient can take po therapy • Etiology / Pathophysiology • Monitor carefully: Abrupt switch may result in ↑ • Evaluation Blood pressure • Management • Most patients may be discharged on oral medication within 24-72 hours • Outcomes • Hospitalization for a hypertension crisis is a “teachable moment”. This is an opportunity to stress improved BP control and medication adherence Vidt DG. In: Hypertension Primer. In press.

STAT Registry: Addressing Study Population knowledge gaps in contemporary Patients 1,588 acute hypertension Age - median 58 (49 - 70) Studying the Treatment of Acute Hypertension Female sex 49%

Patient Black race 56% Frequency characteristics White race 34% Qualifying BP Systolic 200 mm Hg (186 - 220) Diastolic 110 mm Hg (93 - 123) Management Clinical Length of stay 5 days (range 2 - 9) with IV agents outcomes

Am Heart J Volume 158, Issue 4, October 2009, Pages 599–606.e1 Medical History Presenting Characteristics

Condition % Hypertension 89 Symptoms % Tobacco or alcohol use 38 Shortness of breath 29 Diabetes 35 Chest pain 26 Chronic kidney disease 31 End stage renal disease 11 Headache 23 Previous hospitalization for HTN 27 Altered mental status 20 Neurological event 23 Drug abuse 15 Weak and dizzy 17

Am Heart J Volume 158, Issue 4, October 2009, Pages 599–606.e1 Am Heart J Volume 158, Issue 4, October 2009, Pages 599–606.e1

Predisposing Factors Contributing Number of IV Antihypertensives to Hypertensive Event During Hospitalization One Two Three or more

Factors % Labetolol (n=501) 32% 42% 25%

Medication non-adherence 25 Metoprolol (n=277) 40% 37% 23% Chronic 16 Nitroglycerin (n=241) 41% 27% 32% Current 10 Hydralazine (n=235) 41% 45% 14% Missed or incomplete dialysis 3

Nicardapine (n=121) 51% 28% 21% Anxiety/psychosocial reaction 2 Antihypertensive IV First

Drug abuse 11 Sodium nitroprusside (n=82) 22% 32% 46%

Percent of Patients Am Heart J Volume 158, Issue 4, October 2009, Pages 599–606.e1 Am Heart J Volume 158, Issue 4, October 2009, Pages 599–606.e1

Outcomes STAT Results

• 1500 pts, 21 hospitals, 79% Rx in ED • Median time to SBP of <160 mmHg: 4 hrs • Median age 58, Women 49%, AA 58% • 60% increased to >180 after initial control • Initial BP 201/110 • 4% had iatrogenic hypotension

50 • 29% had recurrent, severe HTN 40.2 40.1 40 necessitating reinstitution of parenteral

30 therapy

20 • Multiples antihypertensive agents were 10.4 10 6.5 8.4 necessary to achieve control

0 • 65% had no documentation of follow-up New End-organ In-hospital Admit to 90- 90-day 90-day Damage* Death* day Death* Readmission Readmission appointment being scheduled or attended Due to HTN Am Heart J Volume 158, Issue 4, October 2009, Pages 599–606.e1 Granger et al. SCCM February 2008 Am Heart J Volume 158, Issue 4, October 2009, Pages 599–606.e1 Short-Term (2 to 6 month) Outcomes Summary for various clinical conditions • Acute severe hypertension is - Associated with medical NONadherence Acute Condition Death Rehospitalization - If a hypertensive EMERGENCY, requires ICU ACS1,2,3 5-7% 30% admission, IV drugs - Alarmingly low rates of follow-up CHF4 8.5% 26% - High mortality and morbidity, especially with Severe Hypertension5 7-9% 37% new or worsening end-organ damage

• Major need to improve prevention and 1. OASIS-5 NEJM 2006 2. GUSTO IIb NEJM 1996 treatment of this important clinical 3. GRACE JAMA 2007 4. IMPACT-HF J Cardiac Failure 2004 condition 5. STAT Registry results Am Heart J Volume 158, Issue 4, October 2009, Pages 599–606.e1