1. Evaluation and Management of Hypertensive Emergencies
Kimberly Zammit, Pharm.D., BCPS, FASHP
Clinical Coordinator: Buffalo General Hospital

2. Learning Objectives 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.

3. Epidemiology
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:

4. Epidemiology

5. 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 Hyperlidemia
Vital 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)

6. 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

7. This patient is classified as having a hypertensive emergency because he has a blood pressure of > 180 / 110:
True
False

8. Hypertension Nomenclature: JNC7
Category
SBP (mmHg)
DBP (mmHg)
Normal
<120
<80
Pre-hypertensive
80 – 89
Hypertension
140 – 179
90 – 109
Hypertensive Crisis*
≥ 180
≥ 110
JNC-8 will be release late 2009/early 2010
SBP > 240 mmHg or DBP > 140 mmHg usually for hypertensive emergencies (Mansoor et al.)
* Hypertensive emergency is NOT defined by any absolute blood pressure
measurement

9. Hypertensive Emergency Malignant Hypertension Accelerated Hypertension
Hypertensive Crisis
Hypertensive Urgency
Hypertensive Emergency
Elevated BP WITHOUT evidence of ACUTE end organ damage
Elevated BP WITH evidence of ACUTE end organ damage
Malignant Hypertension
Accelerated Hypertension
Retinal hemorrhages, exudates, and papilledema
Renal involvement in the form of malignant nephrosclerosis
Usually associated with a DBP greater than 130 mm Hg
Similar to malignant hypertension but papilledema is absent
Better prognosis than malignant hypertension
The 1993 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure1 proposed an operational classification of hypertensive crises as either emergencies or urgencies. Severe elevations in blood pressure were classified as "hypertensive emergencies" in the presence of acute or ongoing end-organ damage or as "hypertensive urgencies" in the absence of target-organ involvement, a certain degree of which can pose an immediate threat to the integrity of the cardiovascular system. Distinguishing hypertensive urgencies from emergencies is important in formulating a therapeutic plan. In the former the goal is to reduce blood pressure within 24 hours, whereas in the latter it is to lower blood pressure immediately (not necessarily to normal ranges) to prevent or limit target organ disease.1 2 3

10. Etiology Essential Hypertension Renal Disease Endocrine 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):

11. Etiology Other Medications 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):

12. Organs at Risk Neurovascular Ocular Cardiopulmonary Renal
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

13. Pathophysiology of End-Organ Damage
Abrupt increase in SVR
mediated by humoral vasoconstrictors
RAA activation
Mechanical Stress Endothelial injury
Pressure Natriuresis
Vasoconstriction Cytokine activation
Increased permeability, activation of coagulation and platelets, deposition of fibrin
Renal Vasoconstriction
Endothelial Injury Arteriole Necrosis
End organ hypoperfusion, ischemia and dysfunction
Ischemia and release of vasoactive mediators
Marik PE, Varon J Chest 2007;131:

14. End Organ Damage: Hypertensive Emergency
Frequency (%)
Cardiovascular
Acute Pulmonary Edema
22.5
Acute Congestive Heart Failure
14.3
Acute Coronary Syndrome 12
Eclampsia
4.5
Aortic Dissection
2.0
CNS Complications
Cerebral Infarction
24.5
Hypertensive Encephalopathy
16.3
Intracerebral or subarachnoid hemorrhage
Mean blood pressure 210/130 mmHg. No patients with emergency had a DBP < 120 mmHg.
Total number patients = 108
The aim of the present study was to evaluate the prevalence of hypertensive emergencies and urgencies in an emergency department during 12 months of observation and the frequency of end-organ damage with the related clinical picture during the first 24 hours after presentation of the patient.
Zampaglione B, et al. Hypertension 1996;27:

15. Signs and Symptoms 22 17 27 10 21 Headache 3 Epistaxis Chest Pain 9
Signs & Symptoms
HTN Urgency (%)
HTN Emergency (%)
Headache 22 3
Epistaxis 17
Chest Pain 9 27
Dyspnea
Faintness 10
Agitation 2
N. Deficit 21
Vertigo 7
Paresthesia 6 8
Vomiting
Arrhythmia
Zampaglione B, et al. Hypertension 1996;27:

16. Short-Term (2 to 6 month) Outcomes
Acute Condition Death Rehospitalization ACS1,2,3 5-7% 30% CHF4 8.5% 26% Severe Hypertension5 11% 37%
OASIS-5 NEJM 2006
GUSTO IIb NEJM 1996
GRACE JAMA 2007
IMPACT-HF J Cardiac Failure 2004
STAT Registry results

17. Initial Evaluation Early Triage Medications Patient History PMH
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
Amphetamines, cocaine, phencyclidine

18. Physical Exam and Diagnostics
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

19. Hypertensive Emergency Initial Treatment Goals
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:

20. Hypertensive Emergency Initial Treatment Goal Exceptions
Ischemic Stroke (not a tPA candidate)
Treat SBP > 220 mmHg and/or DBP >120 mmHg only
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

21. Mean Arterial Pressure (mmHg)
Cerebral Auto-regulation
100
Normal Regulatory
Range
Cerebral Blood Flow (ml/min/100 g)
Normotensive 50
Chronically Hypertensive
MAP = (1/3(SBP-DBP) + DBP) 50
100
150
200
Mean Arterial Pressure (mmHg)

22. Death ordependency at 6months
Blood Pressure vs Outcomes in Acute Ischemic Stroke
Death ordependency at 6months
Mortality 14 days
Leonardi-Bee Stroke 2002:33;

23. The ED resident would like a recommendation for the best antihypertensive in this patient?:
Labetalol
Esmolol
Fenoldopam
Nitroglycerin

24. Parenteral Anti-Hypertensives
Beta-Blockers
Labetalol
Esmolol
Metoprolol
Calcium Channel Blockers
Nicardipine
Clevidipine
Verapamil
Diltiazem
Vasodilators
Nitroprusside
Nitroglycerin
Hydralazine
Miscellaneous
Enalaprilat
Fenoldopam

25. First IV Antihypertensive Agent

26. Number of Antihypertensives Required to Gain BP Control

27. Hypertensive Emergency Treatment Disease-specific Recommendations
Conditions
Preferred Agent
Goal
Risks
Pre-eclampsia Eclampsia
Labetalol
Nicardipine Hydralazine Magnesium sulfate (Seizures)
160 / 110
150 / 100 if platelets are <100K
Hypotension
Acute renal failure Microangiopathic anemia
Nicardipine Labetalol Nitroglycerin
Reduce BP 20%
Hypotension and worsening renal failure
Cocaine intoxication: beta blockers are CONTRAINDICATED, even labetalol. Labetalol does NOT reverse coronary artery vasoconstriction.

28. Hypertensive Emergency Treatment
Disease-specific Recommendations
Conditions
Preferred Agent
Goal
Risks
Sympathetic crisis
Cocaine or other sympathomimetic;
Pheochromocytoma
MAOIs/tyramine
Abrupt clonidine or beta-blocker d/c
Fenoldopam Nicardipine, verapamil or diltiazem in combination with benzodiazepine
Phentolamine
(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
Cocaine intoxication: beta blockers are CONTRAINDICATED, even labetalol. Labetalol does NOT reverse coronary artery vasoconstriction.

29. 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
SBP < 160
Keep SBP > 120 to maintain CPP
Hypertensive Encephalopathy
Decrease MAP %
Aggressive BP fall may produce ischemia

30. Hypertensive Emergency Treatment
Disease-specific Recommendations
Conditions
Preferred Agents
Goal
Risks
Acute myocardial ischemia
Labetalol Esmolol and NTG
Reduce SBP – 30%
Beta-blockade could worsen LV function
Acute aortic dissection
Labetalol Nicardipine and esmolol Nitroprusside with esmolol
Reduce shear forces SBP 120 – 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

31. What is the patient’s immediate BP reduction goal?:
Decrease MAP %
Decrease MAP %
SBP no lower than 185
SBP no lower than 160

32. Labetalol 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
Rapid ability to reduce BP – due to alpha effects
HR maintained or slightly reduced, CO maintained
Hepatic metabolism – Hepatic toxicity
Caution with HF, bronchospasms, severe asthma/COPD, heart block
Infusion – may need to start with IV bolus
OKAY in pregnancy

33. Esmolol Ultra-short acting cardioselective beta-blocker
Metabolism: RBC esterases
Onset: within 60 sec
Duration: 10 – 20 minutes
Elimination ½ life: 9 min
Dose (max mcg/kg/min)
0.5 – 1 mg/kg bolus over 1 min, infusion at 50 mcg/kg/min – can increase every 5 minutes

34. Intermediate (peak 5-15 min)
Esmolol
Labetalol
Administration
Bolus +
Continuous infusion
Bolus
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
Cardiac output
Myocardial O2 balance
Positive
Contraindications
Sinus bradycardia
Heart block >1°
Overt heart failure
Cardiogenic shock
Cocaine Intoxication
Severe bradycardia
The onset of action for esmolol is 60 seconds and the duration of action is 10 to 20 minutes. For labetalol, the onset of action begins within 2 to 5 minutes after a loading dose, but the peak effect requires up to 15 minutes. Several bolus doses of labetalol over a period of 1 hour may be required to achieve target BP. Once treatment is stopped, labetalol effects will last 2 to 4 hours.
Esmolol and labetalol differ in their effects on HR, SVR, and CO. In patients treated with esmolol, HR decreases, CO decreases with no change in SVR. Labetalol treatment may increase HR and CO slightly while decreasing SVR. Both agents result in positive effects on myocardial oxygen balance.
1. Varon J, Malik PE. Chest. 2000;118:
2. Hoffman BB. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:

35. Fenoldopam 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
Pressure gradually returning to pretreatment values without rebound once the infusion is stopped

36. Nitroglycerin 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
Red blood cells contain 4 hemoglobin chains. Each hemoglobin molecule is composed of 4 polypeptide chains associated with 4 heme groups. The heme group contains an iron molecule in the reduced or ferrous form (Fe2+). In this form, iron can combine with oxygen, by sharing an electron, to form oxyhemoglobin. When oxyhemoglobin releases oxygen to the tissues, the iron molecule is restored to its original ferrous state. Hemoglobin can accept and transport oxygen only when the iron atom is in its ferrous form. When hemoglobin loses an electron and becomes oxidized, it is converted to the ferric state (Fe3+) or methemoglobin. Methemoglobin lacks the electron that is needed to form a bond with oxygen and, thus, is incapable of oxygen transport. Because red blood cells are continuously exposed to various oxidant stresses, blood normally contains approximately 1% methemoglobin levels.

37. Sodium Nitroprusside 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

38. Sodium Nitroprusside Cyanide Toxicity Protect from light Dosing
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

39. Nicardipine
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.

40. Safety Profiles of Nicardipine and Nitroprusside
Adverse Events
Nicardipine
Nitroprusside
Hypotension
5.6%
36.9%
Flushing NA
9.8%
Nausea
4.9%
11.0%
Dizziness
1.4%
6.8%
Headache
14.6%
27.6%
Thiocyanate
14.0%
Injection site pain
Although nitroprusside is widely used for the treatment of hypertensive emergencies, compared with alternatives such as nicardipine, it is a dangerous drug. A comparison of safety profiles reported in product prescribing information indicates that a higher percentage of patients receiving nitroprusside1experienced more adverse events than those receiving nicardipine. Lower incidence of hypotension associated with nicardipine may be explained by its arterioselective action.2 Lack of effect on venous tone decreases the risk of hypotension caused by drug-induced decreases in preload.
1. Cardene IV [package insert]. ESP Pharma, Inc; 2002.
2. Nitropress [package insert].

41. Clevidipine
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)
Experience beyond 72 hours is limited
Successful transition defined as SBP remaining within target range 6 hours after clevidipine discontinuation
Transitioned to:
Imidazoline receptor agonists (33%)
Angiotensin-converting enzyme inhibitors (29%)
Dihydropyridine calcium channel blockers (24%)
Beta-blocking agents (21%)
Successfully transitioned in 97.5% of patients

42. Enalaprilat Prodrug of enalapril
Pharmacodynamics make it difficult to use in hypertensive crisis:
Onset 15 minutes, peak~1 hr, duration 6 hours
Dose
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 function
Most utility for CHF

43. Hydralazine 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

44. Summary
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

45. References / Suggested Reading
Marik PE et al. Chest 2007;131:
Amin et al. Annals of Emergency Medicine 2008;51(30):S10-S15.
Chobanian A et al. JAMA 2003;289(19):
Haas CE et al AJHP2004; 61:1661–1673
Pollack C et al. Ann Emerg Med 2008