Table 44–1 lists factors that have been suggested to be causes for resistance; they are often displayed as associated factors in the same patient.
Table 44–1. Causes of Refractory Hypertension. ||Download (.pdf)
Table 44–1. Causes of Refractory Hypertension.
Failure to modify lifestyle including obesity, alcohol abuse, tobacco
Isolated office (white-coat) hypertension
Improper blood pressure measurement (one measurement, failure to use large cuff on long arms)
Other associated factors
Volume overload due to excessive sodium intake, inadequate diuretic therapy, and/or progressive renal insufficiency Sleep apnea
Drug-induced resistant hypertension
Nonsteroidal anti-inflammatory drugs (oral contraceptives, sympathicomimetic agents, corticosteroids, cocaine, cyclosporine, erythropoietin)
Renal artery stenosis (fibromuscular dysplasia, atherosclerosis)
Renal parenchymal disease
Some studies suggest that white-coat or isolated clinic hypertension is as least as common in patients with resistant hypertension as the general population, with a prevalence ranging from 28% to 52%. The white-coat effect is defined as an increase in BP that occurs at the time of a clinical visit and dissipates soon after. It has been known for more than 50 years that BP recorded by a physician can be as much as 30 mm Hg higher than BP taken by the patient at home, using the same technique and in the same posture. Physicians also record higher pressures than nurses or technicians. The white-coat effect is usually defined as the difference between the clinic and daytime ambulatory pressure. The underlying mechanisms are not well understood, but may include anxiety, a hyperactive alerting response, or a conditioned response. The white-coat effect is seen to a greater or lesser degree in most if not all hypertensive patients, but is much smaller or negative in normotensive subjects or those with masked hypertension. A closely linked but discrete entity is white-coat hypertension, which refers to a subset of patients who are hypertensive according to their clinic BP but normotensive at other times.
Secondary Causes of Arterial Hypertension
The most common secondary causes of resistant hypertension are hyperaldosteronism, renal parenchymal disease, renal artery stenosis, and sleep apnea (Table 44–2). However, recent prospective studies indicate that hyperaldosteronism is the most common cause of secondary hypertension.
Table 44–2. Indicative Symptoms and Signs of Secondary Hypertension. ||Download (.pdf)
Table 44–2. Indicative Symptoms and Signs of Secondary Hypertension.
Muscle cramps, weakness
Most patients are normokalemic (some of them show hypokalemia) and clinically undistinguishable from essential hypertensives
More severe target-organ damage than other hypertensives
Elevated plasma aldosterone concentrations and increased ratio of aldosterone concentration to plasma renin activity
Renal parenchymal disease
Renal insufficiency indicated by an elevated serum creatinine and reduced creatinine clearance
Patients are often volume expanded and have increased sensitivity to salt
It typically affects young women (15–50 years old)
Patients generally do not develop renal insufficiency
There is usually a good clinical response to interventions such as percutaneous renal artery angioplasty
It generally occurs in patients over 50 years old and is more common in smokers and in patients with other atherosclerotic diseases
Duplex ultrasonography, gadolinium-enhanced magnetic resonance angioplasty, or computed tomography can provide effective screening of atherosclerotic renal disease
Repeated episodes of partial (hypopnea) or complete (apnea) cessation of breathing during sleep; such episodes may be of central origin, or due to mechanical obstruction of the airways, or to a combination of the two
The cardinal manifestations of the obstructive sleep apnea syndrome are snoring and daytime sleepiness
Patients are generally obese
The gold standard for diagnosing sleep apnea is polysomnography
Sustained or episodic hypertension complicated by headache, palpitations, or diaphoresis
Great variability in blood pressure values
Other rare causes of secondary hypertension
Coarctation of the aorta
Central nervous system tumors
Table 44–2 lists the symptoms and signs frequently associated with secondary hypertension; these can guide us toward undertaking the necessary diagnostic tests in each case.
Hyperaldosteronism is being increasingly recognized as a common underlying cause of hypertension. In an extensive evaluation that included more than 600 subjects with hypertension, Mosso et al reported that the prevalence of aldosteronism increases according to the severity of the hypertension. Applying the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure sixth report staging criteria to untreated subjects, primary aldosteronism was diagnosed in 2% of subjects with stage 1 hypertension (140–159 mm Hg/90–99 mm Hg), 8% of subjects with stage 2 hypertension (160–179 mm Hg/100–109 mm Hg), and 13% of subjects with stage 3 hypertension (>180/110 mm Hg). This is just one of many reports that indicate a prevalence of hyperaldosteronism of 15–30% among general and selected hypertensive populations.
Primary aldosteronism (PA) is particularly common in subjects with resistant hypertension. In a prospective evaluation of African-American and white subjects with resistant hypertension, defined as uncontrolled hypertension despite use of three or more antihypertensive agents, the reported prevalence of aldosteronism was approximately 20%. These results are consistent with a study from separate investigators reporting a prevalence of aldosteronism of 17% among subjects referred to hypertension specialists for uncontrolled hypertension. Thus, PA should be excluded in all patients in whom secondary hypertension is suspected.
Sodium Ingestion—Volume Overload
An increased salt sensitivity may be a cause of refractory hypertension. There is a subset of patients who are more likely to manifest increased salt sensitivity, including blacks, the elderly, and patients with underlying renal insufficiency. In any patient, excessive sodium intake can blunt the antihypertensive benefit of most agents. With the exception of calcium channel blockers (CCBs), antihypertensive drugs show greater effectiveness when the patient follows a low sodium diet. Also, treatment with vasodilators or adrenergic blockers can favor an expansion of volume and resistance to the treatment (pseudoresistance). When a volume overload is suspected, 24-hour measurement of sodium urinary excretion can be insufficient to determine sodium intake. The quantification of total plasmatic volume can provide reliable information about the degree of volume overload, and can serve as a guide at the time of prescribing a diuretic.
Special Tests and Examinations
The auscultatory method of BP measurement with a properly calibrated and validated instrument should be used. Patients should be seated and should relax for at least 5 minutes in a chair rather than on an examination table, with feet on the floor and arm supported at heart level. Measurement of BP in the standing position is indicated periodically, especially in those at risk for postural hypotension. An appropriate-sized cuff bladder (encircling at least 80% of the arm) should be used to ensure accuracy. At least two measurements should be made.
The readings should take place in a calm environment, after a rest time of 5–15 minutes, at least 30 minutes after the consumption of stimulants such as coffee or tobacco, since nicotine as much as caffeine can temporarily elevate BP readings. However, the possible alertness reaction that may take place during the consultation limits BP readings and contributes to an increase in the prevalence of uncontrolled hypertension. The use of a correct technique with several consecutive measurements (especially by nurse personnel) offers results comparable to ambulatory measurements and provides a better evaluation of hypertensive patients. When ambulatory BP monitoring (ABPM) is used, 20–50% of patients previously diagnosed with high BP display normal BP values. Noninvasive, 24-hour ABPM has evolved over the past 25 years from a novel research tool of limited clinical use to an important and useful modality for stratifying cardiovascular risk and guiding therapeutic decisions. Early clinical uses of ABPM mostly focused on identifying patients with white-coat hypertension; however, growing evidence now points to greater prognostic significance in determining risk for hypertensive end-organ damage compared with office BP measurements. Ambulatory measurement of BP using automated devices has demonstrated the benefit in treatment resistance and borderline hypertension, and is recommended by the Joint National Committee for the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure in a number of clinical scenarios.
On the other hand, self-measurement of BP (SMBP) at the patient's home with the correct technique and a valid and properly calibrated digital device provides very useful information on BP values of everyday life. The potential advantages of having patients take their own BP are two-fold: The distortion produced by the white-coat effect is eliminated, and multiple readings can be taken over prolonged periods of time. SMBP plays an increasing role in the diagnosis of hypertension. It may be used as a first step in the evaluation of patients with suspected white-coat hypertension, as recommended in JNC 7. There is also evidence that SMBP can improve BP control.
Pseudohypertension is another factor that can lead to a false misdiagnosis of refractory hypertension when intra-arterial pressures are actually normal or below normal. It refers to the phenomenon whereby vascular stiffening results in falsely high auscultatory BP measurements. Some studies suggest that pseudohypertension may be common among the elderly, but definitive evaluation is lacking. Pseudohypertension might be suspected if some of the following occur:
Severe hypertension in the absence of demonstrable target-organ deterioration.
Symptoms of hypotension in patients with seemingly resistant hypertension.
Radiologic evidence of calcification of the brachial artery.
BP values more elevated in the brachial artery than in the legs.
Severe isolated systolic hypertension.
The Osler maneuver (the ability to palpate the brachial or radial a rtery despite ipsilateral occlusion of the artery by a BP cuff inflated to suprasystolic values) constitutes a simple screening test for pseudohypertension. Another of value when pseudohypertension is suspected is the use of ultrasonic or oscillometric measuring instruments since their readings correlate more closely with intra-arterial pressure values than those obtained by an indirect auscultatory sphygmomanometer.