What is the best approach to manage a patient with resistant hypertension (HTN) and palpitations, who is undergoing tests for urine fractionated metanephrines, plasma free metanephrines, renin, and cortisol?

Management of Resistant Hypertension with Palpitations and Endocrine Workup

In a patient with resistant hypertension and palpitations undergoing testing for urine fractionated metanephrines, plasma free metanephrines, renin, and cortisol, you should prioritize ruling out pheochromocytoma/paraganglioma and primary aldosteronism as these are the most dangerous and treatable secondary causes, while simultaneously optimizing the current antihypertensive regimen with spironolactone as fourth-line therapy if biochemical screening is negative. 1

Immediate Diagnostic Priorities

Pheochromocytoma/Paraganglioma Assessment

• The combination of resistant hypertension with palpitations is highly suggestive of pheochromocytoma, which presents with episodic symptoms in approximately 95% of cases and carries significant cardiovascular risk due to blood pressure variability 1
• Plasma free metanephrines (normetanephrine and metanephrine) are the preferred screening test with 99% sensitivity and 89% specificity 1
• The diagnostic triad of headaches, palpitations, and sweating occurring episodically has 90% specificity for pheochromocytoma 1
• If plasma metanephrines are elevated, proceed immediately to adrenal/abdominal imaging with CT or MRI before initiating additional antihypertensive therapy 1

Primary Aldosteronism Screening

• Primary aldosteronism affects 8-20% of patients with resistant hypertension and is the most common treatable secondary cause 1, 2
• The aldosterone-to-renin ratio (ARR) should be measured under standardized conditions: correct hypokalemia first and withdraw aldosterone antagonists for 4-6 weeks if possible 1
• A ratio >20 with elevated aldosterone and suppressed renin is suggestive and requires confirmatory testing with oral sodium loading or IV saline infusion 1, 2
• Review prior potassium levels, as spontaneous or diuretic-induced hypokalemia increases the likelihood of primary aldosteronism 1, 2

Cushing's Syndrome Evaluation

• Hypertension occurs in 70-90% of Cushing's syndrome cases, with 17% having severe hypertension 1
• 24-hour urinary free cortisol is the preferred initial screening test, though midnight salivary cortisol and overnight 1-mg dexamethasone suppression test are alternatives 1
• Look for clinical features: rapid weight gain with central distribution, proximal muscle weakness, wide violaceous striae, moon facies, and dorsal fat pads 1

Concurrent Management Strategy

Exclude Pseudoresistance First

• Before pursuing extensive secondary hypertension workup, confirm true resistant hypertension by excluding poor BP measurement technique, white coat effect, and medication nonadherence 1, 3
• Obtain out-of-office BP measurements with 24-hour ambulatory monitoring or home BP monitoring to exclude white coat hypertension 1, 4
• Review medication adherence and assess for interfering substances (NSAIDs, decongestants, alcohol, cocaine) 1

Optimize Current Antihypertensive Regimen

• Ensure the patient is on maximally tolerated doses of a long-acting calcium channel blocker, renin-angiotensin system blocker (ACE inhibitor or ARB), and appropriate diuretic 1, 4
• Switch from thiazide diuretics to thiazide-like diuretics (chlorthalidone or indapamide) as they are more effective for resistant hypertension 1
• If eGFR <30 mL/min/1.73m² or clinical volume overload exists, switch to loop diuretics 1

Fourth-Line Agent Selection

• Add spironolactone 25-50 mg daily as the fourth-line agent if serum potassium <4.5 mmol/L and eGFR >45 mL/min/1.73m² 1, 5
• Spironolactone provides significant additional BP reduction even without biochemical evidence of aldosterone excess 1, 6
• If spironolactone is contraindicated or not tolerated, alternatives include amiloride, doxazosin, eplerenone, clonidine, or beta-blockers 1, 4
• Monitor serum potassium and creatinine closely, especially when combining with renin-angiotensin system blockers 1

Additional Screening Considerations

Obstructive Sleep Apnea

• OSA is present in 25-50% of resistant hypertension cases and up to 60% in some series 1
• Suspect OSA with snoring, witnessed apneas, daytime sleepiness, obesity, or non-dipping/reverse-dipping pattern on 24-hour BP monitoring 1, 2
• Overnight polysomnography confirms diagnosis (AHI >5) and quantifies severity 1

Renovascular Disease

• Consider if there is abrupt onset or worsening hypertension, flash pulmonary edema, or acute eGFR decline >50% within one week of starting ACE inhibitor/ARB 1, 2, 3
• Initial screening with renal Duplex Doppler ultrasound, followed by CT or MRI angiography if positive 1

Renal Parenchymal Disease

• Assess with serum creatinine, eGFR, urinalysis, and urinary albumin-to-creatinine ratio 1, 2
• CKD is both a common cause and complication of poorly controlled hypertension, with less than 15% achieving BP control <130/80 mmHg despite three agents 1

Critical Pitfalls to Avoid

• Do not delay pheochromocytoma workup in patients with palpitations and resistant hypertension, as this condition carries high cardiovascular risk and can be fatal if undiagnosed 1
• Avoid interpreting aldosterone-to-renin ratio while patient is on medications that affect the ratio: beta-blockers and direct renin inhibitors lower renin (false positive), while mineralocorticoid receptor antagonists raise aldosterone (false negative) 1, 2
• Do not perform expensive imaging studies before completing basic laboratory screening including electrolytes, renal function, and hormonal testing 2, 3
• Recognize that approximately 50% of patients diagnosed with resistant hypertension have pseudoresistance rather than true resistant hypertension 1
• Delayed diagnosis of secondary hypertension leads to vascular remodeling, resulting in residual hypertension even after treating the underlying cause 2, 3

Referral Indications

• Refer to a specialist center with appropriate expertise if screening tests are positive and confirmatory testing is needed 1, 3
• Consider referral if BP remains uncontrolled despite optimal therapy with four antihypertensive agents at maximal tolerated doses 1, 7
• Surgical intervention for unilateral primary aldosteronism or pheochromocytoma requires specialized expertise 2, 8