Kimberly Zammit, Pharm.D., BCPS, FASHPClinical Coordinator: Buffalo General Hospitalkzammit@kaleidahealth.org

Evaluation and Management of Hypertensive Emergencies

Define the JNC-7 classification of blood pressure

Differentiate the presentation and management strategies for hypertensive urgencies and emergencies.

Compare and contrast pharmacotherapeutic agents available for the management for acute blood pressure control.

Identify treatment goals for patients requiring acute blood pressure management

Recommend antihypertensive therapeutic regimens tailored for specific patient characteristics.

American Heart Association estimates 73 million Americans have high blood pressure

~1 – 2% of hypertensive patients will have a hypertensive emergency in their lifetime

Represents 3% of all ED visits and 25% of all medical urgencies/emergences in the ED 113 million ED visits in 2003

American Heart Association. Heart Disease and Stroke Statistics 2008.Zampaglione B, et al. Hypertension 1996;27:144-147.

Epidemiology

Epidemiology

51 yo WM is admitted to your emergency department with a CC of 2 day history of a “dull” headache and blurry vision. He decided to come to ED today because he developed SOB and dizziness while exercising.PMH:

HTN and HyperlidemiaVital Signs:

HR 105 BP 240/ 138 RR 24, T 37.6, Ht 70”, Wt 95 kg

Pertinent physical findings reveal: Papilledema and a grade II/IV SEM

Laboratory Results: Na 135, K 3.5, Cl 108, CO2 22, BUN 50, Cr

2.4 Troponin negative (thus far)

Diagnostics: CXR: Enlarged heart CT Head: No bleeding is evident ECG: No ischemic changes, evidence of LVH

Medications: Metoprolol 100 mg BID (stopped one week

ago) HCTZ 25 mg Daily Simvastatin 20 mg Daily Aspirin 81 mg Daily

Social: Former smoker, “Social” EtOH, Denies illcit

drugs Allergies:

NKDA

True False

Category SBP (mmHg)

DBP (mmHg)

Normal <120 <80

Pre-hypertensive

120 - 139 80 – 89

Hypertension 140 – 179 90 – 109

Hypertensive Crisis*

≥ 180 ≥ 110* Hypertensive emergency is NOT defined by any absolute blood pressure measurement

Hypertension Nomenclature: JNC7

Hypertensive Urgency

Hypertensive Emergency

Elevated BP WITHOUT evidence of ACUTE end

organ damage

Elevated BP WITH evidence of ACUTE end

organ damage

Hypertensive Crisis

Malignant Hypertension Accelerated Hypertension

Retinal hemorrhages, exudates, and papilledema Renal involvement in the form of malignant

nephrosclerosisUsually associated with a DBP greater than 130 mm

Hg

Similar to malignant hypertension but

papilledema is absentBetter prognosis than malignant hypertension

Essential Hypertension

Renal Disease Parenchymal disease Renal artery stenosis Renal crisis from:

▪ Systemic sclerosis▪ Systemic lupus

Post-renal transplant Tubulointerstitial

nephritis

Endocrine Disease Pheochromocytoma Glucocorticoid excess Primary aldosteronism Renin-secreting tumor

Cerebrovascular Disease Ischemic stroke Intracranial hemorrhage Head injury/CNS trauma

Vaidya et al. Hospital Physician March 2007.Chobanian A, et al. Hypertension 2003;42(6):1206-1252.

Etiology

Other Eclampsia/severe

pre-eclampsia Burns Vasculitis Autonomic

hyperactivity Pregnancy Sleep apnea

Medications Non-compliance Illicit drug use Drug interactions Adverse effect

Vaidya et al. Hospital Physician March 2007.Chobanian A, et al. Hypertension 2003;42(6):1206-1252.

Etiology

Neurovascular Subarachnoid

hemorrhage Intracranial

hemorrhage Cerebral infarction Hypertensive

encephalopathy

Ocular Papilledema Retinopathy

Cardiopulmonary Decompensated HF Pulmonary edema Aortic dissection ACS LV dysfunction

Renal Renal failure Proteinuria

Organs at Risk

Marik PE, Varon J Chest 2007;131:1949-62

Pathophysiology of End-Organ Damage

Mechanical Stress Endothelial injury

Increased permeability, activation of coagulation and platelets, deposition

of fibrin

Endothelial Injury Arteriole Necrosis

RAA

activation

Pressure Natriure

sis

End organ hypoperfusion, ischemia and dysfunction

Ischemia and release of vasoactive mediators

Renal Vasoconstric

tion

Abrupt increase in SVR mediated by humoral

vasoconstrictors

Vasoconstriction

Cytokine activation

End-Organ Damage Frequency (%)

Cardiovascular 55.3

Acute Pulmonary Edema 22.5

Acute Congestive Heart Failure 14.3

Acute Coronary Syndrome 12

Eclampsia 4.5

Aortic Dissection 2.0

CNS Complications 45.3

Cerebral Infarction 24.5

Hypertensive Encephalopathy 16.3

Intracerebral or subarachnoid hemorrhage

4.5Zampaglione B, et al. Hypertension 1996;27:144-147.

End Organ Damage: Hypertensive Emergency

Signs & Symptoms

HTN Urgency (%)

HTN Emergency (%)

Headache 22 3Epistaxis 17 0Chest Pain 9 27Dyspnea 9 22Faintness 10 10Agitation 10 2N. Deficit 3 21Vertigo 7 3Paresthesia 6 8Vomiting 2 3Arrhythmia 6 0

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

Acute Condition Death Rehospitalization

ACS1,2,3 5-7% 30%

CHF4 8.5% 26%

Severe Hypertension5 11% 37%

1. OASIS-5 NEJM 20062. GUSTO IIb NEJM 19963. GRACE JAMA 20074. IMPACT-HF J Cardiac Failure 20045. STAT Registry results

Early Triage Obtain BP at least

twice Medications

Current meds/OTCs Compliance Drug Interactions Recreational drugs

▪ Cocaine▪ Amphetamines▪ Phencyclidine

Patient History PMH Family History Baseline BP

recordings Recent activities Symptoms

▪ CV▪ Renal▪ Neurologic

Initial Evaluation

Focus on detection of end organ damage

Physical Examination Neuro exam

▪ Focal findings▪ Mental status changes

Fundoscopic exam▪ Cotton wool exudates▪ Hemorrhages▪ Papilledema

Cardiac exam▪ Heart sounds▪ Pulses

Diagnostic Studies Urinalysis Electrolytes BUN and SCr CBC/platelets Chest X-Ray EKG Serum glucose Brain CT/MRI

Physical Exam and Diagnostics

Prompt, but controlled reduction in BP Reduce MAP by < 25% during the first minute to

1 hr If stable, reduce to 160/110 mmHg within the

next 2 – 6 hours Gradual reduction to goal over next 24 – 48 hours Exceptions: Ischemic stroke, stroke eligible for t-

PA, acute aortic dissection, SAH, ICH

Choice of agent should be tailored to clinical situation Type of end-organ damage / presentation

Chobanian A, et al. Hypertension 2003;42:1206-1252.

Hypertensive Emergency Initial Treatment Goals

Ischemic Stroke (tPA candidate)

Treat SBP > 185 mmHg and/or DBP >110 mmHg

Acute Aortic Dissection

Rapid reduction (5 – 10 minutes) to a SBP between 100 – 120

mmHg (if tolerated)

Subarachnoid or Intracranial Hemorrhage

Balance risk of re-bleeding with risk of

reducing cerebral perfusion pressure

Ischemic Stroke (not a tPA candidate)

Treat SBP > 220 mmHg and/or DBP >120

mmHg only

Hypertensive Emergency Initial Treatment Goal Exceptions

Cere

bra

l B

lood

Flo

w (

ml/

min

/100 g

)

Mean Arterial Pressure (mmHg)

50

100

50 100 150 200

NormotensiveChronically Hypertensive

Normal Regulatory Range

Cerebral Auto-regulation

Mort

ali

ty 1

4 d

ays

Death

ord

ep

en

den

cy

at

6m

on

ths

Leonardi-Bee Stroke 2002:33;1351-1357

Blood Pressure vs Outcomes in Acute Ischemic Stroke

a) Labetalolb) Esmololc) Fenoldopamd) Nitroglycerin

Beta-Blockers Labetalol Esmolol Metoprolol

Calcium Channel Blockers Nicardipine Clevidipine Verapamil Diltiazem

Vasodilators Nitroprusside Nitroglycerin Hydralazine

Miscellaneous Enalaprilat Fenoldopam

8%

5%

8%

15%

15%

17%

32%

0% 10% 20% 30% 40%

Other

Sodium nitroprusside

Nicardapine

Hydralazine

Nitroglycerin

Metoprolol

Labetolol

www.outcome.org/stat

22%

51%

41%

41%

40%

32%

32%

28%

45%

27%

37%

42%

46%

21%

14%

32%

23%

25%

Sodium nitroprusside (n=82)

Nicardapine (n=121)

Hydralazine (n=235)

Nitroglycerin (n=241)

Metoprolol (n=277)

Labetolol (n=501)

Fir

st

IV A

nti

hy

pe

rte

ns

ive

Percent of Patients

One Two Three or more

www.outcomes.org/stat

Conditions Preferred Agent

Goal Risks

Pre-eclampsia Eclampsia

Labetalol Nicardipine Hydralazine Magnesium sulfate (Seizures)

160 / 110150 / 100 if platelets are <100K

Hypotension

Acute renal failure Microangiopathic anemia

Nicardipine Labetalol Nitroglycerin

Reduce BP 20%

Hypotension and worsening renal failure

Hypertensive Emergency Treatment Disease-specific

Recommendations

Conditions Preferred Agent

Goal Risks

Sympathetic crisisCocaine or other sympathomimetic; PheochromocytomaMAOIs/tyramineAbrupt clonidine or beta-blocker d/c

Fenoldopam Nicardipine, verapamil or diltiazem in combination with benzodiazepinePhentolamine(NO beta-blocker)

Reduce excessive sympathetic tone.Relieve symptoms

alpha storm

Acute postoperative hypertension

Esmolol, nicardipine, or labetalol

Cardiac Surgery 140/90 Otherwise no specifc goals

Excess reduction

Hypertensive Emergency Treatment

Disease-specific Recommendations

Conditions Preferred Agent

Goal Risks

Acute ischemic stroke

Nicardipine, labetalol

Treat when > 220/ 120 except w/thrombolytics > 185/ 110

Excessive BP decrease may worsen ischemia

Intracranial Hemorrahge

Nicardipine, labetalol, esmolol

Treat to target MAP 130

Precipitous BP fall may increase mortality

SAH Nicardipine, labetalol, esmolol

SBP < 160 Keep SBP > 120 to maintain CPP

Hypertensive Encephalopathy

Nicardipine, labetalol, esmolol

Decrease MAP 15 - 20%

Aggressive BP fall may produce ischemia

Hypertensive Emergency Treatment

Disease-specific Recommendations

Conditions

Preferred Agents

Goal Risks

Acute myocardial ischemia

Labetalol Esmolol and NTG

Reduce SBP 20 – 30%

Beta-blockade could worsen LV function

Acute aortic dissection

Labetalol Nicardipine and esmolol Nitroprusside with esmolol

Reduce shear forces SBP 120 – 140 HR 60

Need continuous BP monitoring

Acute pulmonary edema or heart failure

Nicardipine or nitroprusside w/ NTG and loop diuretic; May cautiously use enalaprilat

Reduce BP by vasodilatation Promote diuresis Symptom relief

Worsening renal failure

Hypertensive Emergency Treatment

Disease-specific Recommendations

a) Decrease MAP 25-30 %b) Decrease MAP 15 -20 %c) SBP no lower than 185d) SBP no lower than 160

Alpha1 and beta blocking properties (ratio 1:7) Onset: 3 – 5 minutes, peak 5 – 15 minutes Duration: 3 – 6 hours

Safe in pregnancy AE: Bradycardia, bronchospasms, hepatotoxicity Dosing Strategies (IV – Max 300 mg/day)

20 mg IV bolus, repeat 20 – 80 mg increments Q10min

Infusion: 1 – 2 mg/min initial, titrate to effect▪ CAUTION: Accumulation WILL occur

Ultra-short acting cardioselective beta-blocker

Metabolism: RBC esterases Onset: within 60 sec Duration: 10 – 20 minutes Elimination ½ life: 9 min

Dose (max - 300 mcg/kg/min) 0.5 – 1 mg/kg bolus over 1 min, infusion at

50 mcg/kg/min – can increase every 5 minutes

Esmolol LabetalolAdministration Bolus +

Continuous infusion

BolusContinuous

infusion

Onset Rapid (60

seconds)

Intermediate

(peak 5-15 min)

Offset (Duration of action)

Rapid (10-

20 min)

Slower (2-4

h)

Heart Rate Decreased +/-

SVR 0 Decreased

Cardiac output Decreased +/-

Myocardial O2 balance

Positive Positive

Contraindications Sinus bradycardia

Heart block >1°Overt heart

failureCardiogenic

shockCocaine

Intoxication

Severe bradycardia

Heart block >1°Overt heart

failureCardiogenic

shockCocaine

Intoxication

Peripheral Dopamine-1 Agonist Improves creatinine clearance, urine flow rates,

and sodium excretion in severely hypertensive patients with both normal and impaired renal function.

Rapid, extensive hepatic conjugation The onset of action is within 5 min, with the

maximal response being achieved by 15 min. Duration of action is 30 to 60 min

An initial starting dose of 0.1 mcg/kg/min Increase 0.05 to 0.1 mcg/kg/min to max of 1.6

mcg/kg/min Nausea, headache, flushing

Potent venodilator, higher doses affect arterial tone Onset: 2 – 5 minutes Duration: 5 – 10 minutes

Tolerance with prolonged infusions (> 24 hrs)

Second agent often required Primary role in AMI ,Pulmonary edema AE: HA, vomiting, methemoglobinemia

ICP may increase, CO may decrease in volume-depleted

Potent arterial and venous vasodilator Onset: seconds Duration: 2 – 5 minutes

Reduces preload and afterload Arterial line required to monitor BP

Due to potency, rapidity of action, and tachyphylaxis

Disadvantages Cyanide toxicity, increased ICP, coronary

steal May increase mortality after AMI

CN

Cyanide Toxicity Metabolized in liver to

thiocyanate via thiosulfate

Thiocyanate eliminated via kidney

Both cyanide and thiocyanate cause toxicity

Add 1 gm sodium thiosulfate per 100 mg SNP to IV bag to reduce toxicity

Protect from light Dosing

Start 0.3 mcg/kg/min Titrate every 5 minutes

Doses < 2 mcg/kg/min low risk of cyanide

toxicity in “healthy” patients

Max 10 mcg/kg/min Short durations only

due to risk of toxicity

Dihydropyridine CCB, exhibiting selective vasodilatation Onset: 5 – 15 minutes Duration: 2 – 6 hours

Strong cerebral and coronary vasodilatory activity Reduces BP but

increases cerebral perfusion pressure

Dose Initiate at 5mg/hr Titrate by 2.5 mg/hr

increments Rapid control titrate

every 5 minutes▪ When desired result,

reduce dose to 3 mg/hr**

Gradual control titrate every 15 minutes

Max 15 mg/hr** Recommendation comes from post-operative hypertension patients. Experience suggest it often fails to optimize blood pressure management in populations other than post-op hypertension.

Adverse Events

NicardipineNitroprussi

deHypotension 5.6% 36.9%

Flushing NA 9.8%

Nausea 4.9% 11.0%

Dizziness 1.4% 6.8%

Headache 14.6% 27.6%

Thiocyanate NA 14.0%

Injection site pain

1.4% NA

Ultra-rapid acting,L-type calcium channel blocker Short half-life (< 2 min) Eliminated via plasma

esterases No renal/hepatic dosage

adjustments Initiate at 1 – 2 mg/hr

Most patient achieve response with 4 – 6 mg/hour

Limited experience up to 32 mg/hour▪ Maximum 1000 ml daily

Most common Headache (6.3%) Nausea (4.8%) Chest discomfort (3.2%) Vomiting (3.2%)

Disadvantages: Lipid based

▪ Contraindicated in patients with allergies to soybeans, soy products, eggs, or egg products

▪ Must be discarded in 4 hours

$$$$$ (~ $145 per 25 mg vial)

Prodrug of enalaprilPharmacodynamics make it difficult to

use in hypertensive crisis: Onset 15 minutes, peak~1 hr, duration 6

hoursDose

1.25 mg over 5 min every 4 to 6 h, titrate by 1.25-mg increments at 12- to 24-h intervals to max of 5 mg q6h

May further compromise renal functionMost utility for CHF

Direct relaxation of vascular smooth muscle Reflex tachycardia, increased stroke volume

Time and degree of hypotensive effects are variable Onset: 10 – 30 minutes Duration: 3 – 9 hours

Hepatic acetylation and renal elimination

Use: Eclampsia - 10 – 20 mg IV bolus, repeat in 30 min as needed

The most appropriate therapeutic option for hypertensive emergencies requires meticulous attention must be paid to: Distinction between urgency and emergency Precipitating factors Concomitant illnesses Blood pressure goals Pharmacokinetics

Marik PE et al. Chest 2007;131:1949-1962.

Amin et al. Annals of Emergency Medicine 2008;51(30):S10-S15.

Chobanian A et al. JAMA 2003;289(19):2560-72.

Haas CE et al AJHP2004; 61:1661–1673Pollack C et al. Ann Emerg Med 2008