HIGH BLOOD PRESSURE

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• JNC 7
• JNC 7 recommends the following screening intervals based on BP readings. They do not give age-specific guidelines.

• Use the follow-up interval for the reading (SBP or DBP) that is most out of range

Blood pressure reading (mmHg)	Follow-up
< 120 / 80	Recheck in 2 years
120 - 139 / 80 - 89	Recheck in 1 year
140 - 159 / 90 - 99	Recheck within 2 months
160 - 179 / 100 - 110	Recheck within 1 month
≥ 180 / ≥ 110	Treat now or recheck within 1 week

• USPSTF
• Whom to screen
• Screen adults 18 years of age and older for hypertension with an office blood pressure measurement
• Evidence is lacking to recommend routine screening of children and adolescents under 18 years of age
• Frequency
• Adults aged 18 to 39 years with normal blood pressure (< 130/85 mmHg) who do not have other risk factors should be rescreened every 3 to 5 years
• Annual blood pressure screening is recommended in the following patients:
• Age ≥ 40 years
• Initial BP 130 - 139/85 - 89
• Black race
• Obese or overweight
• Confirmation
• Ambulatory blood pressure monitoring (preferred) or home blood pressure monitoring should be performed to confirm the diagnosis of hypertension in patients with elevated office blood pressure measurements [8,52]

• AAP
• The American Academy of Pediatrics recommends routine screening of blood pressure starting at 3 years of age [7]

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• Blood pressure is the resistance to flow that arteries exert against blood pumped from the heart. Arterial wall smooth muscle constricts and relaxes to control the resistance. Systolic blood pressure (top number) is the arterial pressure while the heart is forcing blood into the circulation. Diastolic blood pressure (bottom number) is the resting pressure when blood is not being forced. Both values are expressed in millimeters of mercury (mmHg), which is the pressure generated by a vertical column of mercury 1 mm high.
• High blood pressure or hypertension occurs when resistance enters a range that is associated with an increased risk of CVD events, typically > 130 mmHg for SBP and > 80 for DBP.

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• Auscultatory method
• The auscultatory blood pressure method involves listening with a stethoscope to blood flow through the brachial artery while a cuff is inflated proximal to the stethoscope. Pressure in the cuff is measured with a sphygmomanometer, typically aneroid, which means it contains no fluid; older sphygmomanometers often contained mercury, which is no longer recommended due to concerns over inadvertent exposure.


• Auscultatory method steps:
• 1. A cuff is placed over the brachial artery of the upper arm
• 2. The technician places a stethoscope over the brachial artery just below the cuff and listens for blood flow
• 3. The cuff is inflated until the artery collapses under the cuff's pressure
• 4. The cuff is gradually deflated until pulsatile blood flow is reestablished
• 5. The pressure when blood flow is first heard is the systolic blood pressure
• 6. As the cuff continues to deflate, the pressure when blood flow can no longer be heard is the diastolic blood pressure [2]

• Oscillometric method
• Oscillometric monitors, which are widely used today, do not use sounds. Instead, they measure intracuff pressure oscillations created by the pulse. The readings are entered into an algorithm that calculates the blood pressure. A main advantage of these monitors is that technician hearing does not affect readings. A potential downside is in older patients, where stiff arteries can affect oscillations and cause blood pressure to be underestimated. [2]

• Cuff size
• Blood pressure cuff size is important because cuffs that are too small may give spuriously high readings and vice versa. In one study, using a cuff that was too small gave average SBP readings that were almost 20 mmHg higher compared to an appropriately sized cuff. [PMID 37548984]
• BP cuff bladder length should be 75% – 100% of the measured arm circumference, while the width should be 37% – 50%, giving a length-to-width ratio of 2:1. Some cuffs have a range drawn around their circumference, indicating the appropriate size. Recommended cuff sizes based on arm circumference are provided in the table below. The cuff should be placed on bare skin, but shirtsleeves should not be rolled up because this may create a tourniquet effect. [2,51]

• Arm circumference should be measured at the midpoint of the acromion and olecranon

Arm circumference (cm)	Cuff size
22 - 26	Small adult (size 12X22 cm)
27 - 34	Standard adult (size 16X30 cm)
35 - 44	Large adult (size 16X36 cm)
45 - 52	Extra-large adults (thigh cuff) (size 16X42 cm)

• Reference [1,2,47,51]

Proper BP measurement technique
Measurement preparation The patient should relax for 3 - 5 minutes while sitting in a chair with legs uncrossed, feet flat on the floor, and back supported Caffeine, exercise, and smoking should be avoided within 30 minutes of the measurement The patient should empty their bladder before the measurement if necessary The arm should be bare if possible, but a shirtsleeve should not be rolled up if it is too tight because it may act as a tourniquet Comments If back is not supported, SBP and DBP may be increased by 5 - 15 and 6 mmHg, respectively Crossed legs during a BP measurement can raise SBP by 5 - 8 mmHg and DBP by 3 - 5 mmHg STUDY A small study (N=113) found that different rest periods of 0, 2, and 5 minutes before automated BP measurements did not affect the average reading. [PMID 34601959]
Measurement technique Use an upper arm cuff Arm should be supported (e.g., resting on a table), but not by the patient Position the middle of the cuff on the upper arm at the level of the right atrium (midpoint of the sternum) Use correct cuff size (see cuff size above) Comments If the upper arm is below the level of the right atrium (e.g., when the arm is hanging down while in the seated position), the readings will be too high The cuffed arm should be held up by the observer or resting on a table at heart level. If the arm is held up by the patient, BP will be raised. STUDY A crossover study (N=133) found that allowing the arm used for measurement to hang at the side or sit in the patient's lap raised SBP and DBP by 4 to 7 mmHg compared to the proper technique of supproting it on a table. [PMID 39373998]
Measurement frequency At first clinic visit or reading, measure blood pressure on both arms. The arm that gives the highest reading should be used from then on. At least 2 measurements should be made (at least 1 minute apart), and the average should be used If taking BP medication, take two readings in the morning before taking meds and two readings in the evening Use the average of ≥ 2 readings on ≥ 2 separate occasions to estimate BP. Ideally, BP monitoring period will be ≥ 7 days. Comments Persistent BP differences between arms of ≥ 10 mmHg are common and occur in 11.2% of people with hypertension and 4% of the general population. Significant BP arm differences can be a sign of coarctation of the aorta (see secondary causes), but this condition is rare, affecting only 0.1% of patients with hypertension. STUDIES A study that included over 38,000 patients found that, on average, the median change in clinic SBP on a second reading among patients with hypertension who had a high initial reading was -8 mmHg. [PMID 29710186] In another study, 35% of people with a BP measurement of 140 - 159/90 - 99 mm Hg on their first measurement had a BP < 140/90 mm Hg when the average of 3 measurements was used [51] A small study published in 2021 (N=102) found that a 30-second time interval between automated BP measurements was as accurate and reliable as a 60-second interval [PMID 34488436]

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• See hypertension guidelines for a review of treatment goals and recommendations

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• A large number of blood pressure machines are available for home use. The American Medical Association (AMA) has a website listing devices that have been independently validated to be accurate. Another site, maintained by the dabl Educational Trust, provides ratings from the AAMI, BHS, and ESH for many machines. Links to both websites are available below.
• Upper-arm monitors are preferred, but wrist monitors may be appropriate if the upper arm is too big. When using a wrist monitor, it is important that the device be placed correctly over the radial artery and held at heart level, with limited movement or wrist flexion. Finger monitors are not recommended. All monitors should be compared to a clinician's reading every 1 to 2 years. [2]
• AMA validated blood pressure devices
• dabl Educational Trust blood pressure device ratings

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• When store-based blood pressure machines were introduced in the 1970s, they were not designed to comply with industry standards and often did not perform well when tested. Most newer machines meet AAMI standards and are much more reliable. However, inaccurate readings can occur with small and large arms, as the machines are designed for average-sized people.
• Generally, machines that meet AAMI standards and are calibrated periodically provide accurate readings for patients with average-sized arms. Patients can find out if their store-based machine is AAMI-certified by obtaining the model number at the store and checking the manufacturer's website. The store should know when the machine was last calibrated. [3,4]

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• Overview
• Ambulatory blood pressure monitoring involves wearing a device that takes a blood pressure reading every 20 - 30 minutes for 24 - 48 hours. It is considered the gold standard for diagnosing hypertension but is rarely performed due to inconvenience. Studies have shown that ambulatory monitoring is a better predictor of all-cause mortality and CVD events than office-based monitoring. It can also reduce overdiagnosis, as up to 65% of patients with elevated office-based readings are normotensive on ambulatory monitoring. Recommendations for its use from professional organizations are provided below. [8,49]


• Recommendations
• USPSTF
• In 2015, the USPSTF recommended that patients with elevated office-based blood pressure readings have ambulatory monitoring to confirm a hypertension diagnosis. Ambulatory confirmation is not necessary in patients with readings ≥ 180/110 mmHg or if end-organ damage is present. [8]
• AHA recommends ambulatory monitoring in the following situations:
• Suspected white coat hypertension or masked hypertension
• Monitoring medication efficacy in difficult-to-treat patients
• Assessing the presence of nocturnal hypertension
• Evaluating hypotension (postural, postprandial, and drug-induced)
• Assessing for autonomic hypotension, a condition where blood pressure control is impaired [51]

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• Symptoms
• High blood pressure is mostly asymptomatic. Even when blood pressure is very high (systolic > 200, diastolic > 120), most people have no symptoms. On rare occasions, very high pressure can cause acute end-organ damage, which may present as vision changes, kidney failure, heart failure, headache, nausea, vomiting, seizures, and brain bleeding.

• Diagnosis
• Blood pressure fluctuates throughout the day and is affected by activity and mood. Isolated readings may not accurately reflect a person's typical BP status, so multiple readings should be obtained when diagnosing hypertension. The AHA recommends that the average of ≥ 2 readings on ≥ 2 separate occasions using proper technique be used to diagnose hypertension. The USPSTF recommends that ambulatory blood pressure monitoring be performed to confirm a diagnosis of hypertension in most patients. Ambulatory confirmation is not necessary in patients with readings ≥ 180/110 mmHg or if end-organ damage is present. [8,47]

• Workup
• The AHA recommends the following in patients with newly-diagnosed hypertension:
• BMP
• CBC
• Lipid profile
• TSH
• Urinalysis
• Electrocardiogram (ECG) - to screen for left ventricular hypertrophy

• Essentila hypertension
• Essential hypertension, which accounts for up to 95% of hypertension cases, is high blood pressure with no identifiable cause [11,12,13]

• Known risk factors
• Family history
• Black ethnicity
• Excess alcohol intake - more than 2 drinks/day in men and 1 drink/day in women
• Obesity
• Inadequate intake of fruits, vegetables, and potassium
• Sedentary lifestyle
• Increasing age
• Gender - men have higher SBP up to 60 years old, after which hypertension prevalence in women is equal to or exceeds that of men
• Obstructive Sleep Apnea [1,15,16,18,22,23]
• Possible risk factors
• High salt intake - lowering salt intake lowers blood pressure (see sodium below), but there is inconclusive evidence that higher salt intake increases the risk of hypertension or heart disease
• Smoking
• Personality traits - evidence that personality traits (e.g., anxiety, type A personality, anger issues) increase the hypertension risk is inconsistent and inconclusive [1,20,21,24,25]

• Treatment
• See hypertension treatment guidelines

• Secondary hypertension
• Secondary hypertension is high blood pressure with an identifiable and sometimes treatable cause. Studies suggest secondary hypertension is present in 10% of people with hypertension and up to 30% of those with resistant hypertension. [12,47]
• STUDY
  A cross-sectional study of 2090 adults aged 18 to 40 with hypertension found that 29.6% of them had secondary hypertension, with primary aldosteronism (54.8%), renovascular hypertension (18.4%), primary kidney disease (12.9%), pheochromocytoma/functional paraganglioma (5.9%), and drug-induced hypertension (6.0%) being the most common causes. [PMID 39297209]

• The AHA recommends evaluating for secondary hypertension in adults with new-onset or uncontrolled hypertension and any of the following:
• Drug-resistant/induced hypertension
• Hypertension of abrupt onset or worsening or increasingly difficult to control
• Onset of hypertension at <30 years old
• Exacerbation of previously controlled hypertension
• Disproportionate target organ damage for the degree of hypertension
• Onset of diastolic hypertension in older adults (≥ 65 years)
• Unprovoked or excessive hypokalemia
• Disproportionate target organ damage (TOD) for the degree of hypertension
• Accelerated/malignant hypertension [47]

• Reference [47]

Causes of secondary hypertension (percentages represent prevalence among patients with hypertension)
Obstructive sleep apnea (25 - 50%) Symptoms and findings: Resistant hypertension; snoring; fitful sleep; breathing pauses during sleep; daytime sleepiness Physical exam: Obesity, Mallampati class III-IV; loss of normal nocturnal BP fall Screening tests: Berlin Questionnaire; Epworth Sleepiness Score; overnight oximetry Additional/Confirmatory tests: Polysomnography
Renovascular disease (5 - 34%) Symptoms and findings: Resistant hypertension; hypertension of abrupt onset or worsening or increasingly difficult to control; flash pulmonary edema (atherosclerotic); early-onset hypertension, especially in women (fibromuscular hyperplasia) Physical exam: Abdominal systolic-diastolic bruit; bruits over other arteries (carotid atherosclerotic or fibromuscular dysplasia), femoral Screening tests: Renal Duplex Doppler ultrasound; MRA; abdominal CT Additional/Confirmatory tests: Bilateral selective renal intra-arterial angiography Treatment: See renal artery stenosis
Primary aldosteronism (8 - 20%) Symptoms and findings: Resistant hypertension; hypertension with hypokalemia (spontaneous or diuretic induced); hypertension and muscle cramps or weakness; hypertension and incidentally discovered adrenal mass; hypertension and obstructive sleep apnea; hypertension and family history of early-onset hypertension or stroke. See potassium regulation. Physical exam: Arrhythmias (with hypokalemia); especially atrial fibrillation Screening tests: Plasma aldosterone-to-renin ratio under standardized conditions (correction of hypokalemia and withdrawal of aldosterone antagonists for 4-6 wk). Additional/Confirmatory tests: Oral sodium loading test (with 24-h urine aldosterone) or IV saline infusion test with plasma aldosterone at 4 h of infusion Adrenal CT scan, adrenal vein sampling.
Drug or alcohol induced (2 - 4%) Symptoms and findings: Sodium-containing antacids; caffeine; nicotine (smoking); alcohol; NSAIDs; oral contraceptives; cyclosporine or tacrolimus; sympathomimetics (decongestants, anorectics); cocaine, amphetamines and other illicit drugs; neuropsychiatric agents; erythropoiesis-stimulating agents; clonidine withdrawal; herbal agents (Ma Huang, ephedra). See medications that can raise BP. Physical exam: Fine tremor, tachycardia, sweating (cocaine, ephedrine, MAO inhibitors); acute abdominal pain (cocaine) Screening tests: Urinary drug screen (illicit drugs) Additional/Confirmatory tests: Response to withdrawal of suspected agent
Renal parenchymal disease (1 - 2%) Symptoms and findings: Urinary tract infections; obstruction, hematuria; urinary frequency and nocturia; analgesic abuse; family history of polycystic kidney disease; elevated serum creatinine; abnormal urinalysis Physical exam: Abdominal mass (polycystic kidney disease); skin pallor Screening tests: Renal ultrasound Additional/Confirmatory tests: Tests to evaluate cause of renal disease
Pheochromocytoma/paraganglioma (0.1 - 0.6%) Symptoms and findings: Resistant hypertension; paroxysmal hypertension or crisis superimposed on sustained hypertension; “spells,” BP lability, headache, sweating, palpitations, pallor; positive family history of pheochromocytoma/paraganglioma; adrenal incidentaloma Physical exam: Skin stigmata of neurofibromatosis (café-au-lait spots; neurofibromas); Orthostatic hypotension Screening tests: 24-h urinary fractionated metanephrines or plasma metanephrines under standard conditions (supine position with indwelling IV cannula) Additional/Confirmatory tests: CT or MRI scan of abdomen/pelvis
Hypothyroidism (<1%) Symptoms and findings: Dry skin; cold intolerance; constipation; hoarseness; weight gain Physical exam: Delayed ankle reflex; periorbital puffiness; coarse skin; cold skin; slow movement; goiter Screening tests: Thyroid-stimulating hormone; free thyroxine Additional/Confirmatory tests: None
Hyperthyroidism (<1%) Symptoms and findings: Warm, moist skin; heat intolerance; nervousness; tremulousness; insomnia; weight loss; diarrhea; proximal muscle weakness Physical exam: Lid lag; fine tremor of the outstretched hands; warm, moist skin Screening tests: Thyroid-stimulating hormone; free thyroxine Additional/Confirmatory tests: Radioactive iodine uptake and scan
Aortic coarctation (undiagnosed or repaired) (0.1%) Symptoms and findings: Young patient with hypertension (<30 y of age) Physical exam: BP higher in upper extremities than in lower extremities; absent femoral pulses; continuous murmur over patient’s back, chest, or abdominal bruit; left thoracotomy scar (postoperative) Screening tests: Echocardiogram Additional/Confirmatory tests: Thoracic and abdominal CT angiogram or MRA
Cushing’s syndrome (<0.1%) Symptoms and findings: Rapid weight gain, especially with central distribution; proximal muscle weakness; depression; hyperglycemia Physical exam: Central obesity, “moon” face, dorsal and supraclavicular fat pads, wide (1-cm) violaceous striae, hirsutism Screening tests: Overnight 1-mg dexamethasone suppression test. See HPA axis testing. Additional/Confirmatory tests: 24-h urinary free cortisol excretion (preferably multiple); midnight salivary cortisol
Primary hyperparathyroidism (Rare) Symptoms and findings: Hypercalcemia Physical exam: Usually none Screening tests: Serum calcium Additional/Confirmatory tests: Serum parathyroid hormone
Congenital adrenal hyperplasia (Rare) Symptoms and findings: Hypertension and hypokalemia; virilization (11-beta-hydroxylase deficiency [11-beta-OH]); incomplete masculinization in males and primary amenorrhea in females (17-alpha-hydroxylase deficiency [17-alpha-OH]) Physical exam: Signs of virilization (11-beta-OH) or incomplete masculinization (17-alpha-OH) Screening tests: Hypertension and hypokalemia with low or normal aldosterone and renin Additional/Confirmatory tests: 11-beta-OH: elevated deoxycorticosterone (DOC), 11-deoxycortisol, and androgens17-alpha-OH; decreased androgens and estrogen; elevated deoxycorticosterone and corticosterone
Mineralocorticoid excess syndromes other than primary aldosteronism (Rare) Symptoms and findings: Early-onset hypertension; resistant hypertension; hypokalemia or hyperkalemia Physical exam: Arrhythmias (with hypokalemia) Screening tests: Low aldosterone and renin Additional/Confirmatory tests: Urinary cortisol metabolites; genetic testing
Acromegaly (Rare) Symptoms and findings: Acral features, enlarging shoe, glove, or hat size; headache, visual disturbances; diabetes mellitus Physical exam: Acral features; large hands and feet; frontal bossing Screening tests: Serum growth hormone ≥1 ng/mL during oral glucose load Additional/Confirmatory tests: Elevated age- and sex-matched IGF-1 level; MRI scan of the pituitary

• White coat hypertension
• White coat hypertension is blood pressure that is elevated in a clinical setting and normal in nonclinical settings (e.g., home, work). Studies have found that up to 20% of people diagnosed with stage 1 hypertension may have white coat hypertension.
• STUDY
  A study published in 2021 took 18 people with mild-to-moderate untreated hypertension and measured their blood pressure multiple times over the course of 10 minutes with an automated cuff. The readings were done in the absence of a doctor and then in the presence of a doctor. When the doctor was present, average BP rose from 148/98 to 155/106 mmHg. When the doctor was absent, average BP declined from 146/97 to 140/93 mmHg. Heart rate and sympathetic nerve activity (measured through the skin) were also elevated with the doctor present. [PMID 34365811]
• AHA recommendations for detecting white coat hypertension
• It is reasonable to screen for white coat hypertension with ambulatory and/or home blood pressure monitoring when clinic SBP runs 130 - 160 mmHg and/or DBP runs 80 - 100 mmHg
• White coat hypertension is diagnosed when ambulatory/home readings average < 135/85 and office readings are > 140/90. If home blood pressure machines are used, patients should bring their monitors to the clinic to ensure readings are comparable. [2,47]

• Resistant hypertension
• The AHA defines resistant hypertension as the following:
• Clinic BP > 130/80 mmHg in a patient taking ≥ 3 antihypertensives that include a long-acting calcium channel blocker, an ACE inhibiter or ARB, and a diuretic at maximal or maximally tolerated doses. Patients with CrCl < 30 ml/min should be on a loop diuretic, with torsemide being preferred because it has the longest duration of action.
• Medication adherence should be confirmed along with the performance of 24-hour ambulatory BP monitoring (if unavailable, home BP monitoring) to exclude white coat effect. Secondary causes should be ruled out [50]
• STUDY
  In one study (N=8295), 37% of patients who met the criteria for resistant hypertension had normal ambulatory blood pressure. [PMID 21444835]

• Risk factors for resistant hypertension
• Black race
• Chronic kidney disease
• Diabetes
• Excessive dietary sodium
• Excessive alcohol intake
• Female sex
• Left Ventricular hypertrophy (enlarged heart)
• Older age
• Obesity
• Obstructive sleep apnea
• Secondary hypertension
• Taking medications that raise blood pressure [1,28]

• Reference [50]

AHA 2018 recommendations for treating resistant hypertension
Start with Step 1 and proceed to the next step if blood pressure is still elevated
Step 1 Ensure that the patient meets the definition of resistant hypertension Maximize lifestyle interventions Low sodium diet (< 2400 mg/day) ≥ 6 hours of uninterrupted sleep Weight loss and exercise STUDY A small study (N=60) found that three 40-minute weekly exercise sessions significantly lowered blood pressure in patients with resistant hypertension. [PMID 34347008]
Step 2 If using HCTZ, change to chlorthalidone or indapamide (see thiazide diuretics)
Step 3 Add spironolactone or eplerenone (see aldosterone antagonists)
Step 4 If pulse is ≥ 70 bpm, add a beta blocker If pulse is < 70 bpm, add an alpha-2 agonist If neither is tolerated, add once-daily diltiazem
Step 5 Add hydralazine 25 mg three times a day and titrate Patients with heart failure and reduced EF should receive isosorbide mononitrate with hydralazine Hydralazine can cause tachycardia and edema, so it should be given with a beta blocker and loop diuretic
Step 6 Substitute minoxidil 2.5 mg two to three times a day for hydralazine and titrate Minoxidil can cause tachycardia and edema, so it should be given with a beta blocker and loop diuretic

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• Hypertensive emergency is defined as very high blood pressure, typically greater than 180/120 mmHg, with signs and symptoms of acute end-organ damage; this differs from hypertensive urgency where signs of damage are absent. Affected patients should be admitted to the hospital for rapid blood pressure lowering. Diagnosing hypertensive emergency can be difficult, particularly in an office setting. Symptoms of hypertension-induced end-organ damage include the following:
• Brain (hypertensive encephalopathy) - neurologic symptoms, seizure, change in consciousness, papilledema, retinal hemorrhages and exudates
• Heart - heart failure, pulmonary edema, chest pain, shortness of breath
• Aorta (particularly aortic dissection) - chest pain or back pain
• Kidney - decreased urination, fluid retention and swelling, blood and/or protein in the urine [1,39]

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• Overview
• Hypertensive urgency is defined as very high blood pressure, typically greater than 180/120 mmHg, with no signs of acute end-organ damage. Hypertensive urgencies are common in clinical settings, including emergency rooms and clinics. Some providers give rapid-acting antihypertensives like clonidine to bring pressures down, but this practice has not been found to be beneficial and is discouraged by professional guidelines. [35,36,38,54]


• Professional recommendations
• The American College of Emergency Physicians states that rapidly lowering blood pressure in patients without symptoms is unnecessary and may be harmful [38]
• The AHA/ACC 2017 high blood pressure guidelines state that there is no indication for referral to the emergency department, immediate reduction in BP in the emergency department, or hospitalization for patients with hypertensive urgency.

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• Acetaminophen (Tylenol®) [PMID 35130054]
• ADHD medications
• Antidepressants - particularly serotonin-norepinephrine reuptake inhibitors (SNRIs)
• Appetite suppressants (e.g. phentermine)
• Bromocriptine (Parlodel®)
• Caffeine
• Clozapine (Clozaril®)
• Contrave®
• Corticosteroids (prednisone, Decadron®, Medrol®, etc.)
• Cyclosporine
• Ephedra
• Erythropoietin (Epogen®, Procrit®)
• Estrogens (contraceptive pills)
• Herbal supplements (ephedra, ma huang)
• Licorice
• Ma Huang
• Metoclopramide (Reglan®)
• Mirabegron (Myrbetriq®)
• NSAIDS (Motrin®, Aleve®, ibuprofen, naproxen, etc.)
• Pseudoephedrine (Sudafed®) - effect is small (SBP increase of 1.2 mmHg on average) [PMID 16087815]
• Sodium-containing antacids
• Atomoxetine (Strattera®)
• Testosterone replacement therapies
• Tacrolimus (Prograf®) [1,47]

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• ^✝Heart rate reserve (HRR) = Max heart rate [208 - (age X 0.7)] minus resting heart rate. Add percent of HRR to resting heart rate for target rate.
• References [1,5,6,47,53]

Effect of lifestyle changes on blood pressure
Weight loss SBP reduction: 1 mmHg reduction for every 2.2 lbs (1 kg) of weight loss Maintain a BMI of 18 - 25. See weight loss for more.
Adopt a DASH diet SBP reduction: 8 - 14 mmHg Consume a diet rich in fruits, vegetables, whole grains, and low-fat dairy products, with reduced content of saturated and total fat (see DASH diet for more)
Decrease sodium intake SBP reduction: 2 - 8 mmHg Optimal goal is < 1500 mg of sodium/day, but a 1000 mg/day reduction can be beneficial. See sodium below.
Increase potassium intake SBP reduction: 4 - 5 mmHg Potassium intake of 3500 – 5000 mg/d (89 - 128 mEq), preferably from dietary sources, is recommended. Daily intake of 4 - 5 servings of fruits and vegetables usually provides 1500 to >3000 mg (38 to >77 mEq). See potassium content of foods and potassium homeostasis for more.
Increase exercise Aerobic: SBP reduction - 5 mmHg | 90 – 150 min/wk at 65 - 75% of heart rate reserve✝ Dynamic resistance: SBP reduction - 4 mmHg | 90 - 150 min/wk at 50 - 80% of 1 rep maximum. 6 exercises, 3 sets/exercise, 10 repetitions/set Isometric resistance: SBP reduction - 5 mmHg | 4 sets, each for 2 minutes (e.g., hand grip), 1 min rest between exercises, 30% – 40% maximum contraction, 3 sessions/wk
Moderate alcohol consumption BP reduction: 4 mmHg No more than 2 drinks/day for males, and 1 drink/day for females
Smoking cessation SBP reduction: 7 mmHg See CDC quit smoking recommendations

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• Overview
• Renal artery stenosis (RAS) is be caused by atherosclerosis, and less commonly, fibromuscular dysplasia, a rare arterial wall disorder that typically affects women < 50 years old. For years, atherosclerotic RAS has been treated with stent placement despite clear evidence of a benefit. To examine the issue, the CORAL trial compared RAS with medical therapy to medical therapy alone in patients with severe RAS.

• AHA 2017 recommendations
• Medical therapy is recommended for adults with atherosclerotic renal artery stenosis
• In adults with renal artery stenosis for whom medical management has failed (refractory hypertension, worsening renal function, and/or intractable heart failure) and those with nonatherosclerotic disease, including fibromuscular dysplasia, it may be reasonable to refer the patient for consideration of revascularization (percutaneous renal artery angioplasty and/or stent placement) [47]

• Summary
• In the CORAL trial, stenting did not improve outcomes in patients with atherosclerotic RAS. Stenting has not been studied extensively in other types of RAS (e.g. fibromuscular dysplasia), and its effects in these conditions is unknown.

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• Studies
• Renal denervation is a procedure where a device that emits radiofrequency- or ultrasound-generated energy is placed inside the renal artery and used to ablate the surrounding sympathetic nerves. Decreased sympathetic tone reduces renin-angiotensin-aldosterone system (RAAS) stimulation and, in theory, lowers blood pressure.
• Trials evaluating renal denervation have been mixed and dependent on study design. Four major trials are reviewed below, along with a scientific statement about the procedure from the AHA.


• SYMPLICITY HTN-2 (2010) - 106 patients with resistant hypertension were randomized to radiofrequency renal denervation + continuation of current meds or continuation of current meds only (control). At 6 months, patients treated with renal denervation had office-based blood pressure reductions of 32/12 mmHg from baseline compared to no change in the control group. [PMID 21093036]
• SYMPLICITY HTN-3 (2014) - 535 patients with resistant hypertension were randomized to radiofrequency renal denervation + continuation of current meds or a sham procedure + continuation of meds. At 6 months, there was no significant difference in office-based SBP reduction (14 vs 11 mmHg). [PMID 24678939]
• RADIANCE-HTN TRIO (2021) - 136 patients with resistant hypertension were randomized to ultrasound renal denervation + antihypertensive polypill or a sham procedure + antihypertensive polypill. At 2 months, the daytime ambulatory SBP was significantly lower in the ultrasound group by 4.5 mmHg (p=0.022). [PMID 34010611]
• RADIANCE II (2023) - 224 patients with hypertension were randomized to ultrasound renal denervation or a sham procedure. Antihypertensives were held in all patients during the trial. At 2 months, the daytime ambulatory SBP was significantly lower in the ultrasound group by 6.3 mmHg (p<0.001). [PMID 36853250]

• Comment
  Renal denervation got off to a hot start in the SYMPLICITY HTN-2 trial, but interest in the therapy waned after the sham-controlled SYMPLICITY HTN-3 study found no effect. The two studies that used ultrasound denervation showed a modest benefit over 2 months. However, no long-term data on its effects exists. Currently, there is no good evidence that renal denervation is a worthwhile therapy.


• AHA 2024 scientific statement on renal denervation [PMID 39101202]
• Statement on efficacy
• The overall efficacy of renal denervation (RDN) in lowering blood pressure has been demonstrated across multiple randomized clinical trials, showing a modest but significant reduction in blood pressure, particularly in patients with resistant hypertension. However, the efficacy is not uniform across all patients, and individual responses vary. Studies have shown a meaningful reduction in office or daytime ambulatory systolic blood pressure of at least 5 mmHg in 60% to 70% of patients undergoing ultrasound RDN during 2 to 3 months of follow-up. While the procedure shows promise, further research is needed to identify factors that predict individual responses and to assess long-term efficacy.
• Candidates for therapy (one of the following):
• Resistant hypertension - defined as blood pressure above goal despite concurrent use of 3 antihypertensive agents or blood pressure at goal but requiring 4 or more medications of different classes at maximum or maximally tolerated doses
• Uncontrolled hypertension - patients with hypertension despite being on antihypertensive medication who are intolerant of, unable or unwilling to adhere to sufficient medication to control their blood pressure
• Contraindications to therapy:
• Pregnancy
• Fibromuscular dysplasia
• Stented renal artery
• Renal artery aneurysm
• Significant renal artery stenosis
• Known kidney or secreting adrenal tumors
• Subgroups where there is limited data on its efficacy:
• Stage 1 hypertension
• Isolated systolic hypertension
• Stage 4 or 5 chronic kidney disease (CKD)
• Patients with a single kidney
• Kidney transplant recipients (on native nonfunctional kidneys)

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• Overview
• Nitric oxide, a potent vasodilator produced by endothelial cells, is also formed from dietary nitrates through a multistep process. Beetroot juice, which has a very high nitrate concentration (∼6 mmol per 250ml), has been shown to lower blood pressure. Its effects on patients with hypertension were evaluated in the small study below. [45]

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• Sodium vs salt
• Salt is sodium chloride (NaCl), and its molecular weight is 40% sodium and 60% chloride, meaning 1000 mg of salt contains 400 mg of sodium. Food labels typically list sodium in milligrams, which can be converted to millimoles and milliequivalents by dividing by 23, the atomic weight of sodium (see below).
• In developed nations, the average person consumes 3600 - 4800 mg of sodium/day, equivalent to 9000 - 12,000 mg of salt. In the U.S., the average sodium intake is 3600 mg/day. See sodium homeostasis for more. [48]


• Conversions
• To convert salt (sodium chloride) to sodium, multiply the amount of salt by 0.40
• Example:
• 1000 mg salt X 0.40 = 400 mg of sodium


• To convert milligrams (mg) of sodium to millimoles (mmol) and milliequivalents (mEq), divide mg of sodium by 23
• Example:
• 2300 mg of sodium / 23 = 100 mmol = 100 mEq

• Sodium guidelines
• The AHA recommends consuming less than 2300 mg of sodium a day with an ideal limit of less than 1500 mg a day (3750 mg of salt)
• The USDA recommends consuming less than 2300 mg of sodium a day
• JNC 7 recommends consuming less than 2300 mg of sodium a day
• The Institute of Medicine published a statement in 2013 stating that the available evidence does not support dietary salt reduction [46]

• Sodium intake and blood pressure
• Sodium intake has a direct effect on blood pressure, with significant restriction lowering BP within a week. A trial comparing the effects of a high- and low-sodium diet on BP is detailed below, along with a meta-analysis on the topic.

• RCT
  Effects of a High- vs Low-sodium Diet on Blood Pressure, JAMA (2023) [PubMed abstract]
• Design: Randomized, crossover trial (N=213 | length = 14 days) in adults 50 to 75 years with a median BP of 127/78 mmHg and median daily sodium intake of 4.5 grams
• Treatment: High-sodium diet for 1 week vs Low-sodium diet (500 mg/day) for 1 week. During the high-sodium week, participants were given daily bullion packs containing 2200 mg of sodium to add to their usual diet. During the low-sodium week, participants were provided with pre-made food and beverages containing 500 mg of sodium per day, with instructions not to consume any non-study food.
• Primary outcome: Average 24-hour ambulatory systolic and diastolic BP, mean arterial pressure, and pulse pressure.
• Results:
• Primary outcome (SBP reduction, low vs high week): 8 mmHg (p<0.001)
• Primary outcome (DBP reduction, low vs high week): 3 mmHg (p=0.01)
• BP reduction (baseline vs low-week): SBP 5 mmHg, DBP 2 mmHg
• Findings: Dietary sodium reduction significantly lowered BP in the majority of middle-aged to elderly adults. The decline in BP from a high- to low-sodium diet was independent of hypertension status and antihypertensive medication use, was generally consistent across subgroups, and did not result in excess adverse events.

• OBS
  Effect of longer-term modest salt reduction on blood pressure, Cochrane meta-analysis (2013) [PubMed abstract]
• Study type: Meta-analysis of randomized trials (34 trials with 3230 participants) with a modest reduction in salt intake and duration of at least 4 weeks
• Primary outcome: Effect of long-term modest reductions in salt intake on BP and whether there was a dose-response relationship
• Results
• Patients without hypertension
• Reducing sodium intake by 2400 mg/day caused an average decrease in SBP of 2.42 mmHg and DBP of 1 mmHg
• Patients with hypertension
• Reducing sodium intake by 2400 mg/day caused an average decrease in SBP of 5.39 mmHg and DBP of 2.82 mmHg
• Findings: A modest reduction in salt intake for 4 or more weeks causes significant and, from a population viewpoint, important falls in BP in both hypertensive and normotensive individuals, irrespective of sex and ethnic group.

• Summary
• Dietary sodium restriction has a modest effect on BP. In the RCT above, a diet with 500 mg/day of sodium lowered SBP and DBP by 8 and 3 mmHg, respectively, compared to a diet containing more than 5 grams/day. Average sodium consumption in the U.S. is between 3600 and 4800 mg per day, so this effect is at the extremes of intake and may not apply to most. Moreover, population-based studies (see below) have found that sodium intake below 3000 mg/day is associated with worse CVD outcomes compared to intakes of 4000 - 6000 mg/day.

• Sodium intake and CVD outcomes
• Decreasing sodium intake lowers blood pressure, but its overall effect on CVD is less clear. Measuring sodium intake in a large group of subjects longitudinally is difficult, and randomizing people to diets with different sodium content for long periods is impractical. Therefore, most data on CVD outcomes in relation to sodium intake is from cohort studies where urinary sodium excretion was used as a surrogate marker for intake. Three large studies evaluating the association between urinary sodium excretion and cardiovascular outcomes are detailed below, along with a trial that randomized Chinese villagers with a history of stroke or hypertension to a salt substitute or regular salt.

• OBS
  Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension, Lancet (2016) [PubMed abstract]
• The review pooled data from four studies (PURE, EPIDREAM, ONTARGET, TRANSCEND) encompassing 133,118 participants from 49 countries with a median age of 55. Participants were divided into subgroups based on whether they had hypertension at baseline or not. 24-hour urinary sodium excretion, a surrogate marker for daily sodium intake, was estimated from a morning fasting urine sample using the Kawasaki formula.
• Patients were divided into 6 groups based on their estimated 24-hour urinary sodium:
• 1. < 3000 mg/day (14,553 patients)
• 2. 3000 - 3999 mg/day (27,463 patients)
• 3. 4000 - 4999 mg/day (34,208 patients)
• 4. 5000 - 5999 mg/day (27,670 patients)
• 5. 6000 - 6999 mg/day (15,893 patients)
• 5. ≥ 7000 mg/day (13,331 patients)
• Primary outcome: Composite outcome of death, myocardial infarction, stroke, and heart failure
• After a median follow-up of 4.2 years, the following was seen:
• The average estimated daily urinary sodium excretion was 4956 mg/day and 4823 mg/day for patients with and without hypertension, respectively
• The 4000 - 4999 mg/day cohort was used as the reference cohort
• Hazard ratios for the other cohorts compared to the reference cohort in patients without hypertension (N=69,559) at baseline were as follows:
• < 3000 mg/day: HR 1.26, 95%CI (1.10 - 1.45)
• 3000 - 3999 mg/day: HR 1.05, 95%CI (0.94 - 1.18)
• 4000 - 4999 mg/day: Reference
• 5000 - 5999 mg/day: HR 0.99, 95%CI (0.88 - 1.11)
• 6000 - 6999 mg/day: HR 0.92, 95%CI (0.79 - 1.07)
• ≥ 7000 mg/day: HR 0.90, 95%CI (0.76 - 1.08)
• Hazard ratios for the other cohorts compared to the reference cohort in patients with hypertension (N=63,559) at baseline were as follows:
• < 3000 mg/day: HR 1.34, 95%CI (1.23 - 1.47)
• 3000 - 3999 mg/day: HR 1.09, 95%CI (1.002 - 1.19)
• 4000 - 4999 mg/day: Reference
• 5000 - 5999 mg/day: HR 0.97, 95%CI (0.89 - 1.05)
• 6000 - 6999 mg/day: HR 1.07, 95%CI (0.97 - 1.18)
• ≥ 7000 mg/day: HR 1.23, 95%CI (1.11 - 1.37)
• Findings: Compared with moderate sodium intake, high sodium intake is associated with an increased risk of cardiovascular events and death in hypertensive populations (no association in normotensive population), while the association of low sodium intake with increased risk of cardiovascular events and death is observed in those with or without hypertension. These data suggest that lowering sodium intake is best targeted at populations with hypertension who consume high sodium diets.

• OBS
  Urinary sodium and potassium excretion, mortality, and cardiovascular events, NEJM (2014) [PubMed abstract]
• The PURE study compared mortality and cardiovascular events among 101,945 patients from 17 countries divided into five groups based on their estimated daily urinary sodium excretion, a surrogate marker for daily sodium intake. 24-hour urinary sodium excretion was estimated from a morning fasting urine sample using the Kawasaki formula.
• Patients were divided into 5 groups based on their estimated 24-hour urinary sodium:
• 1. < 3000 mg/day (10,810 patients)
• 2. 3000 - 3999 mg/day (21,131 patients)
• 3. 4000 - 5999 mg/day (46,663 patients)
• 4. 6000 - 6999 mg/day (12,324 patients)
• 5. ≥ 7000 mg/day (11,017 patients)
• Primary outcome: Composite outcome of death and major cardiovascular events
• After an average follow-up of 3.7 years, the following was seen:
• The average estimated daily urinary sodium excretion was 4930 mg/day for the entire study population
• The 4000 - 5999 mg/day cohort had the lowest incidence of the primary outcome and was used as the reference cohort
• Odds ratios for the other cohorts compared to the reference cohort were as follows:
• < 3000 mg/day: OR 1.27, 95%CI (1.12 - 1.44)
• 3000 - 3999 mg/day: OR 1.01, 95%CI (0.93 - 1.09)
• 4000 - 5999 mg/day: Reference
• 6000 - 6999 mg/day: OR 1.05, 95%CI (0.94 - 1.17)
• > 7000 mg/day: OR 1.15, 95%CI (1.02 - 1.30) [44]
• Findings: In this study in which sodium intake was estimated on the basis of measured urinary excretion, an estimated sodium intake between 3 g per day and 6 g per day was associated with a lower risk of death and cardiovascular events than was either a higher or lower estimated level of intake. As compared with an estimated potassium excretion that was less than 1.50 g per day, higher potassium excretion was associated with a lower risk of death and cardiovascular events.

• OBS
  Urinary sodium and potassium excretion and risk of cardiovascular events, JAMA (2011) [PubMed abstract]
• The cohort study compared cardiovascular outcomes among 28,880 patients from 40 countries divided into seven groups based on their estimated daily urinary sodium excretion, a surrogate marker for daily sodium intake. 24-hour urinary sodium excretion was estimated from a morning fasting urine sample using the Kawasaki formula.
• Patients were divided into 7 groups based on their estimated 24-hour urinary sodium:
• 1. < 2000 mg/day (818 patients)
• 2. 2000 - 2999 mg/day (2654 patients)
• 3. 3000 - 3999 mg/day (2654 patients)
• 4. 4000 - 5999 mg/day (14,156 patients)
• 5. 6000 - 6,999 mg/day (3380 patients)
• 6. 7000 - 7999 mg/day (1326 patients)
• 7. > 8000 mg/day (847 patients)
• Primary outcome: Composite of cardiovascular death, myocardial infarction, stroke, and hospitalization for congestive heart failure
• After a median follow-up of 4.6 years, the following was seen:
• The average estimated daily urinary sodium excretion was 4770 mg/day for the entire study population [41]
• The 4000 - 5999 mg/day cohort had the lowest incidence of the primary outcome and was used as the reference cohort
• Hazard ratios for the other cohorts compared to the reference cohort were as follows:
• < 2000 mg/day: HR 1.21, 95%CI (1.03 - 1.43)
• 2000 - 2999 mg/day: HR 1.16, 95%CI (1.04 - 1.28)
• 3000 - 3999 mg/day: HR 1.06, 95%CI (0.98 - 1.14)
• 4000 - 5999 mg/day: Reference
• 6000 - 6999 mg/day: HR 1.09, 95%CI (0.99 - 1.20)
• 7000 - 7999 mg/day: HR 1.15, 95%CI (1.00 - 1.32)
• > 8000 mg/day: HR 1.49, 95%CI (1.28 - 1.75) [41]
• Findings: The association between estimated sodium excretion and CV events was J-shaped. Compared with baseline sodium excretion of 4 to 5.99 g per day, sodium excretion of greater than 7 g per day was associated with an increased risk of all CV events, and a sodium excretion of less than 3 g per day was associated with increased risk of CV mortality and hospitalization for CHF. Higher estimated potassium excretion was associated with a reduced risk of stroke.

• RCT
  Salt Substitute vs Regular Salt in Chinese Patients with a History of Stroke or Hypertension, NEJM (2021) [PubMed abstract]
• Design: Open-label, cluster-randomized trial (N=20,995 | length = 4.74 years) in Chinese patients who had a history of stroke or were ≥ 60 years old with poorly-controlled hypertension (SBP ≥ 140 mmHg if receiving antihypertensives or ≥ 160 mmHg if not)
• Treatment: Salt substitute (75% NaCl and 25% KCl) vs Regular salt. In the salt substitute group, participants were given 20 grams of salt substitute per person per day to cover all household cooking and food preservation requirements. The regular salt group continued to use salt as they had before. Patients taking potassium-sparing diuretics and/or potassium supplements were excluded from the trial.
• Primary outcome: Stroke, defined as an acute disturbance of focal neurologic function resulting in death or symptoms lasting more than 24 hours
• Results:
• Primary outcome: Salt substitute - 2.9%/year, Regular salt - 3.4%/year (p=0.006)
• Overall mortality: Salt substitute - 3.9%/year, Regular salt - 4.5%/year (HR 0.88, 95%CI [0.82 - 0.95])
• The average baseline 24-hour urinary sodium excretion was 4300 mg. During the course of follow-up, the average 24-hour sodium excretion in the salt substitute group was 350 mg less than the regular salt group, and the average systolic blood pressure was 3.34 mmHg lower.
• Findings: Among persons who had a history of stroke or were 60 years of age or older and had high blood pressure, the rates of stroke, major cardiovascular events, and death from any cause were lower with the salt substitute than with regular salt

• Summary
• The three cohort studies above found that sodium intake has a "U-shaped" relationship with CVD, as both lower and higher intakes were associated with worse outcomes. The lowest risk of events was seen in patients who consumed 4000 - 6000 mg/day, a level well above the recommended intake from professional organizations (see sodium guidelines above).
• In the salt substitute trial, reducing sodium intake by 25% lowered the risk of stroke by 0.5%/year and overall mortality by 0.6%/year in a population at high risk for stroke. The average baseline sodium intake was estimated to be 4300 mg/day, dropping by 350 mg/day in the salt substitute group. The average SBP was also 3.34 mmHg lower in the salt substitute group. Because salt substitutes contain a high amount of potassium, patients receiving potassium-sparing diuretics or potassium supplements were excluded from the trial.
• Collectively, these studies show that salt intake is associated with cardiovascular outcomes, but the levels recommended by professional associations (< 2300 mg/day) are lower than what is supported by the evidence (roughly 3500 - 5000 mg/day). In developed nations, the average sodium intake is 3600 - 4800 mg daily; in the U.S., the average intake is 3600 mg. It is also important to note that salt substitutes contain high amounts of potassium (e.g., No-Salt 16.4 mEq per 1/4 tsp), and patients should be aware that they may increase the risk of hyperkalemia when taken with certain antihypertensives (e.g., ACE inhibitors, ARBs, aldosterone antagonists). [48]

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