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

article info abstract

Article history: Where at one hand, the vast majority of hypertensive patients succumb to the complica-
Received 20 November 2012 tions of hypertension like atherosclerosis, cerebrovascular diseases and congestive heart
Accepted 25 January 2013 failure, a subset of these have an exacerbation in this gradual course that needs acute
Available online 15 March 2013 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
Keywords: population than in earlier times.
Hypertensive crises Despite the recognized unmet need of timely evaluation and management, fewer than
Hypertensive emergency 10% receive the recommended investigations and appropriate treatment often gets
Hypertensive urgency delayed. This review emphasizes the therapeutic implications of correct diagnosis, various
Malignant hypertension 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 elevations in blood pressure can result in acute organ damage
& dysfunction. Prompt & precise management of such situa-
Hypertension no longer affects the middle aged & older adults tions is essential to prevent permanent organ damage.
predominantly, but with the rapidly expanding epidemic of Numerous reports in late nineties estimated that around
obesity & sedentary lifestyles, now equally affects the young 1% of hypertensive individuals experience hypertensive crisis
adults & teenagers as well.1 Around 27e30% of population over at some point of time during their lifetime3,4 although before
the age of 20 years is affected by this chronic medical condition.2 the advent of antihypertensive therapy figures were probably
While chronic hypertension is a major risk factor for car- as high as 7%.3,5 Nonetheless, the absolute number of such
diovascular & cerebrovascular outcomes & ESRD, accelerated 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: Sudeep@sgpgi.ac.in (S. Kumar).
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
2 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

time, due to absolute increase in number of hypertensive No matter how high the blood pressure, a patient cannot be
patients, coupled with better survival from major adverse labeled to have malignant hypertension in absence of hyper-
cardiovascular & cerebrovascular events. tensive neuroretinopathy.17 However, some authors believe
Unfortunately, there is a lack of randomized trials & little presence of papilledema to be essential for diagnosis of ma-
long term follow up data.6 Additionally, diagnosis overlap lignant hypertension, & use the term accelerated hypertension
with other cardiac, neurologic, renal or multisystem syn- for patients with haemorrhages, exudates, arteriolar narrow-
dromes makes it difficult to follow & remove confounding ing & spasm but without evidence of papilledema.21,22 Prac-
factors while assessing long term follow up. Questions tically, although, malignant hypertension & accelerated
regarding mortality & morbidity hence remain unanswered.7,8 hypertension are terms used interchangeably for each other.17
Moreover, the impact of these clinical situations is often Hypertensive encephalopathy is a clinical syndrome with
underappreciated, such that timely evaluation & treatment cerebral malfunction due to severe elevation of blood pres-
are often not instituted, leading to serious adverse outcomes. 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
2. Terminology 1928.23 Clinical features include severe headache, blurred
vision or blindness, nausea, vomiting, and mental confusion.
The various terminologies used in context to acute elevations The most dramatic feature is prompt clinical response to
in blood pressures have often been misused. The consensus antihypertensive therapy & in case aggressive treatment is
definitions of the various terms are discussed in succession not initiated, stupor, convulsions, and death can ensue
below. within hours.
Hypertensive crises are defined as clinical scenarios associ- At times, even in absence of hypertensive neuro-
ated with severe elevations in systolic & diastolic blood pres- retinopathy, if acute end-organ dysfunction occurs in the
sure, usually above 180/120 mmHg.2,9,10 presence of even moderate hypertension, it may still qualify
Hypertensive crises are further classified as hypertensive as a hypertensive crisis.
emergencies & urgencies.
Hypertensive emergency is defined as marked elevation in BP
complicated by acute target organ damage such as coronary 3. Pathophysiology of hypertensive crisis
ischemia, acute pulmonary edema, dissecting aortic aneu-
rysm, hypertensive encephalopathy, cerebral hemorrhage & Hypertensive crisis can be the first clinical presentation of hy-
acute renal failure.7,11e14 pertension or may punctuate the clinical course of long stand-
BP should be reduced promptly, preferably within minutes, ing essential, or more commonly, secondary hypertension.
& with rapidly acting parenteral drugs to limit target organ Volhard & Fahr24 first described the rapidly fatal course of
damage. hypertensive crisis and noticed how its pathophysiology dif-
Hypertensive urgency is a less clearly defined condition fers from the changes of chronically elevated blood pressure.
characterized by severe elevation in blood pressure in an in- Situations that qualify as hypertensive emergencies in
dividual who may have evidence of previous end organ clinical practice are enlisted in Table 1. The theme of pre-
damage related to hypertension, but in whom there exists no sentation of hypertensive emergencies is quite expressive, but
evidence of on-going or imminent acute target organ dam- variable, depending on the target organ involvement, super-
age.11 These patients do not require hospital admission and scripted with “R” in the below mentioned table. The triggering
the reduction in blood pressure can be gradual, & by oral causative factors are superscripted with “C” in the table
medications, as per individual patient characteristics.2,9,11,12,15 below.
Chronic elevations in blood pressure causes compensatory
2.1. Malignant hypertension structural & functional changes in arterial cerebral circula-
tion27 & renal microcirculation28 that maintains autor-
The usage of the term malignant with hypertension by Keith & egulation & avoids excessive blood flow at higher BP levels.14
Wagener, as early as in 1928,16 was to emphasize that the These are the subset of patients of presenting with no recent
downhill course would be similar to most cancers. However, evidence of acute target organ damage, & need appropriate
with improvement in inpatient & outpatient management of management, with slow and gradual reduction in blood
hypertension,14 the prognosis of malignant hypertension has pressure.
dramatically improved, & it will not be wrong to say that with In contrast are hypertensive emergencies, in which the
appropriate management instituted at the right time, malig- mechanisms leading to severe and rapid elevations in blood
nant hypertension is no more malignant. Hence, the usage of pressure coupled with failure of autoregulatory mechanisms29
terms hypertensive emergencies & urgencies is more in lead to target organ damage. The triggering factor could be
vogue.2 delineated in few cases like release of a humoral vasoactive
This clinical entity is characterized by marked elevation of factors.30,31 However, in many cases; the hypertensive emer-
blood pressure with widespread acute arteriolar injury that gency is a non-specific consequence of chronically elevated
reveals itself as hypertensive neuroretinopathy with striate blood pressure.13
haemorrhages, cotton-wool exudates, and often papilledema The endothelial injury occurring as a response to chroni-
in funduscopy.17 All these three funduscopic findings portend cally elevated blood pressure leads to further vascular damage
a poor prognosis.18e20 and tissue ischemia by increasing vascular permeability &
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

Table 1 e Common hypertensive emergencies or 4. Epidemiology
urgencies.
Malignant e accelerated hypertension with papilledemaR Exact figures regarding this commonly faced medical emer-
Cardiovascular conditions gency are largely unknown.32,48 They constitute approximately
Acute MI/unstable anginaR one fourth of all medical emergencies.49 Of the hypertensive
Acute LVF/pulmonary edemaR crisis, three fourths were urgencies & one fourth were emer-
Acute aortic dissectionR, C gencies in an Italian study50 while Brazilian series quotes pro-
Severe hypertension after CABG/vascular surgeryR portion of emergencies to be three fifths of hypertensive crisis.51
Renal conditions Despite recent advances & awareness, both at physician &
Rapidly progressive glomerulonephritisC patient level, hypertension control is poorly attainable. It is
Renovascular hypertensionC estimated that only approximately 30% of hypertensive pa-
Scleroderma renal crisisC tients achieve good control of the blood pressure, although
Post renal transplantation severe hypertensionC
clinical trials say that control rates of 60e70% are attainable.
Neurological conditions Despite these discouraging facts, widespread outpatient use
Hypertensive encephalopathyR of antihypertensive drugs has reduced the incidence of hy-
Intracerebral & Subarachnoid haemorrhageC,R pertensive emergencies.6,52 In US, hospitalization for hyper-
Acute head injuryC
tensive emergencies is reported at the rate of 1e2 cases/
Atherothrombotic strokeC, R
million population/year.29 However, poor compliance to
GuillaineBarre’ syndromeC
antihypertensive regime53e55 & inability to access health care
Catecholamine excess states sources56 contribute to increased incidence of hypertensive
Pheochromocytoma crisisC
crisis in the developing nations.
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 5. Diagnostic evaluation
Use of sympathomimetic drugs (Cocaine,
phenylpropanolamine)C
Hypertensive crisis is thematically a hot topic. From pediatric
Surgical conditions to geriatric, from medical to surgical e all subgroups of pa-
Perioperative hypertensionC more commonly with cardiovas- tients either have or are on verge of having target organ
cular & neurosurgical procedures25 damage. The primary goal, hence, is to differentiate between
Postoperative bleeding from vascular suture lines26 R
true hypertensive emergency from hypertensive urgency, as
Hypertension after organ transplantationC
the therapeutic approaches are different. Our approach, clin-
Hypertension associated with severe burnsC ical and investigative, should at least help us to overcome this
R
e result of hypertensive emergency. ambiguity. Another goal is to accurately assess the type and
C
e cause of hypertensive emergency. severity of target organ damage.
This includes a speedy history, current blood pressure &
clinical examination, ECG, chest roentgenogram, basal
biochemistry, funduscopy & urinalysis as essential in-
activation of platelets & coagulation cascade.13,30e33 Various vestigations & targeted investigations as per clinical hints for
vasoactive substances that contribute to this vascular injury ruling out causes of secondary hypertension or analyzing
are catecholamines, renin, angiotensin,34 endothelin, vaso- target organ damage.
pressin35,36 and more recently added to this list are ouabain, History should essentially include assessment of severity
digoxin,37,38 marinobufagenin & telocinobufagin. These newer of hypertension, duration of treatment,9,13 patient’s medica-
chemicals are grouped under the category of CTS (cardiotonic tion & compliance to treatment including history of over the
steroids) that have short term effects on vascular & cardiac counter medications & recreational drugs. Not to be forgotten
smooth muscle cells, resulting in BP elevation & cardiac ac- is a thorough and targeted history for any clue to target organ
tivity modulation.37,38 The activation of the RAAS & other damage (chest or back pain, dyspnea, throbbing headache,
vasoactive mediators lead to further vasoconstriction & pro- pulsatile abdominal mass). Liquorice, nasal drops, cocaine,
duction of proinflammatory cytokines such as IL-6.39,40 amphetamines, oral contraceptives, steroid, NSAIDs, eryth-
NADPH oxidase activity that generates reactive oxygen spe- ropoietin and cyclosporine are drugs that may trigger an acute
cies are increased, leading to oxidative stress.41 hypertensive emergency. Dietary and smoking history can be
Besides this, endothelial dysfunction is a common de- of additional information. Concomitant medical history &
nominator of these hypertensive emergencies and may history of sleep apnea syndrome should be explored.57,58
persist for a long time after the index event.42,43 BP recordings in both sitting & standing position & in the leg
The typical lesion of the hypertensive crisis is fibrinoid are essential.2,59 Recordings need to be done with an appro-
necrosis of small arteries and arterioles.29,44 In the cerebral priate sized cuff as the use of a cuff too small for the arm size,
vasculature, cerebral perfusion seems to affect primarily the as in obese individuals, or use of arm cuff over the thigh
white matter in the parieto-occipital areas of the brain45 & may give spuriously high recordings.49,60 Needless to over-
brainstem,46 possibly because of decreased sympathetic emphasize, that meticulously done clinical examination may
innervation of vessels in the parieto-occipital region.47 sometimes be extremely helpful in instituting early treatment.
4 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

Swift cardiac, pulmonary, peripheral vessel & neurological ex- end organ damage. Table 2 depicts the various agents used for
amination inclusive of fundoscopic inspection essentially this purpose.
needs to be done. Gallop rhythm (suggestive of heart failure) Instead of the absolute value of blood pressure, the gov-
and new murmurs of aortic insufficiency (associated with erning factor for immediate institution of management is the
aortic dissection) and mitral regurgitation (ischemic MR) presence of target organ damage, as patients with recent
deserve special importance in cardiovascular examination. onset or rapidly rising hypertension develop target organ
Some classical signs of secondary hypertension should not be damage earlier than chronically hypertensive patients who
missed in first examination.10,61 These include abdominal bruit tolerate equal or higher blood pressures due to structural &
(renovascular hypertension), radiofemoral delay (aortic coarc- functional autoregulatory changes.14,28,29
tation), palpable abdominal mass (pheochromocytoma/poly- Understanding these autoregulatory mechanisms is
cystic kidney disease), central obesity & abdominal striae equally important from therapeutic point of view, as sudden
(Cushing’s syndrome) & exophthalmos (hyperthyroidism).57,58 lowering of blood pressure may actually lead to inadequate
Laboratory evaluation of such patients should be expedi- tissue perfusion, which may lead to renal, cerebral or coronary
tious. It should include full blood count with peripheral smear ischemia.9 According to current American & European
and a metabolic panel inclusive of renal function indices and guidelines, the mean BP should be reduced by no more than
electrolytes9,10,13 Nephritic urinary sediment suggests acute 20e25% within minutes to 1e2 h2,9 A diastolic blood pressure
glomerulonephritis as a potential cause. Endocrinology eval- between 100 and 110 mm Hg or 25% of initial baseline,
uation for plasma renin activity, aldosterone (in patients who whichever is higher, should be the target in the next 6 h116
are not on diuretics)62 & catecholamines may guide treatment Achieving final target blood pressures gradually in 24e48 h
in selected cases. allows autoregulatory mechanisms to “reset”, and thence-
ECG to rule out myocardial ischemia and left ventricular forth the parenteral medications may be replaced by oral
hypertrophy and strain & Chest X-ray to assess cardiac size & medications. Abrupt lowering of blood pressure is not favor-
pulmonary edema are indispensable investigations and able, and this fact is exemplified by the fact that sublingual
should be routinely performed for each patient.9,10,13 nifedipine, known for its potent, but unpredictable & precip-
As per clinical status & results of preliminary in- itous hypotensive effect, increased mortality & morbidity
vestigations, Echocardiography (for regional wall motion when used for this indication.117
analysis, left ventricular hypertrophy, systolic or diastolic Patients presenting with hypertensive emergencies may be
dysfunction & degree of mitral regurgitation), CT scan or MRI volume depleted owing to pressure natriuresis, and prior to
Brain (in neurologic syndromes), Thoracoabdominal CT/MRI administering parenteral therapy, volume deficit must be
or Abdominal ultrasound (for suspected aortic dissection) may assessed & corrected as it avoids precipitous fall in blood
be needed.63 pressure and maintains adequate organ perfusion.61
Notwithstanding, we should remember that prompt ther- Currently, evidence is insufficient to label one drug or drug
apy should take priority over detailed history, unnecessary class superior over other in reducing morbidity or mortality
physical evaluation & irrelevant time consuming diagnostic related to hypertensive crisis, however logical & consensus
studies. The pursuit of etiology should never deprive a patient opinion regarding choice of pharmacological agent in specific
of hypertensive emergency from receiving the appropriate clinical scenarios exist.
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 7. Specific hypertensive emergencies
appropriate treatment being rendered at the appropriate
time.64,65 7.1. Hypertensive emergencies involving acute coronary
syndromes

6. Treatment of hypertensive emergencies The target blood pressure for hypertensive emergencies
involving cardiac ischemia is that which improves myocardial
What is crucial regarding management of hypertensive perfusion.29
emergencies is the need of immediate reduction in blood Intravenous nitroglycerin & nitroprusside were previously
pressure levels so as to reverse, or at least, halt the on-going proposed as first line drugs.9,67 Nicardipine that can selec-
target organ damage. This usually requires a short acting tively dilate cerebral & coronary arteries71,72 and clevidipine
intravenous drug that helps in tight control of the blood that can protect against ischemia-reperfusion injury118 are
pressure, and can be titrated easily by the clinician both for successful alternatives.
rate of control of blood pressure and the ultimate target. It is In presence of acute LVF, vasodilator agents that reduce
generally accepted that such a patient should be admitted to afterload like nitroglycerine, nitroprusside & fenoldopam are
an ICU or a high dependency unit (HDU) for monitoring & preferred agents. Concomitant loop diuretics & ACE inhibition
administration of an appropriate parenteral agent.2,9,11,12 are essential.
The ideal agent to treat hypertensive crisis should be fast Diazoxide & hydralazine that cause reflex tachycardia
acting, rapidly reversible and titrable without any significant should be avoided.9,29,61,67 Drugs that reduce myocardial
side effects. There is no single ideal agent & the choice of contractility like beta blockers (labetalol, esmolol) should also
pharmacologic agent to treat hypertensive crisis should be be avoided, especially when associated with heart failure,
tailored to each individual based on risks, comorbidities and 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: Adverse Effects: Comments:
1e3 mg/kg/min IV, alternatively  Flushing, hypotension, palpitations,  Strong cerebral & coronary vasodilatory property68
5e15 mg IV every hour (bolus dosing angina, syncope, peripheral edema,  Considered as effective as nitroprusside68,69
independent of body weight) headache, vomiting66  Associated with decreased norepinephrine levels70
Onset of action:
5e15 min Caution: Special Uses:
Duration of action:  Post operative patients as it potentiates  Particular use in CAD patients as it increases
15e30 min; may last for up to 3e4 h effects of curare & interacts with inhalant stroke volume & coronary blood flow with favor-
anesthetics61,67 able effect on myocardial oxygen balance71e74
 Avoid in acute heart failure  Postoperative state75

2. Fenoldopam mesylate: dopamine D1 receptor agonist (10 times more potent than dopamine) promoting natriuresis & diuresis76
Dose: Adverse Effects: Comments:
0.8e1.2 mg/kg/min intravenously  Tachycardia, hypotension, flushing,  Action mainly in renal & splanchnic arteries & less
Begin with 0.1 mg/kg/min headache, hypokalemia, nasal congestion in coronary & cerebral arteries36e38
Increase by 0.1e0.2 at 20 min  Poorly lipid soluble, does not cross blood brain
intervals Caution: barrier (so no CNS activity)80
Onset of action:  Caution in glaucoma 29,67

>5 min Special Uses:
Duration of action:  Most useful in patient with renal impairment81
30 min to 1 h without rebound  Acute heart failure76,82e84
hypertension when infusion is  Those undergoing vascular surgery85
discontinued.77
Tachyphylaxis after 48 h78,79

3. Clevidipine butyrate: L-type calcium channel blocker
Dose: Adverse Effects: Comments:
0.5e3.5 mg/kg/min Intravenously  Headache, nausea, vomiting, hypotension  Reduces PVR without affecting venous vascular
Onset of action:  Heart failure deterioration tone, increases cardiac output with little influence
2e4 min e ultra short acting on left ventricular filling pressure86e89 & without
Duration of action: Caution: causing reflex tachycardia90
5e15 min  Severe aortic stenosis  Rapid metabolism by esterase in blood &
 Acute heart failure 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 release91
Dose: Adverse Effects: Comments:
0.5e10 mg/kg/min I.V with light  Hypotension, palpitations, headache,  For years considered first choice drug9,13,29,67
resistant delivery system15,74,92 nausea, vomiting.  Now relatively abandoned10,32
Onset of action:  Obliterates cerebral autoregulation
Immediate  Thyroid suppression Special Uses :
Intraarterial BP monitoring  Coronary steal phenomenon78  Hypertensive encephalopathy96
recommended because of  Thiocyanate and cyanide toxicity (when  Aortic dissection
tachyphylaxis & rapidity of action used for > 72 h)10,61  Acute heart failure
Duration of action: Cyanide removal requires bioavailability
1e2 min of thiosulphate & normal liver & renal
functions.79,93
Caution:
 High intracranial pressure94
 Hepatic or renal failure
 Acute coronary syndrome94,95

5. Nitroglycerin: powerful venodilator & at higher doses is an arteriolar vasodilator. Acts by increasing nitrate receptor.
Dose: Adverse Effects : Comments:
5e100 mg/kg/min I.V  Profound headache, vomiting, methemo-  Adheres to plastic containers & tubings,61,67
Onset of action: globinemia, tachyphylaxis.
2e5 min Special Uses:
Duration of action:  Coronary ischemia & pulmonary edema
5e10 min

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Table 2 e (continued )
Dosage & pharmacokinetics Adverse Effects & Caution Comments & Special Uses

6. Enalaprilat: Angiotensin-converting enzyme inhibitor
Dose: Adverse Effects: Special Uses:
5e10 mg/kg/dose every 8e24 h  Hypotension, hyperkalemia, oliguria, rash,  Acute left ventricular failure (non ischemic)98
Alternatively 1.25e5 mg every 6 h angioedema, agranulocytosis, neutropenia,
Onset of action: cough, fatal hepatic necrosis (rare)
15e30 min
Duration of action: Caution:
6e12 h  Avoid in acute myocardial infarction
 Abrupt BP reduction in patients with renal
artery stenosis & hypovolemia13,44
 Contraindicated in pregnancy.97,98

7. Hydralazine hydrochloride: direct arteriolar vasodilator e Kþ channel opener
Dose: Adverse Effects: Comments:
0.1e0.6 mg/kg/dose every 4e6 h  Palpitations, flushing, tachycardia  Limited use owing to side effects & unpredictable
intravenously  Fever, rash, headache, arthralgia, SLE-like action61,67,99,100 with precipitous drop in blood
Onset of action: syndrome, positive ANA pressure that may last for 12 h
10e20 min  Peripheral neuropathy
Duration of action:  Fluid retention by activating RAAS34
1e4 h

8. Diazoxide: direct acting vasodilator
Dose: Adverse Effects:
50e150 mg every 5 min I/V or 15  Nausea, flushing
e30 mg/min I/V infusion  Reflex sympathetic stimulation101 &
Onset of action: aggravation of angina
1e5 min  Sodium retention, hyperglycemia
Duration of action:
4e12 h Caution:
 Avoid in angina, acute MI, aortic dissection

9. Isradipine: Second generation calcium channel blocker
Dose: Adverse Effects: Special Uses:
0.15 mg/kg/min I.V., increase by  Headache, flushing, peripheral edema,  Perioperative states & pregnancy102,103
0.0025 mg/kg/min every 15 min. dizziness, tachycardia
Maintenance 0.15 mg/kg/min
Onset of action:
1e10 min
Duration of action:
1e2 h

Adrenergic inhibitors

10. Labetalol hydrochloride: combined alpha 1 and beta blocker (1:7 ratio)104
Dose: Adverse Effects: Comments:
20e80 mg I/V bolus every 10 min  AV conduction disturbances, headache,  Reduces PVR without reflex increase in systolic
or 0.25e3 mg/kg/h intravenously bronchospasm, nasal congestion, scalp volume while cerebral, coronary and renal blood
Onset of action: tingling flow is mantained92,104,106,107
5e10 min13,61  Does not require intraarterial BP monitoring
Duration of action: Caution:  Metabolized in liver by formation of inactive
3e6 h13,61,105  Not to be used in acute heart failure, heart glucuronide conjugate105
block & COPD9,13,61  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: Adverse Effects: Comments:
125e500 mg/kg/min intravenously  AV Conduction disturbance, bronchocon-
0.5e2 mg/kg over 1 min followed striction, skin necrosis after extravasation,  Metabolism independent of renal or hepatic
by 50e100 mg/kg/min61,67 Raynaud’s phenomenon function
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Table 2 e (continued )
Dosage & pharmacokinetics Adverse Effects & Caution Comments & Special Uses

Onset of action:  Metabolized by rapid hydrolysis of ester linkages
1e2 min by RBC esterase
Duration of action:
Caution:
10e20 min108,109 Special Uses:
 Heart failure
 Heart block  Considered by some as “ ideal beta adrenergic
 COPD blocker” 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: Adverse Effects: Special Uses:
12.5e25 mg I.V. bolus followed by  Headache, dizziness  Perioperative states113
5e40 mg/h I/V infusion
Onset of action:
3e5 min
Duration of action:
4e6 h

13. Phentolamine: Non selective alpha-adrenergic blocker
Dose: Adverse Effects: Special Uses:
0.05e0.1 mg/kg/dose intravenously  Tachycardia, palpitations,  Special use in catecholamine excess states114,115
(maximum of 5 mg per dose)67 flushing, headache  Once initial control is achieved, oral
Onset of action:  Nasal congestion phenoxybenzamine a long acting alpha
1e2 min  Exacerbation of peptic ulcer adrenergic antagonist must be used
Duration of action:
15e30 min

heart failure with an intent to reduce myocardial oxygen 7.3. Hypertensive emergencies presenting with acute
consumption9,61,67 where it may be helpful. neurologic syndromes

7.2. Hypertensive emergencies associated with aortic Prompt improvement in patient’s condition with BP reduction
dissection is the only definite criterion to diagnose hypertensive
encephalopathy.127
The blood pressure should be rapidly reduced to Currently, fenoldopam, nicardipine & labetalol are advo-
systolic < 120 mmHg or < 100 mmHg if tolerated.119,120 A cated.29,61,67 Clevidipine has also emerged as an effective
vasodilator alone is not ideal as this can promote reflex alternative128,129 to be preferred over nitroprusside that was
tachycardia, increase aortic ejection velocity & promote typically chosen for many years. Since nitroprusside can in-
dissection propagation. Therefore, the standard treatment is a crease intracranial pressure & reduces cerebral blood flow in
combination of beta blocker & vasodilator recommended to areas with a fixed arterial narrowing130 & recent evidence of
effectively reduce BP, heart rate & cardiac contrac- an increase in mortality in ECLIPSE study when compared to
tility9,29,67,119,120 that lowers the pulsatile load as well as aortic clevidipine,131 its use for this indication has declined.
stress. In patients with acute ischemic stroke, however, aggressive
Esmolol is the drug of choice although metoprolol is a reduction in blood pressure is controversial, as elevated BP
reasonable alternative.121,122 Although nitroprusside has likely represents an adaptive mechanism to maintain blood
traditionally been used as the vasodilator of choice, fenoldo- flow to the affected area132 and aggressive lowering of blood
pam or nicardipine are less toxic & equally effective pressure has even documented to expand the ischemic pen-
alternatives.122,123 umbra61,127,133 that may have deleterious and sometimes
Even presumptive diagnosis of acute aortic dissection catastrophic consequences. Overall, there is no convincing
should prompt us to start parenteral anti hypertensives as evidence that elevated blood pressure affects the outcome
soon as possible. Not invariably, pharmacologic treatment is during the acute phase of an ischemic stroke,127,134 not even
only a bridge to surgery, especially in Type A dissection when initiated in the first few hours of stroke onset.29,61,135,136
involving ascending aorta.124,125 Therefore, all patients of Blood pressure usually declines spontaneously to pre-
aortic dissection of Type A dissection deserve active surgical stroke levels within 4 days of an acute ischemic stroke
consideration. However, patients with Type B dissections can without any antihypertensive treatment.137
be managed with aggressive BP control unless complications The current recommendations are to administer antihy-
like leak, rupture and impaired flow to vital organs pertensive treatment in ischemic stroke only if blood pressure
ensues.125,126 is more than 220/120 with mean BP is more than 130 mmHg, &
8 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

to reduce blood pressure by no more than 10e15% in the first necessary.146,147 Caution needs to be exercised in giving beta
24 h127,134,138 blocker prior to adequate alpha blockade as unopposed alpha-
However, if concomitant non cerebral target organ damage adrenergic stimulation can be dangerous.9,29
is present, other rules may apply & patients who are planned Although labetalol was traditionally considered ideal for
to receive thrombolytic therapy, BP should be kept below this purpose due to its combined alpha & beta adrenergic
185/110 mmHg.9,61,67,134,138 blocking properties, but experimental studies do not support
ACCESS study assessed candesartan (angiotensin receptor its use in this clinical setting.148,149
blocker) & found lower 12 month mortality when used in acute Specifically in cocaine induced hypertensive emergency,
phase of stroke.139 However, in the SCAST trial, there was no use of beta adrenergic antagonists can increase coronary
reduction in the composite of vascular death, myocardial vasoconstriction, fail to control heart rate, increase BP and
infarction or stroke in 6 month follow up with use of cande- decrease survival.150,151
sartan in first 7 days of stroke.140 Nicardipine, fenoldopam and verapamil in combination
Use of labetalol or nicardipine was previously suggested if with benzodiazepines are agents preferred in this setting.152,153
SBP is >220 mm Hg, DBP is 121e140 mmHg & nitroprusside if Diuretics are generally avoided as these patients are generally
DBP is >140 mmHg.61,67 volume depleted.
In intracerebral bleed, rapid BP reduction, although at the
expense of risk of cerebral hypoperfusion141,142 should be
7.6. Perioperative hypertensive emergencies
aimed with intent to prevent further bleeding, & this strategy
of intensive BP lowering significantly attenuated hematoma
Severe perioperative hypertension can occur in conjunction
growth over 72 h in the INTERACT study.143
with anesthesia induction, intraoperatively due to sympa-
Blood pressure more than 180/105 need to be treated in
thetic vasoconstriction, early postoperatively or after 24e48 h
cases of intracranial bleed, except in cases of subarachnoid
due to pain or volume overload.154
hemorrhage with normotensive prehaemorrhage status,
Perioperative hypertensive emergencies most commonly
where target is 130e160 mmHg systolic.9,29,144
occur with carotid surgery, abdominal aortic surgery, periph-
In the setting of haemorrhagic stroke with intracranial
eral vascular procedures, intraperitoneal & intrathoracic
bleed BP of more than 200/110 mm Hg need to be
surgeries155& approximately 50% of patients after cardiac sur-
controlled127,134 However, rapid decline in BP within 24 h is
geries. Amongst these, carotid surgery is notorious for being
independently associated with increased mortality.141
associated with hypertensive emergences, and actually repre-
In general, if neurologic function worsens, the therapy
sents a face of baroreflex failure.156 Regardless of cause, post-
should be suspended, and blood pressure should be allowed to
operative hypertension may be associated with increased risk
increase.
of cardiac & neurologic complications. A conservative target is
to control BP up to 10% above the baseline preoperative mean
7.4. Hypertensive emergencies associated with renal
BP levels.48 However, patients with heart failure & those who
disease
are at high risk of bleeding will benefit from afterload reduction,
and the target in them should be more aggressive.
Either renal arterial disease, acute glomerulonephritis or
Postoperative hypertension also seems to be related to
autoimmune vascular diseases are commonly followed by
catecholamine surge & sympathetic nervous system stimu-
further deterioration of remnant renal function, even when BP
lation 172 & usually requires treatment for 6 h or less.25 Careful
is properly lowered.
monitoring of patient response and temporal adjustments of
Because of its renal vasodilator effects & lack of toxic me-
treatment are of paramount importance for safe management
tabolites, fenoldopam is preferred in this setting.76 Nicardi-
of hypertensive emergencies in perioperative period.
pine, labetalol or clevidipine are other alternatives. Loop
diuretics are to be used only if there is associated volume
overload.13,29,61 7.7. Hypertensive emergencies during pregnancy
ACE inhibitors are usually contraindicated due to the risk
of further deterioration of renal function, except in the case Preeclampsia affects nearly 7% of pregnancies157 and should be
of scleroderma renal crisis where it is the drug of choice. managed with utmost caution, & conservatively, due to presence
The renin-angiotensin-aldosterone system is critically of the developing fetus. The objective of treatment is to prevent
responsible for hypertension associated with renovascular intracerebral bleed and cardiac failure without compromising
disease & some models62 propose a possible explanation of cerebral perfusion and uteroplacental blood flow.158
involvement of this axis in other forms of hypertensive crisis Hence a target SBP of 140e160 mmHg and DBP between 90
as well. Even very old reports of surgical removal of an and 105 mmHg is recommended by most authorities & current
ischemic kidney preventing hypertensive surges have been guidelines from American College of Obstetricians and
documented.145 Gynaecologists.158,159
Hydralazine, though was earlier considered as the drug of
7.5. Hypertensive emergencies due to catecholamine choice,160 has gone out of use due to increased risk of maternal
excess states hypotension & fetal heart rate abnormalities.100,161 Associa-
tion with excess of cesarean sections, placental abruptions &
These situations are best managed with an intravenous alpha low APGAR scores were noted.161 Labetalol, Urapidil100 &
blocker (phentolamine) with a beta blocker added if Nicardipine162,163 have emerged as superior alternatives to
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 9

Table 3 e Drugs used in hypertensive urgencies.
Dosage & Pharmacokinetics Adverse Effects & Caution Comments & Special Uses

1. Captopril: ACE inhibitor
Dose: Adverse Effects: Special Uses:
12.5e25 mg P/O every 1e2 h  Angioedema, cough,  Preferable for patients with evidence
Onset of action: acute renal failure9,44 of left ventricular dysfunction
15e30 min
Duration of action: Caution:
4e6 h  Contraindicated in pregnancy97,98

2. Clonidine: central alpha 2 agonist
Dose: Adverse Effects: Comments:
0.1e0.2 mg P/O every 1e2 h  Sedation, dry mouth, bradycardia,  Poorly lipid soluble, does not cross
Onset of action: rebound hypertension blood brain barrier, No CNS activity
30e60 min
Duration of action:
6e8 h

3. Labetalol: combined alpha 1 and beta blocker (1:7 ratio)104
Dose: Adverse Effects: Special Uses:
200e400 mg P/O every 2e3 h  Bronchoconstriction, Heart block, CHF  Preeclampsia related crises61,92
Onset of action:
30e120 min
Duration of action:
6e8 h

4. Furosemide: loop diuretic
Dose: Adverse Effects: Comments:
20e40 mg P/O every 2e3 h  Volume depletion, hyponatremia,  Not a primary drug but to be
Onset of action: hypokalemia9,11,12 considered as an add on therapy
30e60 min
Duration of action:
8e12 h

5. Isradipine: second generation calcium channel blocker
Dose: Adverse Effects: Special Uses:
5e10 mg P/O every 4e6 h  Headache, tachycardia, flushing,  May be considered in preeclampsia
Onset of action: peripheral edema related crisis & perioperative states102,103
30e90 min
Duration of action:
8e16 h

hydralazine.162,164 Oral treatment with methyldopa, long patients. This raises concern whether BP lowering, even
acting nifedipine & magnesium sulfate may also be useful. gradual, does, at all confer any benefit to a patient presenting
ACE inhibitors & nitroprusside are contraindicated due to with hypertensive urgency.29,165
their teratogenic effects. Notwithstanding, the potential of every hypertensive ur-
gency to transform into a hypertensive emergency should be
kept in mind & appropriate management of hypertension
8. Treatment of hypertensive urgencies with slow and controlled reduction of the blood pressure
should be the cornerstone in management of any form of
Hypertensive crisis without evidence of target organ damage witnessed severe hypertension.
can usually be treated with orally acting antihypertensive The drug of choice for a hypertensive urgency should be
agents with close ambulatory care.29 The lowering of blood effective, quick acting and unlikely to cause alterations in
pressure, if done precipitously, can do more harm than good9 mental status or produce hypotension. This widens the
by causing a shift in the pressure/flow auto-regulatory curve armamentarium of drugs available for this purpose. These
to the right.27 drugs are summarized in Table 3 below.
In essence, if BP lowering at a gradual pace is impor- Although evidence regarding the preferred time to reach
tant,11,12 equally important is assuring adequate follow up to goal BP and type of BP lowering medication is limited, there is
an appropriate site of care of chronic hypertension2,29 making evidence that a steep decrease in BP, such as reported with
sure that the blood pressure has been lowered out of a sublingual nifedipine tablets, can lead to cerebral, cardiac and
potentially dangerous range.11,12 renal ischemia166 & use of nifedipine immediate-release for-
Moreover, placebo-controlled trials have shown that BP mulations must be abandoned as a treatment option of any
decreases spontaneously in a substantial proportion of form of hypertensive crises.58,167,168
10 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

9. Agabiri-Rosei E, Salvetri M, Farsang C. European Society of
9. Conclusion Hypertension Scientific Newsletter: treatment of
hypertensive urgencies and emergencies. J Hypertens.
To summarize, hypertensive crisis as a clinical presentation of 2006;24:2482e2485.
hypertension is far less common than routinely detected 10. Varon J. The diagnosis and treatment of hypertensive crises.
Postgrad Med. 2009;121:5e13.
chronic hypertension. Hypertensive emergencies are a po-
11. Vidt DG. Hypertensive crises: emergencies and urgencies.
tential threat for permanent organ damage, significant
J Clin Hypertens. 2004;6:520e525.
morbidity & mortality. Triage of these emergencies from ur- 12. Flanigan JS, Vitberg D. Hypertensive emergency and severe
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the appropriate candidate in timely fashion. Med Clin North Am. 2006;90:439e451.
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