What is the appropriate workup for a patient with resistant hypertension?

Workup for Resistant Hypertension

Before pursuing an extensive workup, first confirm true resistant hypertension by performing 24-hour ambulatory blood pressure monitoring to exclude white coat effect (which accounts for ~50% of apparent resistant cases) and verify medication adherence through direct questioning, pill counts, or pharmacy records. 1, 2

Step 1: Exclude Pseudoresistance

Confirm the diagnosis systematically before proceeding with costly investigations:

• Perform 24-hour ambulatory BP monitoring to rule out white coat hypertension, as this accounts for approximately half of apparent resistant cases 1, 2
• Verify medication adherence through direct questioning, pill counts, pharmacy records, or if available, blood/urine drug level testing 1, 2
• Ensure proper BP measurement technique using appropriate cuff size and correct patient positioning to avoid falsely elevated readings 1, 2
• Confirm the patient is on ≥3 antihypertensive agents from different classes (long-acting calcium channel blocker, RAS blocker, and diuretic) at optimal/maximal tolerated doses, with BP remaining >140/90 mmHg (or >130/80 mmHg in patients with diabetes or chronic kidney disease) 3, 1

Step 2: Identify Interfering Substances and Lifestyle Factors

Review all medications and substances that may interfere with BP control:

• Stop or minimize NSAIDs, decongestants, oral contraceptives, corticosteroids, stimulants, certain antidepressants, immunosuppressive agents, and herbal supplements 4, 2
• Assess dietary sodium intake and recommend restriction to <1500-2400 mg/day, as excessive sodium is a major contributor to resistance 4, 2
• Evaluate for obesity and recommend weight loss if BMI >25 kg/m², as older age and obesity are the strongest risk factors for resistant hypertension 1, 4
• Limit alcohol intake to ≤2 drinks/day for men and ≤1 drink/day for women 3, 4

Step 3: Screen for Secondary Causes of Hypertension

The most recent International Society of Hypertension guidelines (2020) recommend systematic screening for secondary causes, particularly in specific clinical scenarios. 3

Basic Screening Tests (Perform in All Patients):

• Thorough history and physical examination focusing on symptoms of sleep apnea (snoring, witnessed apnea, excessive daytime sleepiness), signs of Cushing's syndrome, thyroid disease, and renal disease 3, 2
• Basic blood biochemistry: serum sodium, potassium, creatinine with eGFR calculation, TSH 3, 2
• Dipstick urinalysis to assess for proteinuria and hematuria 3
• Fasting blood glucose or HbA1c and lipid profile 2
• ECG to assess for left ventricular hypertrophy 2

Targeted Screening Based on Clinical Suspicion:

Screen systematically for the three most common secondary causes:

1. Primary Aldosteronism (affects 17-23% of resistant hypertension cases):

   • Obtain aldosterone-to-renin ratio as the primary screening test, even with normal potassium levels 1, 4, 2
   • If positive, proceed to confirmatory testing (intravenous saline suppression test) 3
   • If confirmed, obtain adrenal CT imaging and consider adrenal vein sampling 3

2. Obstructive Sleep Apnea:

   • Screen all patients using Berlin Questionnaire or Epworth Sleepiness Score 2
   • If positive, confirm with home sleep apnea testing (level 3 sleep study) or overnight polysomnography 3, 2

3. Chronic Kidney Disease:

   • Calculate eGFR from serum creatinine 1, 4
   • Perform kidney ultrasound if eGFR <60 mL/min/1.73m² or abnormal urinalysis 3

4. Renovascular Hypertension (consider in specific populations):

   • Screen young patients (<30 years, especially women) for fibromuscular dysplasia 3, 2
   • Screen older patients with atherosclerotic risk factors 3
   • Imaging modalities: duplex ultrasound, CT angiography, or MR angiography depending on availability and renal function 3, 2
   • Avoid diagnostic renal arteriograms in the absence of suspicious noninvasive imaging 3

5. Other Endocrine Causes (screen if clinical suspicion exists):

   • Cushing's syndrome: 24-hour urinary free cortisol, dexamethasone suppression tests, followed by abdominal/pituitary imaging if positive 3
   • Pheochromocytoma: plasma or 24-hour urinary metanephrines, followed by abdominal/pelvic CT or MRI if positive 3
   • Thyroid disease: TSH already included in basic screening 3

Important Screening Caveats:

• Do not perform abdominal CT imaging to screen for adrenal adenomas in the absence of biochemical confirmation of hormonally active tumors, due to poor specificity 3
• Investigations for secondary hypertension should generally be preceded by exclusion of pseudoresistant hypertension and drug/substance-induced hypertension 3

Step 4: Document Target-Organ Damage

Assess for end-organ damage to support the diagnosis and influence treatment goals:

• Fundoscopic examination to assess for hypertensive retinopathy 1
• ECG or echocardiography to evaluate for left ventricular hypertrophy 1
• Echocardiogram if cardiac complications suspected 3
• Document chronic kidney disease as this establishes a BP goal of 130/80 mmHg 1
• Screen for atherosclerotic disease given the high cardiovascular risk in this population 1

Step 5: Optimize Treatment Before Further Workup

Before pursuing extensive investigations, ensure the current regimen is optimized:

• Switch to thiazide-like diuretics (chlorthalidone or indapamide) rather than hydrochlorothiazide, as they are significantly more effective 4, 5
• Use loop diuretics if eGFR <30 mL/min/1.73m² or clinical volume overload is present 3, 4
• Ensure maximal tolerated doses of all three first-line agents 3, 5
• Consider adding low-dose spironolactone (25-50 mg daily) as the fourth-line agent if serum potassium <4.5 mmol/L and eGFR >45 mL/min/1.73m² 3, 4

Step 6: Consider Specialist Referral

Refer to a hypertension specialist if:

• BP remains elevated despite 6 months of optimized treatment in the absence of suspected secondary causes 3, 1
• A specific secondary cause is identified requiring specialized management 3
• BP remains uncontrolled after optimizing a four-drug regimen with lifestyle modifications 4, 2
• Complications arise such as severe hyperkalemia, progressive renal dysfunction, or difficulty managing the regimen 4

Hypertension specialists achieve BP control in 52-53% of patients with resistant hypertension, with average BP reductions of 18/9 mmHg at 1-year follow-up. 3, 1

Common Pitfalls to Avoid

• Do not pursue extensive secondary hypertension workup before confirming true resistance with ambulatory BP monitoring and verifying adherence 3, 2
• Do not continue hydrochlorothiazide in resistant hypertension; switch to chlorthalidone or indapamide 4, 5
• Do not screen for primary aldosteronism only in patients with hypokalemia; most cases have normal potassium levels 4, 2
• Do not order abdominal CT for adrenal screening without biochemical confirmation first 3
• Do not delay referral to a specialist if BP remains uncontrolled after 6 months of optimized therapy 3, 1