Download - CRISIS HIPERTENSIVAS. CFEG. 2015 - AEEMmedicina-ucr.com/.../2015/08/CRISIS-HIPERTENSIVAS.-CFEG.-2015.pdf · CRISIS HIPERTENSIVA. OBJETIVOS ... (CHEST 2007; 131:1949–1962) Key words:

Dr. Carlos Fernando Estrada GarzonaDepartamento de FarmacologíaUniversidad de Costa Rica

CRISIS HIPERTENSIVA

OBJETIVOS

•  URGENCIA VS EMERGENCIA HIPERTENSIVA

•  ABORDAJE TERAPEUTICO

•  ANTIHIPERTENSIVOS IV

Franz Volhard (left) and Theodor Fahr (right)

“EMERGENCIA HIPERTENSIVA”. 1914Hypertensive Crises*Challenges and Management

Paul E. Marik, MD, FCCP; and Joseph Varon, MD, FCCP

Hypertension affects > 65 million people in the United States and is one of the leading causes ofdeath. One to two percent of patients with hypertension have acute elevations of BP that requireurgent medical treatment. Depending on the degree of BP elevation and presence of end-organdamage, severe hypertension can be defined as either a hypertensive emergency or a hyperten-sive urgency. A hypertensive emergency is associated with acute end-organ damage and requiresimmediate treatment with a titratable short-acting IV antihypertensive agent. Severe hyperten-sion without acute end-organ damage is referred to as a hypertensive urgency and is usuallytreated with oral antihypertensive agents. This article reviews definitions, current concepts,common misconceptions, and pitfalls in the diagnosis and management of patients with acutelyelevated BP as well as special clinical situations in which BP must be controlled.

(CHEST 2007; 131:1949–1962)

Key words: aortic dissection; !-blockers; calcium-channel blockers; clevidipine; eclampsia; fenoldopam; hypertension;hypertensive crises; hypertensive encephalopathy; labetalol; nicardipine; nitroprusside; pre-eclampsia; pregnancy

Abbreviations: ACE " angiotensin-converting enzyme; APH " acute postoperative hypertension; DBP " diastolicBP; FDA " Food and Drug Administration; JNC " Joint National Committee; MAP " mean arterial pressure;SBP " systolic BP

H ypertension is one of the most common chronicmedical conditions in the United States, affect-

ing close to 30% of the population # 20 years old.1While chronic hypertension is an established riskfactor for cardiovascular, cerebrovascular, and renaldisease, acute elevations in BP can result in acuteend-organ damage with significant morbidity. Hy-pertensive emergencies and hypertensive urgencies(see definitions below) are commonly encounteredby a wide variety of clinicians. Prompt recognition,evaluation, and appropriate treatment of these con-

ditions are crucial to prevent permanent end-organdamage. This article reviews our current understand-ing of hypertensive crises, the common misconcep-tions and pitfalls in its diagnosis and management, aswell as pharmacotherapy and special situations thatclinicians may encounter.

Definitions

The classification and approach to hypertensionundergoes periodic review by the Joint NationalCommittee (JNC) on Prevention, Detection, Evalu-ation, and Treatment of High Blood Pressure, withthe most recent report (JNC 7) having been releasedin 2003 (Table 1).2 Although not specifically ad-dressed in the JNC 7 report, patients with a systolicBP (SBP) # 179 mm Hg or a diastolic BP (DBP)# 109 mm Hg are usually considered to be having a“hypertensive crisis.” The 1993 report3 of the JNCproposed an operational classification of hyperten-sive crisis as either “hypertensive emergencies” or“hypertensive urgencies.” This classification remainsuseful today. Severe elevations in BP were classified

*From the Department of Pulmonary and Critical Care (Dr.Marik), Thomas Jefferson University, Philadelphia, PA; andDepartment of Acute and Continuing Care (Dr. Varon), TheUniversity of Texas Health Science Center at Houston, Houston,TX.The authors have no conflicts of interest to disclose.Manuscript received October 11, 2006; revision accepted January23, 2007.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: Paul E. Marik, MD, FCCP, 834 Walnut St,Suite 650, Philadelphia, PA 19107; e-mail: [email protected]: 10.1378/chest.06-2490

CHEST Postgraduate Education CornerCONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE

www.chestjournal.org CHEST / 131 / 6 / JUNE, 2007 1949

Downloaded From: http://journal.publications.chestnet.org/ on 09/08/2013

•  PA> 180/120•  DAÑO A ORGANO BLANCO

PRESENTE

•  REDUCCION INMEDIATA DE LA PA

•  VIA ENDOVENOSA

•  AUSENCIA DE DAÑO A ORGANO BLANCO

•  REDUCCION DE PA 24-48 HORAS

•  VIA ORAL

CRISIS HIPERTENSIVAS. DEFINICION

URGENCIA EMERGENCIA

Drugs 2008; 68 (3): 283-297REVIEW ARTICLE 0012-6667/08/0003-0283/$53.45/0

© 2008 Adis Data Information BV. All rights reserved.

Treatment of AcuteSevere HypertensionCurrent and Newer Agents

Joseph Varon1,2,3

1 The University of Texas Health Science Center at Houston, Houston, Texas, USA2 The University of Texas Medical Branch at Galveston, Galveston, Texas, USA3 St Luke’s Episcopal Hospital/Texas Heart Institute, Houston, Texas, USA

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2831. Classification of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2842. Hypertensive Crises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

2.1 Hypertensive Urgencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2852.2 Hypertensive Emergencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

2.2.1 Operative and Postoperative Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2852.2.2 Hypertension in Acute Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286

2.3 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2863. Initial Management of Severe Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286

3.1 Pharmacological Agents Used in the Treatment of Hypertensive Crises . . . . . . . . . . . . . . . . . . . . 2873.1.1 Enalaprilat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2883.1.2 Labetalol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2893.1.3 Esmolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2893.1.4 Clevidipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2893.1.5 Nicardipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2903.1.6 Nifedipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2903.1.7 Fenoldopam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2913.1.8 Hydralazine and Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2913.1.9 Nitroglycerin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2913.1.10 Sodium Nitroprusside . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292

4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293

Approximately 72 million people in the US experience hypertension. World-Abstractwide, hypertension may affect as many as 1 billion people and be responsible for≈7.1 million deaths per year. It is estimated that ≈1% of patients with hypertensionwill, at some point, develop a hypertensive crisis. Hypertensive crises are furtherdefined as either hypertensive emergencies or urgencies, depending on the degreeof blood pressure elevation and presence of end-organ damage. Immediate reduc-tion in blood pressure is required only in patients with acute end-organ damage(i.e. hypertensive emergency) and requires treatment with a titratable, short-acting, intravenous antihypertensive agent, while severe hypertension withoutacute end-organ damage (i.e. hypertensive urgency) is usually treated with oralantihypertensive agents.

•  chest pain (27%)•  dyspnea (22%)•  neurologic deficits (21%)

•  The absolute level of BP may not be as important as the .

GENERALIDADES �

Hypertensive Crises*Challenges and Management



(CHEST 2007; 131:1949–1962)






Definitions






For personal use only. Not to be reproduced without permission of The Lancet.

the time of initial assessment can be useful in making aretrospective diagnosis.

Hypertensive encephalopathyCerebral blood flow is autoregulated within specific limits.In normotensive individuals, cerebral blood flow remainsunchanged between mean arterial pressures of 60 mm Hgand 120 mm Hg (figure 2). As mean arterial pressureincreases, compensatory cerebral vasoconstriction limitscerebral hyperperfusion. At a mean arterial pressure ofabout 180 mm Hg this autoregulation is overwhelmed;cerebral vasodilation ensues and cerebral oedema develops.Previously normotensive individuals can develop signsof encephalopathy at blood pressures as low as160/100 mm Hg, whereas individuals with long-standinghypertension may not do so until the blood pressure rises to220/110 mm Hg or greater.

Hypertensive encephalopathy is defined as an acuteorganic brain syndrome (acute encephalopathy or delirium)

occurring as a result of failure of the upper limit of cerebralvascular autoregulation (autoregulation breakthrough).There may be differences between individuals in the degreeof hypertension that can give rise to autoregulatorydysfunction leading to encephalopathy and differenceswithin one person over time depending on comorbidfactors. Clinically, hypertensive encephalopathy ischaracterised by the acute or subacute onset of lethargy,confusion, headache, visual disturbance (includingblindness), and seizures. Encephalopathy can occur with orwithout proteinuria and hypertensive retinopathy. Seizuresmay be the presenting manifestation;25 these may be focal orgeneralised, or focal with secondarily generalised tonic-clonic convulsions. If not adequately treated, hypertensiveencephalopathy can progress to cerebral haemorrhage,coma, and death. It is associated with untreated orundertreated hypertension and other known causes andassociations of severe hypertension such as renal disease,immunosuppressive therapy,26,27 erythropoietin use,28 andthrombotic thrombocytopenic purpura;29 it may also occurin unique circumstances such as in pre-eclampsia andeclampsia.30 In thrombotic thrombocytopenic purpura, andin the syndrome of haemolysis, raised liver enzymes, andlow platelet count associated with pre-eclampsia andeclampsia,31 thrombocytopenia can predispose tointracerebral haemorrhage.

The pathogenesis of hypertensive encephalopathy isincompletely understood, although it seems to be related tohypertensive cerebrovascular endothelial dysfunction,disruption of the blood-brain barrier with increasedpermeability, cerebral oedema, and microhaemorrhageformation. In parallel with the clinical presentation,

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THE LANCET • Vol 356 • July 29, 2000 413

NO PGI2 NO

NO PGI2PGI2NO

ATII

CAT ETI

ADHNO

A B C

CAMs CAMsCAMs

Platelet aggregationDIC

Fibrinoid necrosisPerivascular oedema

Normotensionor

chronic hypertension

Hypertensiveurgency

Hypertensiveemergency

Platelet

RBCFibrinogen

TxA2

TxA2

Figure 1: Putative vascular pathophysiology of hypertensive emergenciesA: the endothelium modulates vascular resistance through the autocrine/paracrine release of vasoactive molecules such as nitric oxide (NO) andprostacyclin (PGI2). B: acute changes in vascular resistance occur in response to excess production of catecholamines, angiotensin II (ATII), vasopressin(ADH), aldosterone, thromboxane (TxA2), and endothelin 1 (ET1), or low production of endogenous vasodilators such as NO and PGI2. Acute or severe risesin blood pressure can also promote expression of cellular adhesion molecules (CAMs) by the endothelium. C: during a hypertensive emergency, endothelialcontrol of vascular tone may be overwhelmed, leading to end-organ hyperperfusion, arteriolar fibrinoid necrosis, and increased endothelial permeability withperivascular oedema. Loss of endothelial fibrinolytic activity coupled with activation of coagulation and platelets promotes disseminated intravascularcoagulation (DIC).

Vasoconstriction

VasodilationAutoregulationfailure

Cerebralhyperperfusion

Cerebralblood flow

(mL 100g–1 min–1)

70

Mean arterialpressure (mm Hg)

60 120

140

00

Figure 2: Autoregulation of cerebral blood flow


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A hypertensive emergency is defined as a situation thatrequires immediate blood-pressure reduction (notnecessarily to .normal values) to prevent or limit target-organ damage, and a hypertensive urgency is defined as asituation in which blood pressure should be lowered withina few hours.1 The distinction between emergencies andurgencies is important because it dictates management.Patients with target-organ damage, such as encephalopathyor aortic dissection, require emergency blood-pressurereduction with intensive monitoring and parenteral drugtherapy. Patients presenting with significantly raised bloodpressure but without evidence of target-organ injury needurgent, but not emergency, blood-pressure reduction. Thisaim can be achieved by use of oral agents and withoutintensive-care monitoring.

EpidemiologyAbout 20–30 % of adults in the more developed countrieshave hypertension. Blood pressure tends to increase withage in most societies, and hypertension is slightly morecommon in men than in women, especially in younger andmiddle-aged groups.2 In the USA, the incidence andprevalence of hypertension are about 1·5–2·0 times greaterin African Americans than in the white population.3 Theexact prevalence of hypertension depends on definition. Ingeneral, definite hypertension has been taken to be a bloodpressure, on two or more clinic readings, of more than160/100 mm Hg in the UK and more than 140/90 mm Hgin North America. The advent of ambulatory blood-pressure monitoring has complicated the definition ofhypertension, but it may help to define risk further.Guidelines from various organisations4,5 have given

Lancet 2000; 356: 411–17Division of Cardiology, Department of Medicine, Weill MedicalCollege of Cornell University, New York Presbyterian Hospital, New York, NY, USA (C J Vaughan MRCPI); and Department of ClinicalNeurological Sciences, Royal College of Surgeons in Ireland, andDivision of Neurology, Beaumont Hospital, Dublin 9, Ireland(N Delanty MRCPI)

Correspondence to: Dr Norman Delanty(e-mail: [email protected])

somewhat varying definitions and recommendations fortreatment. Most guidelines for the treatment ofhypertension discuss the issue in relation to reduction in therisk of chronic end-organ damage and do not specificallyaddress the prevention of acute hypertensive complications.However, the assumption that improved treatment ofchronic hypertension should also lead to a reduction inthe incidence of hypertensive emergencies seemsreasonable. This hypothesis is supported by data from a1988 study of 100 patients with severe hypertension (two-thirds of whom had evidence of end-organ damage)admitted to a large urban hospital.6 In that series, 93% ofpatients had previously been diagnosed as havingchronic hypertension; this finding suggests thatimproved management of pre-existing known hypertensioncould lower the incidence of hypertensive emergencies.Data from the Framingham Heart Study confirm thatappropriate, monitored long-term treatment ofhypertension lowers the incidence of hypertensivecomplications.7 Unfortunately, the recognition and correcttreatment of hypertension in the general population are stillnot adequate, and many physicians may be complacentabout the need for aggressive control of raised bloodpressure.8–10 Thus, many patients with unrecognised orundertreated hypertension may be at increased risk of thedevelopment of hypertensive emergencies, as well as itsmore insidious consequences.

PathophysiologyThe causes of hypertensive emergencies and urgencies areshown in the panel. Any disorder that causes hypertensioncan give rise to a hypertensive emergency. The rate ofchange in blood pressure determines the likelihood that anacute hypertensive syndrome will develop.11 Pre-existingchronic hypertension may lower the probability of ahypertensive emergency (at a particular blood pressure)through adaptive vascular changes that protect end organsfrom acute changes in blood pressure. Conversely, inpatients without pre-existing chronic hypertension (eg,those who have become hypertensive in the setting of acuteglomerulonephritis or pre-eclampsia) a hypertensiveemergency can develop at substantially lower bloodpressures.11

Hypertensive emergencies

Carl J Vaughan, Norman Delanty

Seminar

A hypertensive emergency is a situation in which uncontrolled hypertension is associated with acute end-organ damage.Most patients presenting with hypertensive emergency have chronic hypertension, although the disorder can present inpreviously normotensive individuals, particularly when associated with pre-eclampsia or acute glomerulonephritis. Thepathophysiological mechanisms causing acute hypertensive endothelial failure are complex and incompletely understoodbut probably involve disturbances of the renin-angiotensin-aldosterone system, loss of endogenous vasodilatormechanisms, upregulation of proinflammatory mediators including vascular cell adhesion molecules, and release of localvasoconstrictors such as endothelin 1. Magnetic resonance imaging has demonstrated a characteristic hypertensiveposterior leucoencephalopathy syndrome predominantly causing oedema of the white matter of the parietal and occipitallobes; this syndrome is potentially reversible with appropriate prompt treatment. Generally, the therapeutic approach isdictated by the particular presentation and end-organ complications. Parenteral therapy is generally preferred, andstrategies include use of sodium nitroprusside, !-blockers, labetelol, or calcium-channel antagonists, magnesium for pre-eclampsia and eclampsia; and short-term parenteral anticonvulsants for seizures associated with encephalopathy. Noveltherapies include the peripheral dopamine-receptor agonist, fenoldapam, and may include endothelin-1 antagonists.


The endothelium has a central role in blood-pressurehomoeostasis by secreting substances such as nitric oxideand prostacyclin, which modulate vascular tone throughvasodilation (figure 1).12 Nitric oxide is released under theinfluence of endothelial agonists such as acetylcholine,norepinephrine, and substance P. It is also released by theendothelium in response to mechanical forces such as shearstress.13 The pathophysiology of hypertensive emergencyremains incompletely understood, but an initial abrupt risein vascular resistance seems to be a necessary initiating step(figure 1). Increased vasoreactivity can be precipitated byrelease of vasoconstricting substances such as angiotensin IIor norepinephrine, or can occur as a result of relativehypovolaemia. Activation of the renin-angiotensin-aldosterone system seems to be important in thepathophysiology of severe hypertension. Experiments withtransgenic animals have highlighted the importance of therenin-angiotensin system. Rats expressing the mouse reningene, Ren-2, develop severe hypertension in comparisonwith controls.14 Moreover, rats that are double transgenicfor the human renin and human angiotensinogen genesdevelop not only moderately severe hypertension but alsoan inflammatory vasculopathy similar to that seen in severehuman hypertension.15 There is evidence that angiotensin IIhas direct cytotoxic effects on the vessel wall.16,17 Some ofthese effects seem to be mediated through activation ofexpression of genes for proinflammatory cytokines (such asinterleukin 6) and activation of the transcription factor NF-!" (nuclear factor !") by angiotensin II.16,17 Many of thevascular sequelae and much of the target-organ dysfunctionseen in hypertensive emergencies may be due to theinjurious effects of angiotensin II on the blood vessel wall.Moreover, inhibition of angiotensin-converting enzyme(ACE) prevents the development of malignant hypertensionin transgenic rats expressing the murine renin gene.18

During an initial rise in blood pressure, the endotheliumattempts to compensate for the change in vascularresistance through increased autocrine/paracrine release ofvasodilator molecules such as nitric oxide. When

hypertension is sustained or severe, these compensatoryendothelial vasodilator responses are overwhelmed, leadingto endothelial decompensation, which promotes furtherrises in blood pressure and endothelial damage. Thus, avicious cycle of homoeostatic failure is initiated, withprogressive increases in vascular resistance and furtherendothelial dysfunction. Although the exact cellularmechanisms leading to loss of endothelial function inhypertensive syndromes are poorly understood, putativemechanisms include proinflammatory responses inducedby mechanical stretching, such as secretion of cytokines19

and monocyte chemotactic protein 1,20 increasedendothelial-cell cytosolic calcium concentrations,21 releaseof the vasoconstrictor endothelin 1,22 and upregulatedexpression of endothelial adhesion molecules.23 Increasedexpression of vascular cell adhesion molecules, such as P-selectin, E-selectin, or intracellular adhesion molecule 1, byendothelial cells promotes local inflammation leading toadditive loss of endothelial function. Ultimately, thesemolecular events may trigger increases in endothelialpermeability, inhibit local endothelial fibrinolytic activity,and activate the coagulation cascade. Platelet aggregationand degranulation on damaged endothelium may promotefurther inflammation, thrombosis, and vasoconstriction.

Clinical evaluationThe history and results of physical examination determinethe nature, severity, and subsequent management of acutehypertensive syndromes. The history should include detailsof the duration and severity of pre-existing hypertensionand the presence of previous end-organ damage,particularly renal and cerebrovascular disease. Details ofantihypertensive drug therapy, degree of blood-pressurecontrol, intake of over-the-counter preparations such assympathomimetic agents, and use of illicit drugs such ascocaine should be ascertained promptly.24 Also, thephysician should assess whether specific symptomssuggesting end-organ compromise are present. Thesesymptoms include chest pain (myocardial ischaemia orinfarction, aortic dissection), back pain (aortic dissection),dyspnoea (pulmonary oedema or congestive heart failure),and neurological symptoms, seizures, or alteredconsciousness (hypertensive encephalopathy). The physicalexamination should assess whether end-organ damage ispresent. Blood pressure should be measured with thepatient in both supine and standing positions (if possible) toassess whether there is volume depletion. The bloodpressure should also be measured in both arms; asignificant difference should raise the suspicion of aorticdissection. A funduscopic examination is particularly usefulbecause it can distinguish a true hypertensive emergencyfrom a hypertensive urgency (the presence of newhaemorrhages, exudates, or papilloedema indicating theformer). The cardiovascular examination should focus onthe presence of heart failure (raised jugular venouspressure, crackles, third heart sound, or gallop). Theneurological examination should assess level ofconsciousness, signs of meningeal irritation, visual fields,and focal signs such as drift of the outstretched arms.Important immediate investigations include measurementof concentrations of urea, electrolytes, and serumcreatinine, a full blood count (including a peripheral bloodsmear for evidence of haemolysis indicated by the presenceof schistocytes), an electrocardiogram, chest radiography,and urine analysis. In some cases, measurement of plasmarenin activity and aldosterone in samples of blood drawn at

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412 THE LANCET • Vol 356 • July 29, 2000

Causes of hypertensive emergenciesEssential hypertensionRenal parenchymal diseaseAcute glomerulonephritisVasculitisHaemolytic uraemic syndromeThrombotic thrombocytopenic purpura

Renovascular diseaseRenal-artery stenosis (atheromatous or fibromusculardysplasia)

PregnancyEclampsia

EndocrinePhaeochromocytomaCushing’s syndromeRenin-secreting tumoursMineralocorticoid hypertension (rarely causes hypertensiveemergencies)

DrugsCocaine, sympathomimetics, erythropoietin, cyclosporin,antihypertensive withdrawalInteractions with monoamine-oxidase inhibitors (tyramine),amphetamines, lead intoxication

Autonomic hyper-reactivityGuillain-Barré syndrome, acute intermittent porphyria

Central-nervous-system disordersHead injury, cerebral infarction/haemorrhage, brain tumours


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Seminar


The signs and symptoms therefore vary from patientto patient. Zampaglione and colleagues20 reportedthat the most frequent presenting signs in patientswith hypertensive emergencies were chest pain(27%), dyspnea (22%), and neurologic deficits(21%). No particular BP threshold has been associ-ated with the development of a hypertensive emer-gency. However, organ dysfunction is uncommonwith a DBP ! 130 mm Hg (except in children andpregnancy).21 The absolute level of BP may not be asimportant as the rate of increase. For example, inpatients with long-standing hypertension, a SBP of200 mm Hg or a DBP up to 150 mm Hg may be welltolerated without the development of hypertensiveencephalopathy; whereas in children and pregnantwomen, encephalopathy may develop with a DBP ofonly 100 mm Hg.22

Initial Evaluation

Patients with hypertensive emergency usuallypresent for evaluation as a result of a new symptomcomplex related to their elevated BP. Patient triageand physician evaluation should proceed expedi-tiously to prevent ongoing end-organ damage. Afocused medical history that includes the use of anyprescribed or over-the-counter medications shouldbe obtained. If the patient is known to have hyper-tension, their hypertensive history, previous control,current antihypertensive medications with dosing,adherence with their medication regimen, and thetime from last dose are important facts to acquireprior to initiating treatment. Inquiry into the use ofrecreational drugs (amphetamines, cocaine, phen-cyclidine) or monoamine oxidase inhibitors shouldbe made. Confirmation of the BP should be obtainedby a physician in both arms using an appropriate-sizeBP cuff. The appropriate-size cuff is particularlyimportant because the use of a cuff too small for thearm has been shown to artificially elevate BP read-ings in obese patients.23,24

The physical examination should attempt to iden-tify evidence of end-organ damage by assessing

pulses in all extremities, auscultating the lungs forevidence of pulmonary edema, the heart for mur-murs or gallops, the renal arteries for bruits, andperforming a focused neurologic and fundoscopicexamination. Headache and altered level of con-sciousness are the usual manifestations of hyperten-sive encephalopathy.25,26 Focal neurologic findings,especially lateralizing signs, are uncommon in hyper-tensive encephalopathy, being more suggestive of acerebrovascular accident. Subarachnoid hemorrhageshould be considered in patients with a sudden onsetof a severe headache. The ocular examination mayshow evidence of advanced retinopathy with arterio-lar changes, exudates, hemorrhages, or papilledemaassisting in the identification of hypertensive en-cephalopathy. Cardiac evaluation should aim to iden-tify angina or myocardial infarction with the focus onclarifying any atypical symptoms such as dyspnea,cough, or fatigue that may be overlooked.10,27 On thebasis of this evaluation, the clinician should be ableto distinguish between a hypertensive emergency oran urgency and to formulate the subsequent plan forfurther diagnostic tests and treatment.

If the clinical picture is consistent with aorticdissection (severe chest pain, unequal pulses, wid-ened mediastinum), a contrast CT scan or MRI ofthe chest should be obtained promptly to rule outaortic dissection. Although transesophageal echocar-diography has excellent sensitivity and specificity foraortic dissection, this study should not be performeduntil adequate blood control has been achieved. Inpatients presenting with pulmonary edema, it isimportant to obtain an echocardiogram to distinguishbetween diastolic dysfunction, transient systolic dys-function, or mitral regurgitation.28 Many patients,particularly the elderly, have a normal ejection frac-tion, and in such patients heart failure is due toisolated diastolic dysfunction.28 The managementthese patients differs from those patients with pre-dominant systolic dysfunction and those with tran-sient mitral regurgitation (Table 3).

Initial Management of BP

The majority of patients in whom severe hyper-tension (SBP " 160 mm Hg, DBP " 110 mm Hg) isidentified on initial evaluation will have no evidenceof end-organ damage and thus have a hypertensiveurgency. Since no acute end-organ damage ispresent, these patients may present for evaluation ofanother complaint, and the elevated BP may repre-sent an acute recognition of chronic hypertension. Inthese patients, utilizing oral medications to lower theBP gradually over 24 to 48 h is the best approach tomanagement. Rapid reduction of BP may be associ-ated with significant morbidity in hypertensive ur-

Table 2—Clinical Manifestation of HypertensiveEmergencies*

Hypertensive encephalopathyAcute aortic dissectionAcute myocardial infarctionAcute coronary syndromePulmonary edema with respiratory failureSevere pre-eclampsia, HELLP syndrome, eclampsiaAcute renal failureMicroangiopathic hemolytic anemiaAPH

*HELLP # hemolysis, elevated liver enzymes, low platelets.






(CHEST 2007; 131:1949–1962)






Definitions







reason for the anatomical predilection to the parieto-occipital areas is unclear, although a possible mechanism isa relative paucity of vascular sympathetic (and thusprotective) innervation of the vessels of the posteriorcirculation arising from the basilar artery.35 Hypertensiveencephalopathy predominantly affecting the brainstem hasalso been reported.36 In parallel with the imaging findings,the electroencephalogram can show loss of the posteriordominant alpha rhythm, generalised slowing, and posteriorepileptiform discharges, which resolve after clinicalimprovement.27,29,30

Hypertensive encephalopathy and its clinical andneuroimaging consequences are potentially fully reversiblewith timely and appropriate management; thus the termhypertensive reversible posterior leucoencephalopathysyndrome (PLS) has become popular.26 This syndrome,diagnosed clinicoradiologically, is found in both adults andchildren; it has both hypertensive and non-hypertensivecauses. Non-hypertensive causes and associations of PLSinclude immunosuppressive and cytotoxic therapy(cyclosporin, tacrolimus, cisplatin)27,37,38 interferon-alfa,26

AIDS,39 thrombotic thrombocytopenic purpura,29 bloodtransfusion,40 and carotid endarterectomy hyperperfusionsyndrome.41 However, some of the patients reported inthese settings (eg, some of those treated with cyclosporinand tacrolimus) also had acutely raised blood pressure.26,27

The causes of PLS (and its underlying endothelialdisturbance) are probably multifactorial—for example,cyclosporin neurotoxicity and hypertension occurring afterrenal transplantation, and in patients with thromboticthrombocytopenic purpura, acute renal failure, andassociated hypertension.29

ManagementGeneral principlesThere have been no large clinical trials investigatingoptimum therapy in patients presenting with hypertensiveemergencies. Such studies would be difficult to design andwould be complicated by heterogeneity of patients anddiseases. Therefore, therapy is not evidence based and ingeneral has been dictated by consensus.1,42 Management ofpatients with acute hypertensive syndromes should betailored to the individual patient and based not only on theabsolute value of blood pressure, but on the presence orabsence of end-organ damage (or the imminent threat ofsuch damage). Hypertensive urgencies can be treated withoral antihypertensive agents such as ACE inhibitors,calcium-channel antagonists, !-blockers, "-blockers, or acombination of such drugs. After a period of monitoring,the patient can safely be discharged with close outpatient

follow-up and adjustment of therapy. Ideally, these patientsshould be seen within 1–2 days of initial presentation.

A patient presenting with a hypertensive emergencyshould be admitted to an intensive-care unit, and an arterialline should be placed for accurate monitoring of bloodpressure. However, therapy should not be delayed whilesuch measures are being instituted. Intravenousadministration of antihypertensive drugs is generallypreferred in this situation. Patients may present withevidence of compromise of one or more end organs.Different antihypertensive therapeutic strategies maybe advantageous with particular end-organ syndromes(table 1). In general, most extracerebral end-organdysfunction benefits from rapid lowering of blood pressure.The recommended aims are reduction of mean arterialpressure by no more than 20–25% within a period ofminutes to 2 h or a decrease in diastolic blood pressure to100–110 mm Hg over minutes to hours.42 More rapidreduction in blood pressure is to be avoided, because it canworsen end-organ function.

Specific drug therapyThe aim of drug therapy in patients with hypertensiveemergencies is to reduce blood pressure in a controlled,predictable, and safe way. Various parenteral drugs aresuitable (table 2). Depending on the nature of target-organdamage, a particular drug or therapeutic strategy may bemore or less appropriate. Sodium nitroprusside can be usedsafely in many instances.42 It is a short-acting arterial andvenous dilator and should be given only by continuousintravenous infusion with simultaneous intra-arterial blood-pressure monitoring. Its use may be complicated by theoccurrence of hypotension, which is rapidly reversible whenthe infusion is discontinued. Other complications includecyanate or thiocyanate toxicity when this drug is given for along period (days), especially in patients with hepatic orrenal dysfunction. Although sodium nitroprusside has beenreported to increase intracranial pressure,43 thecontemporaneous fall in systemic vascular resistance seemsto offset this effect. Sodium nitroprusside is generallyrecommended as therapy for hypertensive emergenciesincluding hypertensive encephalopathy.42 Other drugs thatare useful in most instances include intravenous labetalol,44

which has both "-blocking and !-blocking activity, andintravenous calcium-channel antagonists. The !-blockingeffect of labetalol is about a fifth that of propranolol.Adverse effects include nausea, vomiting, and flushing.Bradycardia, heart block, bronchospasm, and heart failurecan also complicate its use.

SEMINAR


End organ Complications Therapeutic considerations

Aorta Aortic dissection !-blockade, labetalol (decrease dp/dt), sodiumnitroprusside with !-blockade, avoid isolateduse of pure vasodilators

Brain Hypertensive Avoid centrally acting antihypertensive drugs encephalopathy such as clonidineCerebral infarction Avoid centrally acting agents; avoid rapidor haemorrhage decreases in blood pressure

Heart Myocardial ischaemia Intravenous glyceryl trinitrate, !-blockadeMyocardial infarctionHeart failure Diuretics and ACE inhibitors useful, !-blockers

with cautionKidney Renal insufficiency Diuretics with caution, calcium antagonists

usefulPlacenta Eclampsia Hydralazine, labetalol, calcium antagonists

useful; avoid sodium nitroprusside

dp/dt=change in pressure/change in time.

Table 1: End-organ complications of hypertensive emergencies

Drug Dose Onset Duration Adverse effects

Sodium 0·25–10 #g kg$1 min$1 Immediate 1–2 min Hypotension, nausea,nitroprusside* vomiting, cyanate

toxicityLabetalol 20–80 mg bolus 5–10 min 2–6 h Nausea, vomiting,

(every 10 min) heart block,2 mg/min infusion bronchospasm

Hydralazine 10–20 mg bolus 10 min 2–6 h Reflex tachycardiaFenoldopam 0·1–0·6 #g kg$1 min$1 5–10 min 10–15 min Hypotension,

headacheGlyceryl 5–100 #g/min 1–3 min 5–15 min Headache, vomitingtrinitrateEnalaprilat 1·25–5·00 mg bolus 15 min 4–6 h Hypotension, renal

failureNicardipine 2–10 mg/h 5–10 min 2–4 h Reflex tachycardia,

flushingPhentolamine 5–10 mg/min 1–2 min 3–5 min Reflex tachycardia

*Risk of toxic effects in patients with renal impairment.

Table 2: Commonly used parenteral antihypertensive drugs


SEMINAR










Seminar


gency due to a rightward shift in the pressure/flowautoregulatory curve in critical arterial beds (cere-bral, coronary, renal).29 Rapid correction of severelyelevated BP below the autoregulatory range of thesevascular beds can result in marked reduction inperfusion causing ischemia and infarction. There-fore, although the BP must be reduced in thesepatients, it must be lowered in a slow and controlledfashion to prevent organ hypoperfusion.

Altered autoregulation also occurs in patients withhypertensive emergency, and since end-organ dam-age is present already, rapid and excessive correctionof the BP can further reduce perfusion and propa-gate further injury. Therefore, patients with a hyper-tensive emergency are best managed with a contin-uous infusion of a short-acting, titratableantihypertensive agent. Due to unpredictable phar-macodynamics, the sublingual and IM route shouldbe avoided. Patients with a hypertensive emergencyshould be managed in an ICU with close monitoring.For those patients with the most severe clinicalmanifestations or with the most labile BP, intra-arterial BP monitoring may be prudent. There are avariety of rapid-acting IV agents that are available foruse in patients with hypertensive emergency, and theagent of choice depends on which manifestation ofend-organ damage is present and the available mon-itored setting (Table 3). Rapid-acting IV agentsshould not be used outside of an ICUs monitoredsetting to prevent precipitous falls of BP that mayhave significant morbidity or mortality. The imme-diate goal is to reduce DBP by 10 to 15% or toapproximately 110 mm Hg over a period of 30 to 60min. In patients with aortic dissection, the BP shouldbe reduced rapidly (within 5 to 10 min), targeting aSBP of ! 120 mm Hg and mean arterial pressure(MAP) ! 80 mm Hg.30,31 Once there is stable BPcontrol with IV agents and end-organ damage has

ceased, oral therapy can be initiated as the IV agentsare slowly titrated down. An important considerationprior to initiating IV therapy is to assess the patient’svolume status. Due to pressure natriuresis, patientswith hypertensive emergencies may be volume de-pleted, and restoration of intravascular volume withIV saline solution will serve to restore organ perfu-sion and prevent a precipitous fall in BP whenantihypertensive regimens are initiated.

Pharmacologic Agents Used in theTreatment of Hypertensive Emergencies

A number of drugs are available for the manage-ment of hypertensive emergency. The agent ofchoice in any particular situation will depend on theclinical presentation (Table 3). The preferred agentsinclude labetalol, esmolol, nicardipine, and fenoldo-pam. Phentolamine and trimethaphan camsylate areless commonly used today; however, they may beuseful in particular situations such as catecholamine-induced hypertensive crises (ie, pheochromocy-toma). Sodium nitroprusside may be used in patientswith acute pulmonary edema and/or severe leftventricular dysfunction and in patients with aorticdissection.32 Oral and sublingual nifedipine are po-tentially dangerous in patients with hypertensiveemergencies and are not recommend. Clonidine andangiotensin-converting enzyme (ACE) inhibitors arelong acting and poorly titratable; however, theseagents may be useful in the management of hyper-tensive urgencies. ACE inhibitors are contraindi-cated in pregnancy.33,34 Clevidipine is a relativelynew agent under investigation for the managementof postoperative hypertension and hypertensiveemergencies.35 At this time, clevidipine is not avail-able in the United States for use outside of clinical

Table 3—Recommended Antihypertensive Agents for Hypertensive Crises

Conditions Preferred Antihypertensive Agents

Acute pulmonary edema/systolicdysfunction

Nicardipine, fenoldopam, or nitroprusside in combination with nitroglycerin and a loop diuretic

Acute pulmonary edema/diastolicdysfunction

Esmolol, metoprolol, labetalol, or verapamil in combination with low-dose nitroglycerin and a loopdiuretic

Acute myocardial ischemia Labetalol or esmolol in combination with nitroglycerinHypertensive encephalopathy Nicardipine, labetalol, or fenoldopamAcute aortic dissection Labetalol or combination of nicardipine and esmolol or combination of nitroprusside with either

esmolol or IV metoprololPre-eclampsia, eclampsia Labetalol or nicardipineAcute renal failure/microangiopathic

anemiaNicardipine or fenoldopam

Sympathetic crisis/cocaine overdose Verapamil, diltiazem, or nicardipine in combination with a benzodiazepineAPH Esmolol, nicardipine, or labetalolAcute ischemic stroke/intracerebral

bleedNicardipine, labetalol, or fenoldopam

1952 Postgraduate Education Corner





(CHEST 2007; 131:1949–1962)






Definitions







reason for the anatomical predilection to the parieto-occipital areas is unclear, although a possible mechanism isa relative paucity of vascular sympathetic (and thusprotective) innervation of the vessels of the posteriorcirculation arising from the basilar artery.35 Hypertensiveencephalopathy predominantly affecting the brainstem hasalso been reported.36 In parallel with the imaging findings,the electroencephalogram can show loss of the posteriordominant alpha rhythm, generalised slowing, and posteriorepileptiform discharges, which resolve after clinicalimprovement.27,29,30

Hypertensive encephalopathy and its clinical andneuroimaging consequences are potentially fully reversiblewith timely and appropriate management; thus the termhypertensive reversible posterior leucoencephalopathysyndrome (PLS) has become popular.26 This syndrome,diagnosed clinicoradiologically, is found in both adults andchildren; it has both hypertensive and non-hypertensivecauses. Non-hypertensive causes and associations of PLSinclude immunosuppressive and cytotoxic therapy(cyclosporin, tacrolimus, cisplatin)27,37,38 interferon-alfa,26

AIDS,39 thrombotic thrombocytopenic purpura,29 bloodtransfusion,40 and carotid endarterectomy hyperperfusionsyndrome.41 However, some of the patients reported inthese settings (eg, some of those treated with cyclosporinand tacrolimus) also had acutely raised blood pressure.26,27

The causes of PLS (and its underlying endothelialdisturbance) are probably multifactorial—for example,cyclosporin neurotoxicity and hypertension occurring afterrenal transplantation, and in patients with thromboticthrombocytopenic purpura, acute renal failure, andassociated hypertension.29

ManagementGeneral principlesThere have been no large clinical trials investigatingoptimum therapy in patients presenting with hypertensiveemergencies. Such studies would be difficult to design andwould be complicated by heterogeneity of patients anddiseases. Therefore, therapy is not evidence based and ingeneral has been dictated by consensus.1,42 Management ofpatients with acute hypertensive syndromes should betailored to the individual patient and based not only on theabsolute value of blood pressure, but on the presence orabsence of end-organ damage (or the imminent threat ofsuch damage). Hypertensive urgencies can be treated withoral antihypertensive agents such as ACE inhibitors,calcium-channel antagonists, !-blockers, "-blockers, or acombination of such drugs. After a period of monitoring,the patient can safely be discharged with close outpatient

follow-up and adjustment of therapy. Ideally, these patientsshould be seen within 1–2 days of initial presentation.

A patient presenting with a hypertensive emergencyshould be admitted to an intensive-care unit, and an arterialline should be placed for accurate monitoring of bloodpressure. However, therapy should not be delayed whilesuch measures are being instituted. Intravenousadministration of antihypertensive drugs is generallypreferred in this situation. Patients may present withevidence of compromise of one or more end organs.Different antihypertensive therapeutic strategies maybe advantageous with particular end-organ syndromes(table 1). In general, most extracerebral end-organdysfunction benefits from rapid lowering of blood pressure.The recommended aims are reduction of mean arterialpressure by no more than 20–25% within a period ofminutes to 2 h or a decrease in diastolic blood pressure to100–110 mm Hg over minutes to hours.42 More rapidreduction in blood pressure is to be avoided, because it canworsen end-organ function.

Specific drug therapyThe aim of drug therapy in patients with hypertensiveemergencies is to reduce blood pressure in a controlled,predictable, and safe way. Various parenteral drugs aresuitable (table 2). Depending on the nature of target-organdamage, a particular drug or therapeutic strategy may bemore or less appropriate. Sodium nitroprusside can be usedsafely in many instances.42 It is a short-acting arterial andvenous dilator and should be given only by continuousintravenous infusion with simultaneous intra-arterial blood-pressure monitoring. Its use may be complicated by theoccurrence of hypotension, which is rapidly reversible whenthe infusion is discontinued. Other complications includecyanate or thiocyanate toxicity when this drug is given for along period (days), especially in patients with hepatic orrenal dysfunction. Although sodium nitroprusside has beenreported to increase intracranial pressure,43 thecontemporaneous fall in systemic vascular resistance seemsto offset this effect. Sodium nitroprusside is generallyrecommended as therapy for hypertensive emergenciesincluding hypertensive encephalopathy.42 Other drugs thatare useful in most instances include intravenous labetalol,44

which has both "-blocking and !-blocking activity, andintravenous calcium-channel antagonists. The !-blockingeffect of labetalol is about a fifth that of propranolol.Adverse effects include nausea, vomiting, and flushing.Bradycardia, heart block, bronchospasm, and heart failurecan also complicate its use.

SEMINAR


End organ Complications Therapeutic considerations

Aorta Aortic dissection !-blockade, labetalol (decrease dp/dt), sodiumnitroprusside with !-blockade, avoid isolateduse of pure vasodilators

Brain Hypertensive Avoid centrally acting antihypertensive drugs encephalopathy such as clonidineCerebral infarction Avoid centrally acting agents; avoid rapidor haemorrhage decreases in blood pressure

Heart Myocardial ischaemia Intravenous glyceryl trinitrate, !-blockadeMyocardial infarctionHeart failure Diuretics and ACE inhibitors useful, !-blockers

with cautionKidney Renal insufficiency Diuretics with caution, calcium antagonists

usefulPlacenta Eclampsia Hydralazine, labetalol, calcium antagonists

useful; avoid sodium nitroprusside

dp/dt=change in pressure/change in time.

Table 1: End-organ complications of hypertensive emergencies

Drug Dose Onset Duration Adverse effects

Sodium 0·25–10 #g kg$1 min$1 Immediate 1–2 min Hypotension, nausea,nitroprusside* vomiting, cyanate

toxicityLabetalol 20–80 mg bolus 5–10 min 2–6 h Nausea, vomiting,

(every 10 min) heart block,2 mg/min infusion bronchospasm

Hydralazine 10–20 mg bolus 10 min 2–6 h Reflex tachycardiaFenoldopam 0·1–0·6 #g kg$1 min$1 5–10 min 10–15 min Hypotension,

headacheGlyceryl 5–100 #g/min 1–3 min 5–15 min Headache, vomitingtrinitrateEnalaprilat 1·25–5·00 mg bolus 15 min 4–6 h Hypotension, renal

failureNicardipine 2–10 mg/h 5–10 min 2–4 h Reflex tachycardia,

flushingPhentolamine 5–10 mg/min 1–2 min 3–5 min Reflex tachycardia

*Risk of toxic effects in patients with renal impairment.

Table 2: Commonly used parenteral antihypertensive drugs


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Seminar


288 Varon

Table III. Agents used in the management of hypertensive crises, preferred conditions and dose administration

Agent Conditions Administration

Enalaprilat Congestive heart failure IV injection of 1.25 mg over 5 min every 6 h, titrated by increments of1.25 mg at 12- to 24-h intervals to a maximum of 5 mg every 6 h

Esmolol Acute myocardial ischaemiaa Loading dose of 500–1000 µg/kg over 1 min, followed by an infusion at25–50 µg/kg/min, which may be increased by 25 µg/kg/min every10–20 min until the desired response to a maximum of 300 µg/kg/min

Fenoldopam Acute myocardial ischaemiab An initial dose of 0.1 µg/kg/min, titrated by increments of 0.05–0.1 µg/Acute pulmonary oedema/diastolic kg/min to a maximum of 1.6 µg/kg/mindysfunctiona,c

Acute ischaemic stroke/intracerebral bleedAcute renal failure/microangiopathic anaemiaHypertensive encephalopathySympathetic crisis

Labetalol Acute aortic dissection Initial bolus 20 mg, followed by boluses of 20–80 mg or an infusionAcute myocardial ischaemiaa starting at 1–2 mg/min and titrated until the desired hypotensive effect isAcute ischaemic stroke/intracerebral bleed achieved is particularly effective. Bolus injections of 1–2 mg/kg haveEclampsia/pre-eclampsia been reported to produce precipitous falls in BP and should thereforeHypertensive encephalopathy be avoided; maximum cumulative dose of 300 mg over 24 h

Nicardipine Acute myocardial ischaemiac 5 mg/h; titrate to effect by increasing 2.5 mg/h every 5 min to aAcute renal failure/ microangiopathic maximum of 15 mg/hanaemiaAcute ischaemic stroke/intracerebral bleedEclampsia/pre-eclampsiaHypertensive encephalopathySympathetic crisis/cocaine overdosed

Nitroprusside Acute pulmonary oedemaa,c 0.5 µg/kg/min; titrate as tolerated to maximum of 2 µg/kg/min

Hydralazine Eclampsia 5 mg bolus then 5–10 mg IV every 20–30 min as needed

Metoprolol Acute pulmonary oedema/diastolictartrate dysfunctiona,c

Phentolamine Sympathetic crisis Sympathetic crisis: IV 5–20 mgCatecholamine toxicity (i.e. Treatment of pralidoxime-induced hypertension (unlabeled use): IV 5 mgpheochromocytoma) Surgery for pheochromocytoma/hypertension: IM, IV 5mg given 1–2 h

before procedure and repeated as needed every 2–4 ha In combination with nitroglycerin (up to 200 µg/min).

b May be added if pressure is controlled poorly with labetalol/esmolol alone.

c In combination with a loop diuretic.

d In combination with a benzodiazepine.

BP = blood pressure; IM = intramuscular; IV = intravenous.

The recommended intravenous antihypertensive for enalaprilat is delayed for 15 minutes, and itagents currently available are reviewed briefly in does not reach peak effect for ≈1 hour, while itssections 3.1.1 to 3.1.10. The agents are presented duration of action is ≈6 hours. The effective half-lifealphabetically by class, not in order of importance or for accumulation of enalaprilat is approximatelypreference. 11 hours.[62] The relatively slow onset and long

duration of action make it a poor choice for use in a3.1.1 Enalaprilathypertensive crisis. In addition, ACE inhibitors haveEnalaprilat is an ACE inhibitor available for in-the potential to cause acute renal failure, acute renaltravenous administration. This class of drugs hasdysfunction or hyperkalaemia in patients in circula-shown efficacy in the treatment of congestive hearttory decompensated states or when MAP is insuffi-failure, essential hypertension, and the prevention ofcient to support renal perfusion. Since surgical pa-worsening renal function in patients with diabetic

and non-diabetic nephropathy. The onset of action tients are at an increased risk for circulatory decom-

© 2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 (3)

Drugs 2008; 68 (3): 283-297REVIEW ARTICLE 0012-6667/08/0003-0283/$53.45/0

© 2008 Adis Data Information BV. All rights reserved.

Treatment of AcuteSevere HypertensionCurrent and Newer Agents

Joseph Varon1,2,3

1 The University of Texas Health Science Center at Houston, Houston, Texas, USA2 The University of Texas Medical Branch at Galveston, Galveston, Texas, USA3 St Luke’s Episcopal Hospital/Texas Heart Institute, Houston, Texas, USA

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2831. Classification of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2842. Hypertensive Crises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

2.1 Hypertensive Urgencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2852.2 Hypertensive Emergencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

2.2.1 Operative and Postoperative Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2852.2.2 Hypertension in Acute Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286

2.3 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2863. Initial Management of Severe Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286

3.1 Pharmacological Agents Used in the Treatment of Hypertensive Crises . . . . . . . . . . . . . . . . . . . . 2873.1.1 Enalaprilat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2883.1.2 Labetalol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2893.1.3 Esmolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2893.1.4 Clevidipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2893.1.5 Nicardipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2903.1.6 Nifedipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2903.1.7 Fenoldopam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2913.1.8 Hydralazine and Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2913.1.9 Nitroglycerin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2913.1.10 Sodium Nitroprusside . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292

4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293

Approximately 72 million people in the US experience hypertension. World-Abstractwide, hypertension may affect as many as 1 billion people and be responsible for≈7.1 million deaths per year. It is estimated that ≈1% of patients with hypertensionwill, at some point, develop a hypertensive crisis. Hypertensive crises are furtherdefined as either hypertensive emergencies or urgencies, depending on the degreeof blood pressure elevation and presence of end-organ damage. Immediate reduc-tion in blood pressure is required only in patients with acute end-organ damage(i.e. hypertensive emergency) and requires treatment with a titratable, short-acting, intravenous antihypertensive agent, while severe hypertension withoutacute end-organ damage (i.e. hypertensive urgency) is usually treated with oralantihypertensive agents.