HYPERTENSIVE CRISES

Prim Care Clin Office Pract 35 (2008) 475–487

Hypertensive Crises Christopher J. Hebert, MD*, Donald G. Vidt, MD Department of Nephrology and Hypertension, Cleveland Clinic, Suite A51, 9500 Euclid Avenue, Cleveland, OH 44195, USA

Hypertension is the most common reason for a physician office visit in the United States [1]. The primary care physician should therefore expect to see the occasional patient with very elevated blood pressure, defined as greater than 180/110 mm Hg. Expedited triage of such patients is necessary to identify the minority of patients that would benefit from acute reduction in blood pressure. Hypertensive crises are those situations in which markedly elevated blood pressure is accompanied by progressive or impending acute target organ damage. The discussion that follows addresses the assessment, treatment, and follow-up care for patients with very elevated blood pressure, with an emphasis on hypertensive crises.

Definitions Patients presenting with very high blood pressuredblood pressure greater than 180/110 mm Hgdshould be triaged into one of three mutually exclusive groups.

1. Severe hypertension is present when blood pressure exceeds 180/110 mm Hg in the absence of symptoms beyond mild or moderate headache, and without evidence of acute target organ damage.

2. Hypertensive urgency is present when blood pressure exceeds 180/ 110 mm Hg in the presence of significant symptoms, such as severe headache or dyspnea, but no or only minimal acute target organ damage.

3. Hypertensive emergency is present when very high blood pressure (often O220/140 mm Hg) is accompanied by evidence of life-threatening organ dysfunction. Box 1 lists the important causes of hypertensive emergencies.

* Corresponding author.

E-mail address: hebertc@ccf.org (C.J. Hebert).

0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2008.05.001 primarycare.theclinics.com

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Box 1. Examples of hypertensive emergencies Acute ischemic or hemorrhagic stroke Subarachnoid hemorrhage Hypertensive encephalopathy Acute myocardial ischemia/infarction Acute heart failure Acute aortic dissection Eclampsia Head trauma Catecholamine excess states Beta-blocker or clonidine withdrawal Cocaine, phencyclidine hydrochloride use Pheochromocytoma crisis Hemorrhage Postsurgical Severe epistaxis

The term hypertensive crisis is used to indicate either a hypertensive urgency or emergency.

There are two older terms that are notable. Malignant hypertension represents markedly elevated blood pressure accompanied by papilledema (grade 4 retinopathy). Accelerated hypertension is considered present if markedly elevated blood pressure is accompanied by grade 3 retinopathy, but no papilledema. However, the three numbered terms above usually suffice for the description of all clinical scenarios involving very high blood pressure.

Epidemiology Among the 65 million Americans with hypertension, the minority have controlled blood pressure, with estimates falling between 38% and 44% [1,2]. Hypertensive crises, however, occur in less than 1% of individuals with hypertension [3].

Although crises are infrequent, very elevated blood pressure is a common clinical scenario facing the physician. In the United States, more that 250,000 emergency department visits in 2005 were attributed to the diagnosis of hypertension (International Classification of Diseases, Ninth Revision [ICD9] diagnoses 401.0, 401.1, 401.9), with 14% resulting in hospital admission [4].

Some have suggested that hospitalization for hypertensive emergency reflects upon the quality of ambulatory care (ie, an ambulatory care– sensitive condition) [5]. There are two ways in which an emergency department evaluation might indicate poor-quality ambulatory care. First, the treating physician may have failed to achieve good blood pressure control,

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resulting in less effective care [6]. Secondly, a patient with very elevated blood pressure may have been referred to the emergency department when office management was possible, making care less efficient. With high effectiveness and high efficiency being two key aims of high quality care [6], failure to achieve good blood pressure control and inappropriate referral undermine efforts to streamline and improve health care. An appropriate assessment of patients with very elevated blood pressure will identify the few patients requiring admission and acute reduction in blood pressure among the many who require initiation of oral medication on an outpatient basis and follow-up care.

Bender and colleagues [7] studied 50 patients who presented to an emergency department and found that the most common reason precipitating the crisis was running out of medication. Furthermore, the average cost was $1543 per visit, which underscores the importance of effective primary care. Particularly common is rebound hypertension after abrupt discontinuation of clonidine or a beta-blocker [8]. This rebound hypertension is thought to be due to an acute increase in sympathetic outflow.

Assessment A timely and focused history, physical examination, and select testing is important in the initial assessment of the patient with very elevated blood pressure.

History The history should be completed in a timely manner and capture several key pieces of information. The physician should assess the duration and severity of hypertension. The relevant symptoms to address include headache, chest pain, dyspnea, edema, acute fatigue, weakness, epistaxis, seizure, or change in level of consciousness. Such symptoms as tachycardia, diaphoresis, and tremor may suggest pheochromocytoma, and thinning of skin and weight gain may suggest Cushing syndrome. Any history of comorbid conditions or end organ damage is important, such as left ventricular hypertrophy, chronic kidney disease, or prior stroke or myocardial infarction.

Direct questioning regarding adherence to any prescribed antihypertensive medications is necessary, as well as recent use of such medications as oral contraceptives, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory drugs, cyclosporine, stimulant/anorectic agents, and prednisone. The patient should be questioned for use of alcohol as well as recreational drugs, particularly cocaine, amphetamines, and phencyclidine hydrochloride.

Physical examination The measurement of blood pressure should be performed with proper technique and, in the setting of diminished pedal pulses, should include

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both arms and at least one leg measurement. A fundus examination should be performed to assess for papilledema, hemorrhages, and exudates.

A careful cardiovascular examination should include assessment of the jugular venous pulse, auscultation for abdomenal bruits, and assessment of peripheral pulses. A lung examination and assessment for dependent edema should be performed to estimate volume status. Finally, a neurologic examination, including assessment of mental status, is important.

Testing In the emergency department setting, a limited but expeditious battery of tests should include a chemistry panel, urinalysis with microscopic examination of the sediment, and ECG. A chest radiograph is important if there is a suspicion of heart failure or pulmonary disease. A CT scan of the head is indicated if history or examination suggests a central nervous system disorder. In the office setting or with less severe elevations of blood pressure, clinical judgment should guide testing, but in all cases a careful history and examination are critical.

In practice, emergency department evaluations often are lacking. For example, Karras and colleagues [9] observed care for patients with severely elevated blood pressure at four academic emergency departments. Serum chemistry was performed in only 73% of cases, ECG in 53%, and urinalysis in 43%. The goal should be a timely evaluation that includes the essential clinical tests.

Goals of treatment Proper triage prepares the physician to establish short- and long-term goals for the patient with very elevated blood pressure (Table 1).

There is a distinct lack of trial evidence that patients with severe hypertension (without crisis) benefit from acute lowering of blood pressure, and it may be associated with risk. For example, short-acting nifedipine has been associated with severe hypotension, stroke, acute myocardial infarction, and death, and is no longer a part of the management of severe hypertension [10]. Although other oral medications for acute blood pressure reduction may not have such clear documentation of harm, the evidence of benefit is lacking, and the edict ‘‘first, do no harm’’ is advisable.

Therefore, management of severe hypertension should include brief office observation (hours), initiation or resumption of oral antihypertensive medication, and arrangement for timely follow-up care, usually within 72 hours.

For patients with hypertensive urgency, again clear evidence of benefit of acute lowering of blood pressure is lacking, but expert opinion [11–13] favors judicious acute treatment with an oral agent with rapid onset of action. The short-term goal is to reduce the blood pressure within 24 to 72 hours, and appropriate follow-up should be mandatory. For noncompliant patients,

Table 1 Triage of patients with very elevated blood pressure Hypertensive urgency

Hypertensive emergency

Blood Pressure Clinical features: symptoms

O180/110 mm Hg May be asymptomatic; headache

O180/110 mm Hg Severe headache, dyspnea, edema

Clinical features: findings

No acute target organ damage

Acute target organ damage usually absent, but may include elevated serum creatinine

Immediate goal

Lower blood pressure within days

Lower blood pressure within 24–72 hours

Treatment setting Medications

Outpatient Long-acting, oral

Follow-up

Within 3–7 days

Usually outpatient Oral medications with rapid onset of action; occasionally intravenously Within 24–72 hours

Often O220/140 mm Hg Chest pain, severe dyspnea, altered mental status, focal neurologic deficit Life-threatening target organ damage (eg, acute myocardial infarction, stroke, encephalopathy, acute renal failure, heart failure) Immediate blood pressure reduction; decrease by 15%–25% within 2 hours Inpatient, intensive care unit Intravenous medication

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Severe hypertension

As appropriate after hospital management

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resumption of prior medications may be sufficient. For untreated patients, initiation of long-acting agents is appropriate.

Hypertensive emergency warrants admission to an intensive care unit and treatment with a parenteral agent. The short-term goal is to reduce the blood pressure by 15% to 25% within 4 hours. A reduction beyond 25% may exceed the autoregulatory capacity of the cerebrovascular circulation [14] and therefore elicit hypoperfusion, ischemia, and stroke.

Pharmacotherapy For severe hypertension, initiation or resumption of long-acting antihypertensive medication is warranted.

If immediate reduction of blood pressure is indicated (urgency), medications with rapid onset of action are preferred. Oral medications that may be appropriate include clonidine, (0.1–0.2 mg), labetalol (200–400 mg), or captopril (12.5–25 mg). Use of drugs with rapid onset carries two caveats. First, a large dose should be followed by a longer period of observation in the office or emergency department to assess for hypotension. Secondly, the effect of a drug with short onset of action (eg, clonidine) may decrease shortly after discharge to home, resulting in return of very elevated blood pressure. To avoid this occurrence, one can either continue dosing of the same drug as an outpatient, or begin a long-acting drug (eg, amlodipine, extended-release metoprolol, diuretic) in the office. Table 2 lists some commonly used oral agents in the treatment of hypertensive crises.

Parenteral agents are indicated for some cases of hypertensive urgency and all cases of hypertensive emergency. Table 3 lists some commonly used intravenous medications.

Table 2 Preferred medications for hypertensive urgencies Agent

Dose

Onset of action

Comment

Labetalol

200–400 mg po

20–120 min

Clonidine

0.1–0.2 mg po

30–60 min

Captopril

12.5–25 mg po

15–60 min

Nifedipine, extended release

30 mg po

20 min

Amlodipine

5–10 mg po

30–50 min

Prazosin

1–2 mg po

2–4 hours

Bronchoconstriction, heart block, aggravate heart failure Rebound hypertension with abrupt withdrawal Can precipitate acute renal failure in setting of bilateral renal artery stenosis Avoid short-acting oral or sublingual nifedipine due to risk of stroke, acute myocardial infarction, severe hypotension Headache, tachycardia, flushing, peripheral edema Syncope (first dose), tachycardia, postural hypotension

Table 3 Preferred medications for hypertensive emergencies Onset/duration of action (after discontinuation)

0.25–10.00 mg/kg/min as intravenous infusion; maximal dose for 10 min only

Immediate/2–3 min after infusion

Glyceral trinitrate

5–100 mg as intravenous infusion

2–5 min/5–10 min

Nicardipine

5–15 mg/h intravenous infusion

Verapamil

5–10 mg intravenous; can follow with infusion of 3–25 mg/h

1–5 min/15–30 min, but may exceed 12 h after prolonged infusion 1–5 min/30–60 min

Fenoldopam Hydralazine

0.1–0.3 mg/kg/min intravenous infusion 10–20 mg as intravenous bolus or 10–40 mg intramuscularly; repeat every 4–6 h

Enalaprilat

0.625–1.250 mg intravenous every 6 h

Parenteral vasodilators Sodium nitroprusside

2–5 min/2–4 h 1–5 min/15–30 min

1–2 min/10–30 min

Nausea, vomiting, muscle twitching; with prolonged use, may cause thiocyanate intoxication, methemoglobinemia acidosis, cyanide poisoning; bags, bottles, and delivery sets must be light-resistant Headache, tachycardia, vomiting, flushing, methemoglobinemia; requires special delivery systems due to the drug’s binding to polyvinyl chloride tubing Tachycardia, nausea, vomiting, headache, increased intracranial pressure, possible protracted hypotension after prolonged infusions Heart block (first-, second-, and third-degree), especially with concomitant digitalis or b-blockers; bradycardia Headache, tachycardia, flushing, local phlebitis Tachycardia, headache, vomiting, aggravation of angina pectoris

Renal failure in patients with bilateral renal artery stenosis; hypotension Bronchoconstriction, heart block, orthostatic hypotension First-degree heart block, congestive heart failure, asthma

Tachycardia, orthostatic hypotension

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Parenteral adrenergic inhibitors Labetalol 10–80 mg as intravenous bolus every 10 min; up to 2 mg/min as intravenous infusion Esmolol 500 mg/kg bolus injection intravenously or 25–100 mg/kg/min by infusion; may repeat bolus after 5 min or increase infusion rate to 300 mg/kg/min Phentolamine 5–15 mg as intravenous bolus

!5 min/30 min 10 min intravenous/O1 h (intravenous); 20–30 min intramuscularly/ 4–6 h intramuscularly 15–60 min/12–24 h

Precautions

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Dose

Agent

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Sodium nitroprusside is very appropriate in the treatment of hypertensive emergencies because it is easily titratable, having an onset of action that is immediate and a duration of action only 2 to 3 minutes after discontinuation. It is a nonspecific vasodilator that has the same mechanism of action as endogenous nitric oxide. Adverse effects include nausea and vomiting, and thiocyanate intoxication with prolonged use is an important precaution.

Despite these drawbacks, the drug is easily titrated and has become a mainstay of the management of hypertensive emergencies. When used in the setting of aortic dissection, concomitant use of a beta-blocker is important.

Nitroglycerin improves coronary blood flow and is the drug of choice for hypertensive emergency associated with acute myocardial infarction when blood pressure is moderately elevated. It is a vasodilator of capacitance vessels more so than arteries, and is less potent than nitroprusside. Disadvantages include side effects, such as headache and vomiting, and tolerance with prolonged use is a limitation.

Labetalol is commonly used for hypertensive emergencies, particularly aortic dissection. Its mechanism of action includes both alpha and beta blockade, and has a rapid onset of action. It can be continued orally on an outpatient basis, although it requires multiple doses per day. The disadvantages are those common to the beta-blocker class, including the potential for bradycardia, heart block, and bronchoconstriction. Esmolol is an intravenous beta-blocker that has very rapid onset of action along with short duration of action after discontinuation, making it particularly useful in the perioperative setting. It does not come in an oral form.

Enalaprilat is an intravenous angiotensin-converting enzyme (ACE) inhibitor that has a fairly rapid onset of action. Like all ACE inhibitors, it carries the risk of acute renal failure in the setting of bilateral renal artery stenosis.

Fenoldopam is particularly useful in the setting of renal insufficiency in that it has been shown to improve renal blood flow [15,16]. The drug acts as a dopamine receptor agonist and therefore causes renal as well as systemic vasodilatation. Like nitroprusside, it is easily titrated, but it is a much more costly drug.

For hypertensive urgency, oral amlodipine or extended-release nifedipine may be useful if the goal is to lower the blood pressure within 72 hours. As mentioned previously, immediate-release nifedipine should be avoided because of risk of hypotension.

Verapamil has a rapid onset of action and is available in both intravenous and oral forms, but carries a risk of heart block. Nicardipine is a calcium blocker without substantial risk of heart block, but tachycardia and the tendency toward prolonged action after discontinuation are limitations.

Hydralazine is a direct vasodilator of arterioles and for years has been a useful drug in the management of hypertensive crises, particularly eclampsia of pregnancy. Its advantages include a rapid onset of action, intravenous and oral dosing, and a track record of safety in the setting of pregnancy.

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Limiting its use are several potential side effects, including reflex tachycardia, headache, and vomiting. The reflex tachycardia makes this drug generally undesirable for treatment of crises associated with acute coronary syndrome or acute aortic dissection.

Phentolamine is a potent alpha-1 antagonist with a rapid onset of action that has traditionally been used in cases of catecholamine excess, such as pheochromocytoma crisis. Side effects can be problematic with this drug, particularly orthostatic hypotension, flushing, headache, and reflex tachycardia.

Oral clonidine is a useful drug for hypertensive urgency due to its rapid onset of action. However, multiple doses of clonidine can be a setup for hypotension if the patient is not observed for a sufficient amount of time.

The practice of clonidine loading has largely fallen out of favor. One small trial of clonidine loading among patients with severe asymptomatic hypertension found no benefit [17].

Assessment and management of selected hypertensive emergencies In addition to the general principles outlined above, the clinical features and management of several specific hypertensive emergencies deserve special attention.

Neurologic hypertensive emergencies A neurologic hypertensive emergency is present if severe hypertension is associated with encephalopathy, stroke, subarachnoid hemorrhage, or acute head trauma.

When neurologic findings, such as a focal deficit or altered mental status, are present, the physician should attempt to accurately place the case into one of the preceding four categories. A careful physical examination is important both for diagnosis and to establish the level of neurologic functioning at the time of presentation. The optic fundus and mental status must be examined, and the patient must be assessed for motor deficits and cerebellar dysfunction.

Hypertensive encephalopathy is a manifestation of cerebral edema and is suggested by such symptoms as severe headache, nausea, vomiting, confusion, seizure, or coma. Papilledema is found on optic fundus examination, and rapid reduction of blood pressure is indicated. Sodium nitroprusside is the drug of choice, and a reduction in blood pressure by 20% to 25% over the first few hours is advisable.

Stroke is typically diagnosed by history and examination indicating a focal neurologic insult along with corresponding abnormalities on brain CT or MRI. In such situations, watershed areas of brain parenchyma surrounding the stroke are dependent on perfusion pressure to remain viable.

For that reason, acute and aggressive lowering of blood pressure may confer a risk.

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Severe hypertension resulting from head trauma (Cushing’s reflex) should be evident from the clinical presentation. The ideal target blood pressure in this setting is unknown. Blood pressure reduction should be accomplished cautiously and with close neurologic surveillance.

Acute aortic dissection Aortic dissection is a life-threatening condition in which timely diagnosis and aggressive treatment of blood pressure are key. Severe hypertension and tachycardia are typically present, and efforts to reduce blood pressure and heart rate to reduce shear stress will decrease the likelihood of propagation of the dissection. Upon diagnosis, systolic blood pressure should be reduced to less than 120 mm Hg within 20 minutes. The drugs of choice are betablockers, such as labetalol or esmolol, as well as sodium nitroprusside.

Acute coronary syndrome Acute coronary syndrome includes unstable angina and acute myocardial infarction. In these settings, an elevated adrenergic response is typical, leading to increased blood pressure and increased myocardial oxygen demand.

The drugs of choice in these situations are intravenous nitroglycerin, which improves coronary perfusion, and beta-blockers.

Acute pulmonary edema Treatment of acute heart failure with pulmonary edema requires drugs that decrease preload and left ventricular volume. Sodium nitroprusside and fenoldopam are good choices, along with a loop diuretic.

Renal emergencies Measurement of serum creatinine and a urinalysis with examination of the sediment is important for all patients with hypertensive emergency. A renal emergency is present if new or acutely worsening renal dysfunction is present or if the urine sediment contains red cell casts or dysmorphic red cells.

Fenoldopam is a strong choice of agent in this case due to its efficacy in reducing blood pressure along with its action to increase renal blood flow and urine output. Sodium nitroprusside and labetalol are also useful.

A temporary reduction in glomerular filtration rate may occur with acute reduction of severely elevated blood pressure, even in crises of nonrenal causes.

Short-term dialysis is sometimes necessary. Careful monitoring of renal function, electrolytes, and volume status is necessary throughout the clinical course.

Adrenergic crises Examples of adrenergic crises include pheochromocytoma crisis, cocaine or amphetamine intoxication, and clonidine withdrawal. Drugs to consider

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in these cases include the pure alpha-blocker phentolamine (adding a beta-blocker if needed), the combined alpha-/beta-blocker labetalol, or clonidine in the case of clonidine withdrawal.

Pregnancy Pregnancy-associated crises pose a challenge because many of the commonly used drugs for acute lowering of blood pressure are contraindicated in pregnancy. The drugs of choice include hydralazine, methyldopa, and magnesium sulfate. Beta-blockers or nifedipine are sometimes used in addition.

Follow-up Studies suggest that patients treated for hypertensive crises often do not get adequate discharge instructions. Karras and colleagues [9] found that only 29% of such patients seen in four urban academic emergency departments received written instructions to follow up with a primary care provider. For many such patients, the risk attributable to ongoing poor control of blood pressure clearly outweighs the short-term risk of a transient rise in blood pressure.

Prevention Hypertensive crises are largely preventable. Inadequate management of hypertension by the physician, poor adherence to therapy by the patient, and insufficient access to care are important factors leading to crises.

Patients presenting with hypertensive crisis often have a history of poorly controlled blood pressure. Failure to intensify the treatment regimen in response to an elevated blood pressure in the office has been repeatedly correlated with poor control. More aggressive and effective execution of a treatment plan for hypertension is important in the effort to prevent crises.

Another common scenario preceding a crisis is a patient discontinuing medications. Discontinuation of any antihypertensive medication can precipitate a crisis as the antihypertensive effect wears off. In addition, rebound hypertension can follow abrupt discontinuation of high-dose beta-blockers or clonidine.

Poor access to care may be considered a system-level factor that contributes to the occurrence of hypertensive crises. Often a timely office visit or telephone call is all it takes to prevent a crisis.

Pitfalls in office management of very elevated blood pressure A physician encountering a patient with very high blood pressure in the office or emergency department should be wary of several common pitfalls in assessment and treatment.

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The first pitfall is error in measurement of blood pressure. This can be due to any of several deviations from recommended technique, such as use of an ill-fitting cuff or omission of a brief rest period before measurement. A thorough discourse on the topic is provided elsewhere [18]. Particular attention should be given to the white coat effect, in which the patient’s blood pressure rises when in a medical setting, often due to anxiety about the blood pressure reading itself or about the examination in general. The physician then finds the blood pressure elevated and may assume it is normally this high, when the typical blood pressure is actually lower. This can lead to treatment based on overestimates of blood pressure. Measurement by a nonphysician provider or with an automated device with physician absent [19] can help avoid the confusion brought on by the readings that are possibly misleading because of the white coat effect.

The next pitfall lies in treating the number. As discussed previously, the symptoms, physical examination, and findings on initial testing (laboratory tests, EKG, chest radiography) are more appropriate guides to decisionmaking than the blood pressure itself. Keep in mind that the clinical status of the patient rather than the level of blood pressure determines a hypertensive urgency or emergency.

Another common mistake is to overestimate the benefit and underestimate the risk of acute lowering of blood pressure. Blood pressure should be acutely lowered if there is reason to believe there will be a benefit, such as in the case of an acute aortic dissection. Where the benefit is less clear, the physician should proceed with the approach of ‘‘first, do no harm.’’

Finally, after the urgency of the acutely elevated blood pressure passes, the physician should not underestimate the risk of chronic elevation of blood pressure. Consider the faulty logic of the following scenario: A patient presents to the office with a blood pressure of 190/112 mm Hg, without symptoms. The patient is medicated in the office to achieve a blood pressure of 170/100 mm Hg 3 hours later, and is discharged to home. The patient is then re-evaluated for this chronic condition 2 months later, at which time the blood pressure is still poorly controlled. In the majority of cases of patients with very elevated blood pressure, the patient has chronic hypertension, and the physician and patient should proceed accordingly to achieve good ongoing blood pressure control.

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[2] Ong KL, Cheung BM, Man YB, et al. Prevalence, awareness, treatment, and control of hypertension among United States adults 1999–2004. Hypertension 2007;49:69–75.

[3] Gudbrandsson T. Malignant hypertension. A clinical follow-up study with special reference to renal and cardiovascular function and immunogenetic factors. Acta Med Scand Suppl 1981;650:1–62.

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[4] Agency for Healthcare Research and Quality. Available at: http://hcup.net.gov/HCUPnet. jsp.

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[8] Calhoun DA, Oparil S. Treatment of hypertensive crisis. N Engl J Med 1990;323:1177–83.

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[10] Grossman E, Messerli FH, Grodzicki T, et al. Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? JAMA 1996;276:1328–31.

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[14] Strandgaard S, Paulson OB. Cerebral autoregulation. Stroke 1984;15:413–6.

[15] Shusterman NH, Elliott WJ, White WB. Fenoldopam, but not nitroprusside, improves renal function in severely hypertensive patients with impaired renal function. Am J Med 1993;95: 161–8.

[16] Brienza N, Malcangi V, Dalfino L, et al. A comparison between fenoldopam and low-dose dopamine in early renal dysfunction of critically ill patients. Crit Care Med 2006;34:707–14.

[17] Zeller KR, Von Kuhnert L, Matthews C. Rapid reduction of severe asymptomatic hypertension. A prospective, controlled trial. Arch Intern Med 1989;149:2186–9.

[18] Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood pressure measurement in humans and experimental animals: Part 1: blood pressure measurement in humans: a statement for professionals from the subcommittee of professional and public education of the American Heart Association council on high blood pressure research. Hypertension 2005; 45:142–61.

[19] Beckett L, Godwin M. The BpTRU automatic blood pressure monitor compared to 24 hour ambulatory blood pressure monitoring in the assessment of blood pressure in patients with hypertension. BMC Cardiovasc Disord 2005;5(1):18.