HIGH BLOOD PRESSURE

• ACRONYMS AND DEFINITIONS

• AAMI - Association for the Advancement of Medical Instrumentation
• AAP - American Academy of Pediatrics
• ACC - American College of Cardiology
• AHA - American Heart Association
• BHS - British Hypertension Society
• BP - Blood pressure
• DBP - Diastolic blood pressure
• EKG - Electrocardiogram
• ESH - European Society of Hypertension Working Group on Blood Pressure Monitoring
• HTN - Hypertension
• RCT - Randomized controlled trial
• JNC 7 and 8 - Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure
• SBP - Systolic blood pressure
• USPSTF - U.S. Preventive Services Task Force

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• SCREENING RECOMMENDATIONS

• JNC 7
• The JNC 7 makes no specific recommendation for screening based on age
• JNC 7 recommends the following based on blood pressure measurements:

• Follow guideline for number 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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• PHYSIOLOGY OF BLOOD PRESSURE

• Blood pressure
• Blood pressure is a measure of the resistance to flow that the arteries of the circulatory system exert against blood that is being forced into them by the heart
• Arteries have muscles in their walls that contract and relax
• When arterial muscles contract, the diameter of the artery lumen decreases and resistance increases
• When arterial muscles relax, the diameter of the artery lumen increases and resistance decreases


• One way to think about blood pressure is to consider two straws:
• A soda straw has a diameter of about a quarter inch
• A coffee straw has a very small diameter of about 1-2 millimeters
• It is much easier to blow air through a soda straw than a coffee straw
• The coffee straw is much narrower and therefore is more "resistant" to airflow
• The same principle applies for the arteries of the body
• When the arteries are narrower or constricted, then the heart must pump harder to force blood through them


• High blood pressure
• High blood pressure (also called "hypertension") occurs when the resistance exceeds a "normal" value
• The "normal" value is derived from population averages, and the risk of disease that is directly proportional to rising blood pressure values

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• BLOOD PRESSURE NUMBERS

• Overview
• Blood pressure is expressed as two numbers and is written as SBP/DBP (Example 140/90)
• The higher or "top" number is called the systolic blood pressure (SBP)
• The lower or "bottom" number is called the diastolic blood pressure (DBP)

• Systolic blood pressure (SBP)
• SBP is a measure of the resistance the heart experiences when it is forcing blood through the arteries
• It is measured in mmHg (millimeters of mercury)
• SBP tends to continually rise as a person ages

• Diastolic blood pressure (DBP)
• DBP is the baseline pressure that the arteries maintain when the heart is not forcing blood through them
• It is measured in mmHg (millimeters of mercury)
• DBP tends to rise until the age of 50 where it levels off

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• MEASURING BLOOD PRESSURE

• Auscultatory method
• For over 100 years, the auscultatory method has been the most widely used method for measuring blood pressure
• The pressure in the cuff can be measured with a mercury or aneroid (means "no fluid") sphygmomanometer
• Mercury sphygmomanometers are less common today because of concerns over exposure to mercury


• Steps of the auscultatory method:
• 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 and pulsatile blood flow is gradually reestablished
• 5. The pressure at which the first sound of reestablished blood flow can be heard is the systolic blood pressure
• 6. The cuff continues to deflate until the sound of pulsatile blood flow can no longer be heard
• 7. The pressure at which the last sound of pulsatile blood flow is heard is the diastolic blood pressure [2]

• Oscillometric method
• Oscillometric monitors are widely used today in many settings - home monitors, clinics, hospitals, pharmacies, etc.
• Oscillometric devices do not measure systolic and diastolic pressures directly
• Oscillometric devices measure pressure oscillations in the cuff created by the pulse
• The machine then uses an algorithm to calculate the systolic and diastolic pressure based on these oscillations
• Oscillometric monitors have some advantages and disadvantages
• Advantages
• Does not rely on sound so external noise and technician hearing are not factors
• Does not require another person to measure the pressure
• Disadvantages
• Stiff arteries in older patients can affect the oscillations and cause blood pressure to be underestimated
• Measurements during exercise can be affected by movement artifact [2]

• Cuff size
• Cuff size is important because a cuff that is too small will give a spuriously high reading and vice versa
• Some cuffs have a range drawn around their circumference that indicates if the arm fits appropriately
• BP cuff bladder length should be 75% – 100% of the patient’s measured arm circumference
• BP cuff bladder width should be at 37% – 50% of the patient’s arm circumference (a length-to-width ratio of 2:1)
• BP cuff should be placed on bare skin, but shirtsleeves should not be rolled up because this may create a tourniquet effect
• If an adult thigh cuff is still too small for morbidly obese patients, then a wrist cuff may be used
• Recommended cuff sizes based on arm circumference are presented in the table below [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 Relax for 3 - 5 minutes while sitting in a chair with feet flat on floor (legs uncrossed) and back supported. Do not talk to anyone during this period. Caffeine, exercise, and smoking should be avoided ≥ 30 minutes prior to measurement Patient should empty bladder before 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 mm Hg, respectively Having legs that are crossed during BP measurement may raise SBP by 5 – 8 mm Hg and DBP by 3 – 5 mm Hg A small study (N=113) published in 2021 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 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 (eg, 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
Measurement frequency At first clinic visit or reading, measure blood pressure on both arms. 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 2 readings in the morning before taking meds and two readings in the evening Use 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 about 4% of the general population. Significant BP arm differences can be a sign of coarctation of the aorta (see secondary causes above), but this condition is rare (0.1% of patients with hypertension). 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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• BLOOD PRESSURE GOALS

• Blood pressure recommendations vary by organization and comorbidities
• See hypertension guidelines for a review of treatment recommendations

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• DISEASES ASSOCIATED WITH HYPERTENSION

• Hypertension facts
• For every 20 mmHg systolic or 10 mmHg diastolic increase in blood pressure, the risk of death from heart disease and stroke doubles
• SBP in the range of 130-139 mmHg and DBP in the range 85-89 mmHg has been associated with a twofold increase in the relative risk for heart disease when compared to blood pressure below 120/80
• As blood pressure rises above 115/75, risk of death from stroke and heart disease increases linearly [1]


• If left untreated, years of high blood pressure will greatly increase a person's risk of developing:
• Coronary artery disease
• Stroke
• Heart failure
• Kidney failure
• Peripheral artery disease
• Retinopathy (eye disease) [1]

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• HOME BLOOD PRESSURE MONITORS

• An extensive array of blood pressure measuring devices is available for purchase. Several organizations have developed methods for validating the accuracy of these devices, and their recommendations are published on websites.
• The American Medical Association (AMA) has a website that lists BP 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 a large number of devices. Links to both websites are available below.
• In general, upper arm monitors are preferred, but wrist monitors may be appropriate in certain situations (e.g. upper arm too big for arm cuff). If wrist monitors are used, it's important that the device be correctly placed over the radial artery and held at heart level when readings are taken, with limited movement or wrist flexion. Finger monitors are not recommended.
• All monitors should be compared to a clinician's reading every 1 - 2 years to validate their accuracy [2]
• AMA validated blood pressure devices
• dabl Educational Trust blood pressure device ratings

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• STORE-BASED BLOOD PRESSURE MACHINES

• When store-based blood pressure machines were first introduced in the 1970s, they were not designed to comply with industry standards and often did not perform well when tested
• Since that time, machines have been developed and tested to meet AAMI standards for accuracy
• Studies evaluating the performance of these machines have shown that they are not always accurate [3,4]
• Arms that are larger or smaller than normal tend to have less accurate readings [4]
• While these machines are not always precise, for many patients, they are the only practical and convenient method for periodic monitoring of blood pressure
• In general, machines that meet AAMI standards and are calibrated periodically provide accurate readings of blood pressure for patients with average size arms
• To find out if the store-based machine you use is AAMI certified, obtain the model number at the store and check the manufacturer's website. The store should be able to tell you if it is calibrated periodically.

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• AMBULATORY BLOOD PRESSURE MONITORING

• Procedure
• Ambulatory blood pressure monitoring is a procedure where a patient wears a small portable device for 24 - 48 hours
• The device takes blood pressure measurements every 20 - 30 minutes over the period it is worn
• The blood pressure readings are then averaged


• Accuracy
• Ambulatory BP monitoring is considered the gold standard for diagnosing hypertension
• In a recent large study, ambulatory BP measurements were a better predictor of all-cause and cardiovascular mortality than office BP measurements [PMID 29669232]
• In studies, 5 - 65% of patients with elevated office BP measurements were not diagnosed with hypertension after ambulatory BP monitoring was performed [8]
• Although ambulatory BP readings are generally believed to be lower on average than clinic readings, a study published in 2016 found that ambulatory readings were actually higher among patients who were not being treated for hypertension [PMID 27920072]


• Recommendations
• USPSTF
• In 2015, the USPSTF recommended that patients with elevated office blood pressure readings have ambulatory blood pressure monitoring performed to confirm the diagnosis of hypertension. Ambulatory blood pressure confirmation was not considered necessary in patients with blood pressure ≥ 180/110 mmHg or evidence of end-organ damage. [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 which is a dysfunction in the body's ability to sense and control blood pressure (typically requires monitoring during sleep for supine hypertension) [51]

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• DIAGNOSING HYPERTENSION

• Overview
• Because high blood pressure is a diagnosis that is often treated for life, it is important to make sure the diagnosis is based on accurate information
• Blood pressure fluctuates throughout the course of a day depending on a person's activity and mood
• Studies have shown that systolic blood pressure readings done at home can average 8 - 10 mmHg lower than readings done in a clinic [9]
• A recent study showed that averaging at least 5 blood pressure measurements over the course of months greatly increased the likelihood of estimating a person's true average blood pressure [9]


• Professional guidelines
• The AHA/ACC 2017 blood pressure guidelines recommend that the average of ≥ 2 readings on ≥ 2 separate occasions using proper technique be used to diagnose hypertension [47]
• The USPSTF now recommends that ambulatory blood pressure monitoring be performed to confirm a diagnosis of hypertension in most patients. Patients with blood pressure readings ≥ 180/110 mmHg or end-organ damage do not need confirmation with ambulatory blood pressure monitoring. [8]


• General guidelines for patients with suspected hypertension:
• 1. Patients with suspected high blood pressure should make an effort to obtain multiple measurements (at least 5, but more is better) over the course of several weeks or months
• 2. These measurements should be recorded and averaged
• 3. Blood pressure measurements should be done following correct procedures (see measuring blood pressure above)
• 4. Patients with SBP readings > 180 or DBP readings > 110 should notify their physician and be followed closely

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• SYMPTOMS OF HIGH BLOOD PRESSURE

• For the most part, high blood pressure by itself has no symptoms
• Even when the blood pressure is very high (systolic > 200, diastolic > 120), most people will not experience any symptoms
• On rare occasions, very high pressure may present with acute end-organ damage. Symptoms of end-organ damage may include visual changes, kidney failure (decreased urination and swelling), heart failure (swelling and shortness of breath), headache, nausea, vomiting, seizures, and brain bleeding.

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• RECOMMENDED WORKUP FOR HIGH BLOOD PRESSURE

• Overview
• Recommendations for routine testing in patients with newly diagnosed hypertension are listed below
• Patients with signs or symptoms of secondary hypertension should undergo further testing


• Labs
• The JNC 7 recommends the following routine labs:
• Blood sugar
• Hematocrit
• Potassium
• Creatinine
• Calcium
• Cholesterol profile


• The AHA/ACC 2017 blood pressure guidelines recommend the following routine labs:
• BMP
• CBC
• Lipid profile
• TSH
• Urinalysis


• EKG
• JNC 7 and the AHA/ACC 2017 high blood pressure guidelines recommend routine electrocardiogram (EKG) in newly diagnosed hypertensive patients
• Studies
• EKG is primarily recommended to screen for left ventricular hypertrophy. In practice, clinicians vary widely in following this recommendation.
• A recent review found that routine EKG in patients with hypertension was not effective in identifying patients with an enlarged heart, and it questioned its utility in guiding treatment [PMID 17726091]

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• ESSENTIAL HYPERTENSION

• Overview
• "Essential hypertension" is hypertension where no identifiable cause of high blood pressure can be found
• The majority of hypertension (90 - 95% of cases ) is essential hypertension [11,12,13]

• Known risk factors for developing essential hypertension
• Family history - risk tends to be greater as number of affected relatives increases [22,23]
• African-American race [1]
• Excess alcohol intake - more than 2 drinks a day in men or 1 a day in women [1,15]
• Obesity [1,15]
• Inadequate intake of fruits, vegetables, and potassium [1,15]
• Sedentary lifestyle (no exercise) [1,15]
• Age (as people get older, blood pressure tends to rise) [1]
• Gender - men tend to have higher systolic blood pressure up to 60 years old, then the prevalence of hypertension in women is equal to, or exceeds that in men [1]
• Obstructive Sleep Apnea [16,18]

• Possible risk factors for essential hypertension
• High salt intake - while lowering salt intake does tend to lower blood pressure (see sodium below), there is inconclusive evidence that higher salt intake increases the risk for hypertension or heart disease [1,25]
• Smoking - there is inconclusive evidence that chronic smokers have a higher risk for hypertension [1,20,21]
• Personality traits - evidence that personality traits (ex. anxiety, type A personality, anger issues, etc.) increase the risk for hypertension is inconsistent and inconclusive [24]
• Bisphenol A (BPA) exposure - BPA is a chemical used in plastic bottles and inner coatings of beverage cans. Some studies have found that BPA exposure raises blood pressure. [PubMed 25489056]

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• SECONDARY HYPERTENSION

• Overview
• Secondary hypertension is hypertension from an identifiable cause that may be treatable
• Secondary hypertension accounts for 5 - 10% of the cases of hypertension, depending on the study [12]

• Signs of secondary hypertension
• High blood pressure that responds poorly to treatment
• High blood pressure that is not accompanied with typical risk factors (obesity, family history, etc.)
• Blood pressure increases after period of good control
• High blood pressure that is labile and/or intermittent
• Sudden onset of high blood pressure
• Abnormalities on labs and physical exam (ex. high creatinine, low potassium, abdominal bruit, etc.) [1,27]

• Percentages represent prevalence among patients with hypertension

Causes of secondary hypertension
Obstructive sleep apnea (25 - 50%) Signs and symptoms: snoring; daytime sleepiness; obesity; apnea during sleep Diagnosis: sleep study
Renal vascular disease (5 - 34%) Signs and symptoms: resistant hypertension; hypertension of abrupt onset; young females (fibromuscular hyperplasia); abdominal bruit Diagnosis: renal doppler ultrasound; MRA/CT Treatment: A randomized controlled trial found no benefit of renal artery stenting in atherosclerotic renal artery stenosis (see renal artery stenosis below)
Primary aldosteronism (8 - 20%) Signs and symptoms: resistant hypertension with hypokalemia (see potassium regulation) Diagnosis: aldosterone-to-renin ratio
Drugs and alcohol (2 - 4%) Signs and symptoms: see medications that raise blood pressure below Diagnosis: urine drug screen; medication review
Renal parenchymal disease (1 - 2%) Signs and symptoms: family history of polycystic kidney disease; abnormal urinalysis; elevated serum creatinine Diagnosis: renal ultrasound
Aortic coarctation (0.1%) Signs and symptoms: young patient (< 30 years) with hypertension; BP higher in upper extremities than in lower extremities; absent femoral pulses Diagnosis: Echocardiogram
Cushing's syndrome (rare, < 0.1%) Signs and symptoms: central obesity; moon face; supraclavicular fat pads; violaceous striae, hirsutism Diagnosis: see HPA axis testing
Hyper / hypothyroidism (rare, < 0.1%) Signs and symptoms: depends on cause Diagnosis: TSH
Primary hyperparathyroidism (rare) Signs and symptoms: none Diagnosis: Serum calcium
Pheochromocytoma (rare, 2 - 8 cases per million persons annually) [27] Signs and symptoms: resistant hypertension; paroxysmal hypertension with headache, sweating, palpitations, and pallor Diagnosis: 24-hour urinary fractionated metanephrines or plasma metanephrines; CT/MRI of adrenals [47]
Congenital adrenal hyperplasia (rare) Signs and symptoms: virilization or incomplete masculinization Diagnosis: Newborn screening, hormone studies
Acromegaly (rare) Signs and symptoms: large hands, feet, head Diagnosis: Growth hormone level

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• WHITE COAT HYPERTENSION / WHITE COAT EFFECT

• Definitions
• White coat effect - a general increase in blood pressure (hypertensive or not) when measured in a clinical setting as compared to measurements at home or in other settings
• White coat hypertension - hypertension that is only present when blood pressure is measured in a clinical setting. Blood pressure measurements at home or elsewhere are normal.


• Overview
• White coat effect/hypertension occurs when blood pressure readings run higher in a clinical setting. 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 first 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]
• As many as 20 - 35% of patients with hypertension may have some white coat effect, and up to 20% of people diagnosed with stage 1 hypertension may have white coat hypertension as opposed to true hypertension.


• AHA recommendations
• The AHA/ACC 2017 blood pressure guidelines state that it is reasonable to screen for white coat hypertension when clinic SBP runs 130 - 160 mmHg and/or DBP runs 80 - 100 mmHg [47]


• Detecting white coat hypertension/effect
• Ambulatory and/or home blood pressure monitoring can be used to screen for white coat hypertension/effect
• White coat hypertension may be diagnosed when ambulatory/home readings average < 135/85 and office readings are > 140/90 [2]
• If home self-monitoring is to be done, patients should bring their home monitors to their clinic visits to ensure that the two machines give comparable readings

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• RESISTANT HYPERTENSION

• Definition
• In 2018, the AHA defined resistant hypertension as the following: Clinic BP > 130/80 mmHg in patient taking ≥ 3 antihypertensives (including long-acting calcium channel blocker, an ACE or ARB, and a diuretic^✝ ) at maximal or maximally tolerated doses
• ^✝Patients with CrCl < 30 ml/min should be on a loop diuretic. Torsemide is preferred over bumetanide or furosemide because it has a longer duration of action.
• Medication adherence should be confirmed along with performance of 24-hour ambulatory BP monitoring (if unavailable, home BP monitoring) to exclude white coat effect. In one study, 37% of patients who met the criteria for resistant hypertension had normal ambulatory blood pressures. [PMID 21444835]
• Secondary causes of hypertension should be ruled out (see secondary hypertension above) [50]

• 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 (see secondary hypertension above)
• Taking other medications that raise blood pressure (see medications below) [1,28]

• Reference [50]

AHA 2018 recommendations for treating resistant hypertension (Start with Step 1. Proceed to next step if BP does not reach target.)
Step 1 Ensure that patient meets definition Maximize lifestyle interventions Low sodium diet (< 2400 mg/day) ≥ 6 hours of uninterrupted sleep Weight loss and exercise. A small study (N=60) found that three 40-minute exercise sessions per week 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 beta blocker If pulse is < 70 bpm, add 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 Because of side effects (edema, tachycardia), hydralazine 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 Because of side effects (edema, tachycardia), minoxidil should be given with a beta blocker and loop diuretic

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• HYPERTENSIVE EMERGENCY

• Overview
• Hypertensive emergency is defined as very high blood pressure with symptoms or signs that the elevated blood pressure is having an acute, detrimental effect on an organ (end organ damage). Contrast with the much more common hypertensive urgency which is very high blood pressure with no signs of acute end organ damage.
• The organs of concern in hypertensive emergency are brain, heart, kidney, aorta, and placenta (pregnant women only, not discussed here)
• Patients with hypertensive emergency are typically admitted to intensive care units and treated with IV blood pressure medications [1,39]


• Symptoms of end organ damage
• 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 [39]


• StraightHealthcare analysis:
• It's important to understand that hypertensive emergencies are rare - patients with a typical headache and elevated blood pressure are not likely to be having a hypertensive emergency
• In some cases, the diagnosis can be challenging (ex. protein in the urine and elevated serum creatinine may be a chronic as opposed to an acute effect of high blood pressure; eye exams can be challenging in the primary care setting)
• Good studies evaluating the ideal treatment of hypertensive emergency are sparse, and the optimal workup is not well-defined [37]

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• HYPERTENSIVE URGENCY

• Overview
• Hypertensive urgency is defined as very high blood pressure with no symptoms or signs of acute organ damage. Contrast with hypertensive emergency which is very high blood pressure with signs of acute end organ damage.
• Hypertensive urgencies are common in various clinical settings (emergency room, clinic, etc.) [35]
• All patients with very high blood pressure readings need follow-up arranged within a week (preferably with their primary care doctor) for recheck or treatment [1]
• The question arises as to whether treating very high blood pressures immediately provides a benefit over early follow-up alone
• Many practitioners will give patients quick-acting medications such as clonidine to lower blood pressure before the patient is discharged from the emergency room or clinic

• Review articles
• A review by the American College of Emergency Physicians found that there was no evidence to support rapidly lowering blood pressures in the emergency room setting [PMID 16492490]
• A review of 19 studies in the Journal of Internal Medicine found that there was insufficient data from available trials to make recommendations on treating hypertensive urgencies [PMID 12472930]

• STUDY
  Characteristics and Outcomes of Patients Presenting With Hypertensive Urgency in the Office Setting JAMA Internal Medicine (2016) [PubMed abstract]
• A propensity score matching study published in JAMA Internal Medicine utilized data from 58,535 patients who presented to a clinic with hypertensive urgency (SBP ≥ 180, DBP ≥ 110)
• The study compared cardiovascular outcomes between patients who were immediately referred to a hospital to those who were sent home
• In the propensity-matched analysis, 852 patients who were sent home were compared to 426 patients who were referred to the hospital
• The average BP in the cohort was 183/96 mmHg
• The study found the following:
• Composite of acute coronary syndrome, stroke, or TIA at 7 days: Home - 0%, Hospital - 0.5% (p=0.11)
• Composite of acute coronary syndrome, stroke, or TIA at 8 to 30 days: Home - 0%, Hospital - 0.5% (p=0.11)
• Composite of acute coronary syndrome, stroke, or TIA at 6 months: Home - 0.9%, Hospital - 0.9% (p=0.99)
• Uncontrolled hypertension (BP ≥ 140/90) at 1 month: Home - 86.3%, Hospital - 81.9% (p=0.04)
• Uncontrolled hypertension (BP ≥ 140/90) at 6 month: Home - 64.6%, Hospital - 66.6% (p=0.56)
• Findings: Hypertensive urgency is common, but the rate of major adverse cardiovascular events in asymptomatic patients is very low. Visits to the ED were associated with more hospitalizations, but not improved outcomes. Most patients still had uncontrolled hypertension 6 months later.

• Professional recommendations
• The American College of Emergency Physicians (ACEP) 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.

• Summary
• There is no evidence that rapidly lowering blood pressure with medications like clonidine provides any short-term or long-term benefit
• Despite the lack of evidence, doctors frequently give clonidine and monitor patients until their blood pressure comes down
• A prudent approach to hypertensive urgency is to verify compliance with current meds, adjust therapy as needed, and arrange for follow-up

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• MEDICATIONS THAT CAN RAISE BLOOD PRESSURE

• Acetaminophen (Tylenol®) [PMID 35130054]
• 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
• Testosterone enanthate (Xyosted®)
• Testosterone undecanoate (Jatenzo®)
• Testosterone undecanoate (Tlando®)
• Tacrolimus (Prograf®) [1,47]

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• LIFESTYLE CHANGES TO LOWER BLOOD PRESSURE

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• BP MEDICATION RECOMMENDATIONS

• Bedtime vs morning dosing
• A large randomized controlled trial (N=19,084) published in 2019 found that patients who took all of their blood pressure medications at bedtime had a lower incidence of CVD events (median follow-up 6.3 years) than those who took all of their BP meds in the morning. [PMID 31641769]

• Professional recommendations
• See hypertension guidelines for medication recommendations from professional associations

• Compelling indications
• In many cases, patients may have other medical conditions which may make a certain class of blood pressure medications a compelling choice

Medication class	Compelling indication
ACE inhibitors	diabetes, heart failure, kidney disease
Aldosterone antagonists	heart failure, liver failure, resistant hypertension, acne
ARBs	diabetes, heart failure, kidney disease
Alpha-2 agonists	hypertensive urgency
Alpha blockers	benign prostatic hyperplasia
Beta blockers	heart failure, heart attack, angina, atrial fibrillation, esophageal varices
Calcium channel blockers	angina, atrial fibrillation (nondihydropyridines), black patients
Loop diuretics	heart failure, kidney failure, liver failure
Thiazide diuretics	heart failure, calcium-based kidney stones, black patients
Vasodilators	angina, heart failure, resistant hypertension

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• RENAL ARTERY STENOSIS

• Overview
• Renal artery stenosis is narrowing of the arteries that perfuse the kidneys. It is typically caused by atherosclerotic vascular disease but may also occur secondary to fibromuscular dysplasia (more common in women < 50 years old)
• Renal artery stenosis can lead to resistant hypertension and decreased kidney function. Revascularization with stent placement has been used for years to treat renal artery stenosis despite clear evidence that it is beneficial.
• The CORAL trial detailed below was specifically designed to evaluate what benefit, if any, that stenting has over medical therapy alone.

• 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 detailed above, renal artery stenting did not improve outcomes in patients with atherosclerotic renal artery stenosis
• Stenting has not been studied extensively in other types of renal artery stenosis (e.g. fibromuscular dysplasia), and its effects on these conditions is unknown

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• RENAL DENERVATION FOR RESISTANT HYPERTENSION

• 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 stimulation of the renin-angiotensin-aldosterone system (RAAS) and, in theory, lowers blood pressure.
• Trials evaluating the effects of renal denervation have had mixed results, depending on the study design and comparator used. Four major renal denervation trials are described below.


• 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]


• 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 short-term benefit. Currently, there is no good evidence that renal denervation is a worthwhile therapy.

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• BEETROOT JUICE TO LOWER BLOOD PRESSURE

• Overview
• Nitric oxide is a potent vasodilator produced by endothelial cells
• Nitric oxide is formed from the reduction of nitrite, and nitrite is formed from the reduction of nitrate
• Nitrates consumed in the diet are converted to nitric oxide through a multistep process. Dietary nitrates are absorbed through the small intestine. The nitrates are then extracted from the blood by the salivary glands and secreted into the oral cavity. Bacteria in the oral cavity reduce nitrates to nitrites. Nitrites are swallowed and absorbed into the circulation where they come into contact with nitrite reductase. Nitrite reductase converts nitrites to nitric oxide. [45]
• Beetroot juice has a very high nitrate concentration (∼6 mmol per 250ml)
• A study published in 2015 compared beetroot juice to nitrate-depleted beetroot juice for blood pressure lowering

• Summary
• This study is interesting because it found that beetroot juice lowers blood pressure
• Beetroot juice may be the only dietary treatment ever proven to lower blood pressure in a randomized controlled trial
• The long-term efficacy and side effects of consuming daily beetroot juice are unknown

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• SODIUM/SALT AND HYPERTENSION

• Sodium vs salt
• It is important to understand the difference between salt and sodium. Salt is sodium chloride (NaCl). In terms of molecular weight, salt is 40% sodium and 60% chloride, so 1000 mg of salt would contain 400 mg of sodium.
• In developed nations, the average person consumes 3600 - 4800 mg of sodium a day (9000 - 12,000 mg of salt). In the U.S., the average sodium intake is 3600 mg per day. See sodium homeostasis for more. [48]
• Food labels typically list the total amount of sodium in a food in milligrams. Milligrams of sodium can be converted to millimoles and milliequivalents by dividing by the atomic weight of sodium which is 23.


• 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 1500 mg of sodium a day (3750 mg of salt)
• The USDA recommends consuming less than 2300 mg of sodium a day (5750 mg of salt)
• JNC 7 recommends consuming less than 2300 mg of sodium a day (5750 mg of salt)
• 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
• A number of studies have shown that restricting sodium intake lowers blood pressure
• A Cochrane meta-analysis that looked at the effects of sodium restriction on blood pressure found the following:
• Patients with hypertension (20 trials)
• Reducing sodium intake by 2400 mg a day results in a decrease in SBP of 7.2 mmHg
• Reducing sodium intake by 2400 mg a day results in a decrease in DBP of 3.8 mmHg
• Patients without hypertension (11 trials)
• Reducing sodium intake by 2400 mg a day results in a decrease in SBP of 3.6 mmHg
• Reducing sodium intake by 2400 mg a day results in a decrease in DBP of 1.7 mmHg [40]

• Sodium intake and heart disease outcomes
• Decreasing sodium intake lowers blood pressure, but its overall effect on cardiovascular outcomes is less clear
• Measuring sodium intake in a large group of subjects longitudinally is difficult, and controlled trials where subjects are randomly assigned diets with different sodium content for long periods of time are impractical. Most of the data on cardiovascular outcomes in relation to sodium intake is from cohort studies. Daily urinary sodium excretion is thought to mirror daily intake, so the studies typically use urinary sodium excretion as a surrogate for sodium intake. Three large studies that looked at the association between urinary sodium excretion and cardiovascular outcomes are detailed below.
• In 2021, a study was published that randomized Chinese villagers with a history of stroke or hypertension to a salt substitute or regular salt. The trial lasted 4.74 years, and the primary outcome was stroke. Details of that study are provided below.

• STUDY
  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

• STUDY
  Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension, Lancet (2016) [PubMed abstract]
• A study published in the Lancet pooled data from four studies (PURE, EPIDREAM, ONTARGET, TRANSCEND) that encompassed 133,118 participants. Patients were from 49 different countries and had a median age of 55 years.
• The analysis divided the participants into subgroups based on whether they had hypertension at baseline or not
• 24-hour urinary sodium excretion was estimated from a morning fasting urine sample using the Kawasaki formula
• Daily urinary sodium excretion is thought to mirror daily sodium intake
• 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.

• STUDY
  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 who were divided into five groups based on their estimated daily urinary sodium excretion
• 24-hour urinary sodium excretion was estimated from a morning fasting urine sample using the Kawasaki formula
• Daily urinary sodium excretion is thought to mirror daily sodium intake
• 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.

• STUDY
  Urinary sodium and potassium excretion and risk of cardiovascular events, JAMA (2011) [PubMed abstract]
• A JAMA cohort study compared cardiovascular outcomes among 28,880 patients from 40 countries who were divided into seven groups based on their estimated daily urinary sodium excretion
• 24-hour urinary sodium excretion was estimated from a morning fasting urine sample using the Kawasaki formula
• Daily urinary sodium excretion is thought to mirror daily sodium intake
• 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.

• Summary
• The three cohort studies detailed above found that sodium intake has a "U-shaped" relationship with cardiovascular outcomes, 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, and this dropped by 350 mg/day in the salt substitute group. The salt substitute group also achieved a SBP that was lower by 3.34 mmHg. Patients who were taking potassium-sparing diuretics and/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 a day, and in the U.S., the average intake is 3600 mg per day. It's also important to note that salt substitutes often contain a lot 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. [48]

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