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Review Article

Hypertension emergencies and urgencies

Sudeep Kumar a,*, Tanuj Bhatia b, Aditya Kapoor c

a Additional Professor, Department of Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road,

Lucknow 226014, UP, Indiab Senior Resident, Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, UP, Indiac Professor, Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, UP, India

a r t i c l e i n f o

Article history:

Received 20 November 2012

Accepted 25 January 2013

Available online 15 March 2013

Keywords:

Hypertensive crises

Hypertensive emergency

Hypertensive urgency

Malignant hypertension

a b s t r a c t

Where at one hand, the vast majority of hypertensive patients succumb to the complica-

tions of hypertension like atherosclerosis, cerebrovascular diseases and congestive heart

failure, a subset of these have an exacerbation in this gradual course that needs acute

management in the blood pressure control and plays a role in short term outcomes. These

hypertensive crises are now encountered more frequently, in more diverse and aging

population than in earlier times.

Despite the recognized unmet need of timely evaluation and management, fewer than

10% receive the recommended investigations and appropriate treatment often gets

delayed. This review emphasizes the therapeutic implications of correct diagnosis, various

treatment options and targets in different clinical circumstances.

Nicardipine, clevidipine, esmolol and fenoldopam have emerged as potentially superior

drugs in most hypertensive emergencies as compared to other conventional drugs. For

hypertensive urgencies, blood pressure lowering at a gradual pace with oral drugs &

adequate follow up are two important facets of management, making sure that the blood

pressure has been lowered out of a potentially dangerous range.

Impact of optimal management of hypertensive crisis should translate into lesser target

organ damage and eventually fewer complications of stroke, myocardial infarction, or

congestive heart failure.

Copyright ª 2013, Reed Elsevier India Pvt. Ltd. All rights reserved.

1. Introduction

Hypertension no longer affects the middle aged & older adults

predominantly, but with the rapidly expanding epidemic of

obesity & sedentary lifestyles, now equally affects the young

adults & teenagers as well.1 Around 27e30% of population over

the ageof 20 years is affected by this chronicmedicalcondition.2

While chronic hypertension is a major risk factor for car-

diovascular & cerebrovascular outcomes & ESRD, accelerated

elevations in blood pressure can result in acute organ damage& dysfunction. Prompt & precise management of such situa-

tions is essential to prevent permanent organ damage.

Numerous reports in late nineties estimated that around

1% of hypertensive individuals experience hypertensive crisis

at some point of time during their lifetime3,4 although before

the advent of antihypertensive therapy figures were probably

as high as 7%.3,5 Nonetheless, the absolute number of such

individuals has been gradually increasing over the period of

* Corresponding author. Tel.: þ91 522 2495198 (O), þ91 522 2495199 (R); fax: þ91 522 2668573, þ91 522 2668017.E-mail address: [email protected] (S. Kumar).

Available online at www.sciencedirect.com

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c om / l o c a t e / c q n

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 e1 4

2211-9477/$ e see front matter Copyright ª 2013, Reed Elsevier India Pvt. Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.cqn.2013.01.004

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time, due to absolute increase in number of hypertensive

patients, coupled with better survival from major adverse

cardiovascular & cerebrovascular events.

Unfortunately, there is a lack of randomized trials & little

long term follow up data.6 Additionally, diagnosis overlap

with other cardiac, neurologic, renal or multisystem syn-

dromes makes it difficult to follow & remove confounding

factors while assessing long term follow up. Questionsregarding mortality & morbidity hence remain unanswered.7,8

Moreover, the impact of these clinical situations is often

underappreciated, such that timely evaluation & treatment

are often not instituted, leading to serious adverse outcomes.

2. Terminology

The various terminologies used in context to acute elevations

in blood pressures have often been misused. The consensus

definitions of the various terms are discussed in succession

below.

Hypertensive crises are defined as clinical scenarios associ-ated with severe elevations in systolic & diastolic blood pres-

sure, usually above 180/120 mmHg.2,9,10

Hypertensive crises are further classified as hypertensive

emergencies & urgencies.

Hypertensive emergency is defined as marked elevation in BP

complicated by acute target organ damage such as coronary

ischemia, acute pulmonary edema, dissecting aortic aneu-

rysm, hypertensive encephalopathy, cerebral hemorrhage &

acute renal failure.7,11e14

BP should be reducedpromptly, preferably within minutes,

& with rapidly acting parenteral drugs to limit target organ

damage.

Hypertensive urgency is a less clearly defined conditioncharacterized by severe elevation in blood pressure in an in-

dividual who may have evidence of previous end organ

damage related to hypertension, but in whom there exists no

evidence of on-going or imminent acute target organ dam-

age.11 These patients do not require hospital admission and

the reduction in blood pressure can be gradual, & by oral

medications, as per individual patient characteristics.2,9,11,12,15

2.1. Malignant hypertension

The usage of the term malignant with hypertension by Keith &

Wagener, as early as in 1928,16 was to emphasize that the

downhill course would be similar to most cancers. However,with improvement in inpatient & outpatient management of

hypertension,14 the prognosis of malignant hypertension has

dramatically improved, & it will not be wrong to say that with

appropriate management instituted at the right time, malig-

nant hypertension is no more malignant. Hence, the usage of

terms hypertensive emergencies & urgencies is more in

vogue.2

This clinical entity is characterized by marked elevation of

blood pressure with widespread acute arteriolar injury that

reveals itself as hypertensive neuroretinopathy with striate

haemorrhages, cotton-wool exudates, and often papilledema

in funduscopy.17 All these three funduscopic findings portend

a poor prognosis.18e20

No matter how high theblood pressure, a patientcannot be

labeled to have malignant hypertension in absence of hyper-

tensive neuroretinopathy.17 However, some authors believe

presence of papilledema to be essential for diagnosis of ma-

lignant hypertension, & use the term accelerated hypertension

for patients with haemorrhages, exudates, arteriolar narrow-

ing & spasm but without evidence of papilledema.21,22 Prac-

tically, although, malignant hypertension & acceleratedhypertension are terms used interchangeably for each other.17

Hypertensive encephalopathy is a clinical syndrome with

cerebral malfunction due to severe elevation of blood pres-

sure. Though mostly associated with malignant hyperten-

sion, it may at times occur without neuroretinopathy.19 The

first use of this term was by Oppenheimer & Fishberg in

1928.23 Clinical features include severe headache, blurred

vision or blindness, nausea, vomiting, and mental confusion.

The most dramatic feature is prompt clinical response to

antihypertensive therapy & in case aggressive treatment is

not initiated, stupor, convulsions, and death can ensue

within hours.

At times, even in absence of hypertensive neuro-retinopathy, if acute end-organ dysfunction occurs in the

presence of even moderate hypertension, it may still qualify

as a hypertensive crisis.

3. Pathophysiology of hypertensive crisis

Hypertensive crisis can be the first clinical presentation of hy-

pertension or may punctuate the clinical course of long stand-

ing essential, or more commonly, secondary hypertension.

Volhard & Fahr24 first described the rapidly fatal course of

hypertensive crisis and noticed how its pathophysiology dif-

fers from the changes of chronically elevated blood pressure.Situations that qualify as hypertensive emergencies in

clinical practice are enlisted in Table 1. The theme of pre-

sentation of hypertensive emergencies is quite expressive, but

variable, depending on the target organ involvement, super-

scripted with “R” in the below mentioned table. The triggering

causative factors are superscripted with “C” in the table

below.

Chronic elevations in blood pressure causes compensatory

structural & functional changes in arterial cerebral circula-

tion27 & renal microcirculation28 that maintains autor-

egulation & avoids excessive blood flow at higher BP levels.14

These are the subset of patients of presenting with no recent

evidence of acute target organ damage, & need appropriatemanagement, with slow and gradual reduction in blood

pressure.

In contrast are hypertensive emergencies, in which the

mechanisms leading to severe and rapid elevations in blood

pressure coupled with failure of autoregulatory mechanisms29

lead to target organ damage. The triggering factor could be

delineated in few cases like release of a humoral vasoactive

factors.30,31 However, in many cases; the hypertensive emer-

gency is a non-specific consequence of chronically elevated

blood pressure.13

The endothelial injury occurring as a response to chroni-

cally elevated blood pressure leads to furthervascular damage

and tissue ischemia by increasing vascular permeability &


http://dx.doi.org/10.1016/j.cqn.2013.01.004http://dx.doi.org/10.1016/j.cqn.2013.01.004http://dx.doi.org/10.1016/j.cqn.2013.01.004http://dx.doi.org/10.1016/j.cqn.2013.01.004


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activation of platelets & coagulation cascade.13,30e33 Various

vasoactive substances that contribute to this vascular injury

are catecholamines, renin, angiotensin,34 endothelin, vaso-

pressin35,36 and more recently added to this list are ouabain,

digoxin,37,38 marinobufagenin & telocinobufagin. These newer

chemicals are grouped under the category of CTS (cardiotonic

steroids) that have short term effects on vascular & cardiac

smooth muscle cells, resulting in BP elevation & cardiac ac-

tivity modulation.37,38 The activation of the RAAS & othervasoactive mediators lead to further vasoconstriction & pro-

duction of proinflammatory cytokines such as IL-6.39,40

NADPH oxidase activity that generates reactive oxygen spe-

cies are increased, leading to oxidative stress.41

Besides this, endothelial dysfunction is a common de-

nominator of these hypertensive emergencies and may

persist for a long time after the index event. 42,43

The typical lesion of the hypertensive crisis is fibrinoid

necrosis of small arteries and arterioles.29,44 In the cerebral

vasculature, cerebral perfusion seems to affect primarily the

white matter in the parieto-occipital areas of the brain45 &

brainstem,46 possibly because of decreased sympathetic

innervation of vessels in the parieto-occipital region.47

4. Epidemiology

Exact figures regarding this commonly faced medical emer-

gency are largely unknown.32,48 They constitute approximately

one fourth of all medical emergencies.49 Of the hypertensive

crisis, three fourths were urgencies & one fourth were emer-

gencies in an Italian study50

while Brazilian series quotes pro-portionof emergencies to be three fifths of hypertensive crisis.51

Despite recent advances & awareness, both at physician &

patient level, hypertension control is poorly attainable. It is

estimated that only approximately 30% of hypertensive pa-

tients achieve good control of the blood pressure, although

clinical trials say that control rates of 60e70% are attainable.

Despite these discouraging facts, widespread outpatient use

of antihypertensive drugs has reduced the incidence of hy-

pertensive emergencies.6,52 In US, hospitalization for hyper-

tensive emergencies is reported at the rate of 1e2 cases/

million population/year.29 However, poor compliance to

antihypertensive regime53e55 & inability to access health care

sources56

contribute to increased incidence of hypertensivecrisis in the developing nations.

5. Diagnostic evaluation

Hypertensive crisis is thematically a hot topic. From pediatric

to geriatric, from medical to surgical e all subgroups of pa-

tients either have or are on verge of having target organ

damage. The primary goal, hence, is to differentiate between

true hypertensive emergency from hypertensive urgency, as

the therapeutic approaches are different. Our approach, clin-

ical and investigative, should at least help us to overcome this

ambiguity. Another goal is to accurately assess the type andseverity of target organ damage.

This includes a speedy history, current blood pressure &

clinical examination, ECG, chest roentgenogram, basal

biochemistry, funduscopy & urinalysis as essential in-

vestigations & targeted investigations as per clinical hints for

ruling out causes of secondary hypertension or analyzing

target organ damage.

History should essentially include assessment of severity

of hypertension, duration of treatment,9,13 patient’s medica-

tion & compliance to treatment including history of over the

counter medications & recreational drugs. Not to be forgotten

is a thorough and targeted history for any clue to target organ

damage (chest or back pain, dyspnea, throbbing headache,pulsatile abdominal mass). Liquorice, nasal drops, cocaine,

amphetamines, oral contraceptives, steroid, NSAIDs, eryth-

ropoietin and cyclosporine are drugs that may trigger an acute

hypertensive emergency. Dietary and smoking history can be

of additional information. Concomitant medical history &

history of sleep apnea syndrome should be explored.57,58

BP recordings in both sitting & standing position & in the leg

are essential.2,59 Recordings need to be done with an appro-

priate sized cuff as the use of a cuff too small for the arm size,

as in obese individuals, or use of arm cuff over the thigh

may give spuriously high recordings.49,60 Needless to over-

emphasize, that meticulously done clinical examination may

sometimes be extremely helpful in instituting early treatment.

Table 1 e Common hypertensive emergencies orurgencies.

Malignant e accelerated hypertension with papilledemaR

Cardiovascular conditions

Acute MI/unstable anginaR

Acute LVF/pulmonary edemaR

Acute aortic dissectionR, C

Severe hypertension after CABG/vascular surgeryR

Renal conditions

Rapidly progressive glomerulonephritisC

Renovascular hypertensionC

Scleroderma renal crisisC

Post renal transplantation severe hypertensionC

Neurological conditions

Hypertensive encephalopathyR

Intracerebral & Subarachnoid haemorrhageC,R

Acute head injuryC

Atherothrombotic strokeC, R

GuillaineBarre’ syndromeC

Catecholamine excess states

Pheochromocytoma crisisC

MAO Inhibitor e tyramine interactionsC

Alpha-2 agonists drug (Clonidine, alpha methyl dopa)C with-

drawal leading to rebound hypertension

Automatic hyperreflexia after spinal cord injury C

Use of sympathomimetic drugs (Cocaine,

phenylpropanolamine)C

Surgical conditions

Perioperative hypertensionC more commonly with cardiovas-

cular & neurosurgical procedures25

Postoperative bleeding from vascular suture lines26 R

Hypertension after organ transplantationC

Hypertension associated with severe burnsC

Re result of hypertensive emergency.

Ce cause of hypertensive emergency.

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 e1 4 3



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Swift cardiac, pulmonary, peripheral vessel & neurological ex-

amination inclusive of fundoscopic inspection essentially

needs to be done. Gallop rhythm (suggestive of heart failure)

and new murmurs of aortic insufficiency (associated with

aortic dissection) and mitral regurgitation (ischemic MR)

deserve special importance in cardiovascular examination.

Some classical signs of secondary hypertension should not be

missed in first examination.10,61 These include abdominal bruit(renovascular hypertension), radiofemoral delay (aortic coarc-

tation), palpable abdominal mass (pheochromocytoma/poly-

cystic kidney disease), central obesity & abdominal striae

(Cushing’s syndrome) & exophthalmos (hyperthyroidism).57,58

Laboratory evaluation of such patients should be expedi-

tious. It should include full blood count with peripheral smear

and a metabolic panel inclusive of renal function indices and

electrolytes9,10,13 Nephritic urinary sediment suggests acute

glomerulonephritis as a potential cause. Endocrinology eval-

uation for plasma renin activity, aldosterone (in patients who

are not on diuretics)62 & catecholamines may guide treatment

in selected cases.

ECG to rule out myocardial ischemia and left ventricularhypertrophy and strain & Chest X-ray to assess cardiac size &

pulmonary edema are indispensable investigations and

should be routinely performed for each patient.9,10,13

As per clinical status & results of preliminary in-

vestigations, Echocardiography (for regional wall motion

analysis, left ventricular hypertrophy, systolic or diastolic

dysfunction & degree of mitral regurgitation), CT scan or MRI

Brain (in neurologic syndromes), Thoracoabdominal CT/MRI

or Abdominal ultrasound (for suspected aortic dissection) may

be needed.63

Notwithstanding, we should remember that prompt ther-

apy should take priority over detailed history, unnecessary

physical evaluation & irrelevant time consuming diagnosticstudies. The pursuit of etiology should never deprive a patient

of hypertensive emergency from receiving the appropriate

antihypertensive drug at the minimum time possible after

contact with the medical care team, especially after knowing

that most of these complications are largely reversible with

appropriate treatment being rendered at the appropriate

time.64,65

6. Treatment of hypertensive emergencies

What is crucial regarding management of hypertensive

emergencies is the need of immediate reduction in bloodpressure levels so as to reverse, or at least, halt the on-going

target organ damage. This usually requires a short acting

intravenous drug that helps in tight control of the blood

pressure, and can be titrated easily by the clinician both for

rate of control of blood pressure and the ultimate target. It is

generally accepted that such a patient should be admitted to

an ICU or a high dependency unit (HDU) for monitoring &

administration of an appropriate parenteral agent.2,9,11,12

The ideal agent to treat hypertensive crisis should be fast

acting, rapidly reversible and titrable without any significant

side effects. There is no single ideal agent & the choice of

pharmacologic agent to treat hypertensive crisis should be

tailored to each individual based on risks, comorbidities and

end organ damage. Table 2 depicts the various agents used for

this purpose.

Instead of the absolute value of blood pressure, the gov-

erning factor for immediate institution of management is the

presence of target organ damage, as patients with recent

onset or rapidly rising hypertension develop target organ

damage earlier than chronically hypertensive patients who

tolerate equal or higher blood pressures due to structural &functional autoregulatory changes.14,28,29

Understanding these autoregulatory mechanisms is

equally important from therapeutic point of view, as sudden

lowering of blood pressure may actually lead to inadequate

tissue perfusion, which maylead to renal,cerebral or coronary

ischemia.9 According to current American & European

guidelines, the mean BP should be reduced by no more than

20e25% within minutes to 1e2 h2,9 A diastolic blood pressure

between 100 and 110 mm Hg or 25% of initial baseline,

whichever is higher, should be the target in the next 6 h116

Achieving final target blood pressures gradually in 24e48 h

allows autoregulatory mechanisms to “reset”, and thence-

forth the parenteral medications may be replaced by oralmedications. Abrupt lowering of blood pressure is not favor-

able, and this fact is exemplified by the fact that sublingual

nifedipine, known for its potent, but unpredictable & precip-

itous hypotensive effect, increased mortality & morbidity

when used for this indication.117

Patients presenting with hypertensive emergencies may be

volume depleted owing to pressure natriuresis, and prior to

administering parenteral therapy, volume deficit must be

assessed & corrected as it avoids precipitous fall in blood

pressure and maintains adequate organ perfusion.61

Currently, evidence is insufficient to label one drug or drug

class superior over other in reducing morbidity or mortality

related to hypertensive crisis, however logical & consensusopinion regarding choice of pharmacological agent in specific

clinical scenarios exist.

7. Specific hypertensive emergencies

7.1. Hypertensive emergencies involving acute coronary

syndromes

The target blood pressure for hypertensive emergencies

involving cardiac ischemia is that which improves myocardial

perfusion.29

Intravenous nitroglycerin & nitroprusside were previouslyproposed as first line drugs.9,67 Nicardipine that can selec-

tively dilate cerebral & coronary arteries71,72 and clevidipine

that can protect against ischemia-reperfusion injury118 are

successful alternatives.

In presence of acute LVF, vasodilator agents that reduce

afterload like nitroglycerine, nitroprusside & fenoldopam are

preferred agents. Concomitant loop diuretics & ACE inhibition

are essential.

Diazoxide & hydralazine that cause reflex tachycardia

should be avoided.9,29,61,67 Drugs that reduce myocardial

contractility like beta blockers (labetalol, esmolol) should also

be avoided, especially when associated with heart failure,

except in cases with diastolic dysfunction29 or those without




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Table 2 e Drugs used in hypertensive emergencies.

Dosage & pharmacokinetics Adverse Effects & Caution Comments & Special Uses

Vasodilators

1. Nicardipine hydrochloride: second generation dihydropyridine calcium channel blocker

Dose:

1e3 mg/kg/min IV, alternatively

5e

15 mgIV every hour(bolus dosing independent of body weight)

Onset of action:

5e15 min

Duration of action:

15e30 min; may last for up to 3e4 h

Adverse Effects:

Flushing, hypotension, palpitations,

angina, syncope, peripheral edema,headache, vomiting 66

Caution:

Post operative patients as it potentiates

effects of curare & interacts with inhalant

anesthetics61,67

Avoid in acute heart failure

Comments:

Strong cerebral & coronary vasodilatory property68

Considered as effective as nitroprusside68,69

Associated with decreased norepinephrine levels70

Special Uses:

Particular use in CAD patients as it increases

stroke volume & coronary blood flow with favor-

able effect on myocardial oxygen balance71e74

Postoperative state75

2. Fenoldopam mesylate: dopamine D1 receptor agonist (10 times more potent than dopamine) promoting natriuresis & diuresis76

Dose:

0.8e1.2 mg/kg/min intravenously

Begin with 0.1 mg/kg/min

Increase by 0.1e0.2 at 20 min

intervals

Onset of action:>5 min

Duration of action:

30 min to 1 h without rebound

hypertension when infusion is

discontinued.77

Tachyphylaxis after 48 h78,79

Adverse Effects:

Tachycardia, hypotension, flushing,

headache, hypokalemia, nasal congestion

Caution:

Caution in glaucoma29,67

Comments:

Action mainly in renal & splanchnic arteries & less

in coronary & cerebral arteries36e38

Poorly lipid soluble, does not cross blood brain

barrier (so no CNS activity)80

Special Uses:

Most useful in patient with renal impairment81

Acute heart failure76,82e84

Those undergoing vascular surgery85

3. Clevidipine butyrate: L-type calcium channel blocker

Dose:

0.5e3.5 mg/kg/min Intravenously

Onset of action:

2e4 min e ultra short acting

Duration of action:

5e15 min

Adverse Effects:

Headache, nausea, vomiting, hypotension

Heart failure deterioration

Caution:

Severe aortic stenosis

Acute heart failure

Comments:

Reduces PVR without affecting venous vascular

tone, increases cardiac output with little influence

on left ventricular filling pressure86e89 & without

causing reflex tachycardia90

Rapid metabolism by esterase in blood &

extravascular tissues

Special Uses:

Critically ill patients, minimizing risk of prolonged

hypotension & overshoot hypotension32,86

Post anesthesia hypertension90

4. Sodium nitroprusside: direct arteriolar & venous dilator by releasing nitric oxide, increases cGMP, blocks intracellular calcium release 91

Dose:

0.5e10 mg/kg/min I.V with light

resistant delivery system15,74,92

Onset of action:

Immediate

Intraarterial BP monitoring

recommended because of

tachyphylaxis & rapidity of action

Duration of action:1e2 min

Adverse Effects:

Hypotension, palpitations, headache,

nausea, vomiting.

Obliterates cerebral autoregulation

Thyroid suppression

Coronary steal phenomenon78

Thiocyanate and cyanide toxicity (when

used for > 72 h)10,61

Cyanide removal requires bioavailabilityof thiosulphate & normal liver & renal

functions.79,93

Caution:

High intracranial pressure94

Hepatic or renal failure

Acute coronary syndrome94,95

Comments:

For years considered first choice drug 9,13,29,67

Now relatively abandoned10,32

Special Uses :

Hypertensive encephalopathy96

Aortic dissection

Acute heart failure

5. Nitroglycerin: powerful venodilator & at higher doses is an arteriolar vasodilator. Acts by increasing nitrate receptor.

Dose:

5e100 mg/kg/min I.V

Onset of action:

2e5 min

Duration of action:

5e10 min

Adverse Effects :

Profound headache, vomiting, methemo-

globinemia, tachyphylaxis.

Comments:

Adheres to plastic containers & tubings,61,67

Special Uses:

Coronary ischemia & pulmonary edema

(continued on next page)




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Table 2 e ( continued )


6. Enalaprilat: Angiotensin-converting enzyme inhibitor

Dose:

5e10 mg/kg/dose every 8e24 h

Alternatively 1.25e5 mg every 6 h

Onset of action:15e30 min

Duration of action:

6e12 h

Adverse Effects:

Hypotension, hyperkalemia, oliguria, rash,

angioedema, agranulocytosis, neutropenia,

cough, fatal hepatic necrosis (rare)

Caution:

Avoid in acute myocardial infarction

Abrupt BP reduction in patients with renal

artery stenosis & hypovolemia13,44

Contraindicated in pregnancy.97,98

Special Uses:

Acute left ventricular failure (non ischemic)98

7. Hydralazine hydrochloride: direct arteriolar vasodilator e Kþ channel opener

Dose:

0.1e0.6 mg/kg/dose every 4e6 h

intravenously

Onset of action:

10e20 min

Duration of action:

1e

4 h

Adverse Effects:

Palpitations, flushing, tachycardia

Fever, rash, headache, arthralgia, SLE-like

syndrome, positive ANA

Peripheral neuropathy

Fluid retention by activating RAAS34

Comments:

Limited use owing to side effects & unpredictable

action61,67,99,100 with precipitous drop in blood

pressure that may last for 12 h

8. Diazoxide: direct acting vasodilator

Dose:

50e150 mg every 5 min I/V or 15

e30 mg/min I/V infusion

Onset of action:

1e5 min

Duration of action:

4e12 h

Adverse Effects:

Nausea, flushing

Reflex sympathetic stimulation101 &

aggravation of angina

Sodium retention, hyperglycemia

Caution:

Avoid in angina, acute MI, aortic dissection

9. Isradipine: Second generation calcium channel blocker

Dose:

0.15 mg/kg/min I.V., increase by

0.0025 mg/kg/min every 15 min.

Maintenance 0.15 mg/kg/minOnset of action:

1e10 min

Duration of action:

1e2 h

Adverse Effects:

Headache, flushing, peripheral edema,

dizziness, tachycardia

Special Uses:

Perioperative states & pregnancy102,103

Adrenergic inhibitors

10. Labetalol hydrochloride: combined alpha 1 and beta blocker (1:7 ratio)104

Dose:

20e80 mg I/V bolus every 10 min

or 0.25e3 mg/kg/h intravenously

Onset of action:

5e10 min13,61

Duration of action:

3e6 h13,61,105

Adverse Effects:

AV conduction disturbances, headache,

bronchospasm, nasal congestion, scalp

tingling

Caution:

Not to be used in acute heart failure, heart

block & COPD9,13,61

Comments:

Reduces PVR without reflex increase in systolic

volume while cerebral, coronary and renal blood

flow is mantained92,104,106,107

Does not require intraarterial BP monitoring

Metabolized in liver by formation of inactive

glucuronide conjugate105

Maintains cardiac output unlike pure beta adren-ergic blockers107

Special Uses:

Aortic dissection

Acute coronary syndrome

Hypertensive encephalopathy

Adrenergic crises

Preeclampsia related crises61,92

11. Esmolol hydrochloride: cardioselective beta-1 adrenergic blocker

Dose:

125e500 mg/kg/min intravenously

0.5e2 mg/kg over 1 min followed

by 50e100 mg/kg/min61,67

Adverse Effects:

AV Conduction disturbance, bronchocon-

striction, skin necrosis after extravasation,

Raynaud’s phenomenon

Comments:

Metabolism independent of renal or hepatic

function




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heart failure with an intent to reduce myocardial oxygen

consumption9,61,67 where it may be helpful.

7.2. Hypertensive emergencies associated with aorticdissection

The blood pressure should be rapidly reduced to

systolic < 120 mmHg or < 100 mmHg if tolerated.119,120 A

vasodilator alone is not ideal as this can promote reflex

tachycardia, increase aortic ejection velocity & promote

dissection propagation. Therefore, the standard treatment is a

combination of beta blocker & vasodilator recommended to

effectively reduce BP, heart rate & cardiac contrac-

tility9,29,67,119,120 that lowers the pulsatile load as well as aortic

stress.

Esmolol is the drug of choice although metoprolol is a

reasonable alternative.121,122 Although nitroprusside hastraditionally been used as the vasodilator of choice, fenoldo-

pam or nicardipine are less toxic & equally effective

alternatives.122,123

Even presumptive diagnosis of acute aortic dissection

should prompt us to start parenteral anti hypertensives as

soon as possible. Not invariably, pharmacologic treatment is

only a bridge to surgery, especially in Type A dissection

involving ascending aorta.124,125 Therefore, all patients of

aortic dissection of Type A dissection deserve active surgical

consideration. However, patients with Type B dissections can

be managed with aggressive BP control unless complications

like leak, rupture and impaired flow to vital organs

ensues.125,126

7.3. Hypertensive emergencies presenting with acute

neurologic syndromes

Prompt improvement in patient’s condition with BP reductionis the only definite criterion to diagnose hypertensive

encephalopathy.127

Currently, fenoldopam, nicardipine & labetalol are advo-

cated.29,61,67 Clevidipine has also emerged as an effective

alternative128,129 to be preferred over nitroprusside that was

typically chosen for many years. Since nitroprusside can in-

crease intracranial pressure & reduces cerebral blood flow in

areas with a fixed arterial narrowing 130 & recent evidence of

an increase in mortality in ECLIPSE study when compared to

clevidipine,131 its use for this indication has declined.

In patients with acute ischemic stroke, however, aggressive

reduction in blood pressure is controversial, as elevated BP

likely represents an adaptive mechanism to maintain bloodflow to the affected area132 and aggressive lowering of blood

pressure has even documented to expand the ischemic pen-

umbra61,127,133 that may have deleterious and sometimes

catastrophic consequences. Overall, there is no convincing

evidence that elevated blood pressure affects the outcome

during the acute phase of an ischemic stroke,127,134 not even

when initiated in the first few hours of stroke onset.29,61,135,136

Blood pressure usually declines spontaneously to pre-

stroke levels within 4 days of an acute ischemic stroke

without any antihypertensive treatment.137

The current recommendations are to administer antihy-

pertensive treatment in ischemic stroke only if blood pressure

is more than 220/120with mean BP is more than 130 mmHg, &

Table 2 e ( continued )


Onset of action:

1e2 min

Duration of action:

10e20 min108,109 Caution:

Heart failure

Heart block COPD

Metabolized by rapid hydrolysis of ester linkages

by RBC esterase

Special Uses:

Considered by some as “ ideal beta adrenergicblocker” to be used in critically ill patients32

Aortic dissection

Perioperative states110,111

Any hypertensive crisis with increased heart

rate/cardiac output

Acute MI112

12. Urapidil: selective post synaptic alpha-1 blocker, 5 HT1A receptor agonist

Dose:

12.5e25 mg I.V. bolus followed by

5e40 mg/h I/V infusion

Onset of action:

3e5 min

Duration of action:

4e6 h

Adverse Effects:

Headache, dizziness

Special Uses:

Perioperative states113

13. Phentolamine: Non selective alpha-adrenergic blocker

Dose:

0.05e0.1 mg/kg/dose intravenously

(maximum of 5 mg per dose)67

Onset of action:

1e2 min

Duration of action:

15e30 min

Adverse Effects:

Tachycardia, palpitations,

flushing, headache

Nasal congestion

Exacerbation of peptic ulcer

Special Uses:

Special use in catecholamine excess states114,115

Once initial control is achieved, oral

phenoxybenzamine a long acting alpha

adrenergic antagonist must be used




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to reduce blood pressure by no more than 10e15% in the first

24 h127,134,138

However, if concomitant non cerebral target organ damage

is present, other rules may apply & patients who are planned

to receive thrombolytic therapy, BP should be kept below

185/110 mmHg.9,61,67,134,138

ACCESS study assessed candesartan (angiotensin receptor

blocker) & found lower 12 month mortalitywhen used in acutephase of stroke.139 However, in the SCAST trial, there was no

reduction in the composite of vascular death, myocardial

infarction or stroke in 6 month follow up with use of cande-

sartan in first 7 days of stroke.140

Use of labetalol or nicardipine was previously suggested if

SBP is >220 mm Hg, DBP is 121e140 mmHg & nitroprusside if

DBP is >140 mmHg.61,67

In intracerebral bleed, rapid BP reduction, although at the

expense of risk of cerebral hypoperfusion141,142 should be

aimed with intent to prevent further bleeding, & this strategy

of intensive BP lowering significantly attenuated hematoma

growth over 72 h in the INTERACT study. 143

Blood pressure more than 180/105 need to be treated incases of intracranial bleed, except in cases of subarachnoid

hemorrhage with normotensive prehaemorrhage status,

where target is 130e160 mmHg systolic.9,29,144

In the setting of haemorrhagic stroke with intracranial

bleed BP of more than 200/110 mm Hg need to be

controlled127,134 However, rapid decline in BP within 24 h is

independently associated with increased mortality.141

In general, if neurologic function worsens, the therapy

should be suspended, and blood pressure should be allowed to

increase.

7.4. Hypertensive emergencies associated with renal

disease

Either renal arterial disease, acute glomerulonephritis or

autoimmune vascular diseases are commonly followed by

furtherdeterioration of remnant renal function, evenwhen BP

is properly lowered.

Because of its renal vasodilator effects & lack of toxic me-

tabolites, fenoldopam is preferred in this setting.76 Nicardi-

pine, labetalol or clevidipine are other alternatives. Loop

diuretics are to be used only if there is associated volume

overload.13,29,61

ACE inhibitors are usually contraindicated due to the risk

of further deterioration of renal function, except in the case

of scleroderma renal crisis where it is the drug of choice.The renin-angiotensin-aldosterone system is critically

responsible for hypertension associated with renovascular

disease & some models62 propose a possible explanation of

involvement of this axis in other forms of hypertensive crisis

as well. Even very old reports of surgical removal of an

ischemic kidney preventing hypertensive surges have been

documented.145

7.5. Hypertensive emergencies due to catecholamine

excess states

These situations are best managed with an intravenous alpha

blocker (phentolamine) with a beta blocker added if

necessary.146,147 Caution needs to be exercised in giving beta

blocker prior to adequate alpha blockade as unopposed alpha-

adrenergic stimulation can be dangerous.9,29

Although labetalol was traditionally considered ideal for

this purpose due to its combined alpha & beta adrenergic

blocking properties, but experimental studies do not support

its use in this clinical setting.148,149

Specifically in cocaine induced hypertensive emergency,use of beta adrenergic antagonists can increase coronary

vasoconstriction, fail to control heart rate, increase BP and

decrease survival.150,151

Nicardipine, fenoldopam and verapamil in combination

with benzodiazepines are agents preferred in this setting.152,153

Diuretics are generally avoided as these patients are generally

volume depleted.

7.6. Perioperative hypertensive emergencies

Severe perioperative hypertension can occur in conjunction

with anesthesia induction, intraoperatively due to sympa-thetic vasoconstriction, early postoperatively or after 24e48 h

due to pain or volume overload.154

Perioperative hypertensive emergencies most commonly

occur with carotid surgery, abdominal aortic surgery, periph-

eral vascular procedures, intraperitoneal & intrathoracic

surgeries155& approximately 50% of patients after cardiac sur-

geries. Amongst these, carotid surgery is notorious for being

associated with hypertensive emergences, and actually repre-

sents a face of baroreflex failure.156 Regardless of cause, post-

operative hypertension may be associated with increased risk

of cardiac & neurologic complications. A conservative target is

to control BP up to 10% above the baseline preoperative mean

BP levels.

48

However, patients with heart failure & those whoare at high riskof bleeding willbenefit fromafterload reduction,

and the target in them should be more aggressive.

Postoperative hypertension also seems to be related to

catecholamine surge & sympathetic nervous system stimu-

lation 172 & usually requires treatment for 6 h or less.25 Careful

monitoring of patient response and temporal adjustments of

treatment are of paramount importance for safe management

of hypertensive emergencies in perioperative period.

7.7. Hypertensive emergencies during pregnancy

Preeclampsia affects nearly 7% of pregnancies157 and should be

managed withutmostcaution,& conservatively,due to presenceof the developing fetus. The objective of treatment is to prevent

intracerebral bleed and cardiac failure without compromising

cerebral perfusion and uteroplacental blood flow.158

Hence a target SBP of 140e160 mmHg and DBP between 90

and 105 mmHg is recommended by most authorities & current

guidelines from American College of Obstetricians and

Gynaecologists.158,159

Hydralazine, though was earlier considered as the drug of

choice,160 has gone out ofuse due to increasedrisk ofmaternal

hypotension & fetal heart rate abnormalities.100,161 Associa-

tion with excess of cesarean sections, placental abruptions &

low APGAR scores were noted.161 Labetalol, Urapidil100 &

Nicardipine162,163 have emerged as superior alternatives to




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hydralazine.162,164 Oral treatment with methyldopa, long

acting nifedipine & magnesium sulfate may also be useful.

ACE inhibitors & nitroprusside are contraindicated due to

their teratogenic effects.

8. Treatment of hypertensive urgencies

Hypertensive crisis without evidence of target organ damage

can usually be treated with orally acting antihypertensive

agents with close ambulatory care.29 The lowering of blood

pressure, if done precipitously, can do more harm than good9

by causing a shift in the pressure/flow auto-regulatory curve

to the right.27

In essence, if BP lowering at a gradual pace is impor-

tant,11,12 equally important is assuring adequate follow up to

an appropriate site of care of chronic hypertension2,29 making

sure that the blood pressure has been lowered out of a

potentially dangerous range.11,12

Moreover, placebo-controlled trials have shown that BP

decreases spontaneously in a substantial proportion of

patients. This raises concern whether BP lowering, even

gradual, does, at all confer any benefit to a patient presenting

with hypertensive urgency.29,165

Notwithstanding, the potential of every hypertensive ur-

gency to transform into a hypertensive emergency should be

kept in mind & appropriate management of hypertension

with slow and controlled reduction of the blood pressure

should be the cornerstone in management of any form of witnessed severe hypertension.

The drug of choice for a hypertensive urgency should be

effective, quick acting and unlikely to cause alterations in

mental status or produce hypotension. This widens the

armamentarium of drugs available for this purpose. These

drugs are summarized in Table 3 below.

Although evidence regarding the preferred time to reach

goal BP and type of BP lowering medication is limited, there is

evidence that a steep decrease in BP, such as reported with

sublingual nifedipine tablets, can lead to cerebral, cardiac and

renal ischemia166 & use of nifedipine immediate-release for-

mulations must be abandoned as a treatment option of any

form of hypertensive crises.58,167,168

Table 3 e Drugs used in hypertensive urgencies.

Dosage & Pharmacokinetics Adverse Effects & Caution Comments & Special Uses

1. Captopril: ACE inhibitor

Dose:

12.5e25 mg P/O every 1e2 h

Onset of action:

15e

30 minDuration of action:

4e6 h

Adverse Effects:

Angioedema, cough,

acute renal failure9,44

Caution:

Contraindicated in pregnancy97,98

Special Uses:

Preferable for patients with evidence

of left ventricular dysfunction

2. Clonidine: central alpha 2 agonist

Dose:

0.1e0.2 mg P/O every 1e2 h

Onset of action:

30e60 min

Duration of action:

6e8 h

Adverse Effects:

Sedation, dry mouth, bradycardia,

rebound hypertension

Comments:

Poorly lipid soluble, does not cross

blood brain barrier, No CNS activity

3. Labetalol: combined alpha 1 and beta blocker (1:7 ratio)104

Dose:

200e400 mg P/O every 2e3 h

Onset of action:

30e120 minDuration of action:

6e8 h

Adverse Effects:

Bronchoconstriction, Heart block, CHF

Special Uses:

Preeclampsia related crises61,92

4. Furosemide: loop diuretic

Dose:


Onset of action:

30e60 min

Duration of action:

8e12 h

Adverse Effects:

Volume depletion, hyponatremia,

hypokalemia9,11,12

Comments:

Not a primary drug but to be

considered as an add on therapy

5. Isradipine: second generation calcium channel blocker

Dose:


Onset of action:

30e90 minDuration of action:

8e16 h

Adverse Effects:

Headache, tachycardia, flushing,

peripheral edema

Special Uses:

May be considered in preeclampsia

related crisis & perioperative states102,103




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9. Conclusion

To summarize, hypertensive crisis as a clinical presentation of

hypertension is far less common than routinely detected

chronic hypertension. Hypertensive emergencies are a po-

tential threat for permanent organ damage, significant

morbidity & mortality. Triage of these emergencies from ur-gencies is crucial to ensure delivery of appropriate therapy to

the appropriate candidate in timely fashion.

Still, the potential threat of permanent target organ damage

associated with this clinical diagnosis, if not detected & treated

in time, should make the optimal implementation of recom-

mended therapy a commitment on part of the treating physi-

cian. The appropriate therapeutic approach needs to be

individualized for every patient. However, admission to ICU,

use of titratable IV hypotensive agents, and expeditious eval-

uation are cornerstone in management of hypertensive emer-

gencies. The pharmacological evolution in the last decade has

witnessed the transition of usage from nifedipine, hydralazine

& nitroprusside to esmolol, nicardipine & fenoldopam that areequally potent, if not more, and have fewer adverse effects. It

should be stressed that the use of oral or sublingual nifedipine

should be avoided to prevent increased mortality.

Conflicts of interest

All authors have none to declare.

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