Refractory Hypertension

Refractory Hypertension, also known as a refractory hypertensive state, RfHTN, or status angiotensus, is a hypertensive condition which can occur, for no apparent reason, in patients with previously well-managed hypertension.[1] Refractory hypertension is characterized by a blood pressure that remains uncontrolled on maximal or near-maximal therapy, which is the use of ≥5 antihypertensive agents of different classes, including a long-acting thiazide-like diuretic (such as chlorthalidone) and spironolactone.[2] Patients with refractory hypertension typically exhibit increased sympathetic nervous system activity.[2][3] The phenotype of refractory hypertension was first proposed in a retrospective analysis of patients referred to the University of Alabama at Birmingham Hypertension Clinic whose blood pressure could not be controlled on any antihypertensive regimen.[2][4]

Observational studies suggest that RfHTN is rare, affecting <5% of patients.[3]

Apparent Versus True

The term apparent refractory hypertension, as opposed to true refractory hypertension is used by investigators to refer to patients with resistant hypertension based on the number of prescribed medications, without accounting for common causes of pseudo-resistance, ie, inaccurate blood pressure measurements, nonadherence, undertreatment, or white-coat effects.[5] These phenomena are well understood in resistant hypertension, but not in refractory hypertension.[3] The white-coat effect is reportedly much more prevalent in RfHTN than in resistant hypertension, but the other causes of apparent resistant hypertension remain unstudied in refractory hypertension.[6] Specifically, none of the studies of refractory hypertension has reported adherence based on measurement of drug or drug metabolite levels in serum or urine.[3]

Cause

Transthoracic impedance cardiography, combined with assessment of arterial stiffness, suggests that status angiotensus may not be secondary to persistent excess fluid retention, but instead is likely neurogenic in pathogenesis, and attributable to heightened sympathetic outflow.[6][5]

Risk Factors

Risk factors for RfHTN overlap with those for resistant hypertension including black race, obesity, diabetes mellitus, and chronic kidney disease. However, patients with refractory hypertension tend to be younger and more often women than those with resistant hypertension.[2][7]

Treatment

By definition, refractory hypertension cannot be effectively treated. RfHTN does not respond to diuretics; calcium channel blockers; ACE, or renin inhibitors; endothelium receptor blockers; Angiotensin II, Adrenergic, Aldosterone, or Alpha-2 adrenergic receptor agonists; or Vasodilators.

Terminology

The term resistant hypertension has been used since the early 1960s to identify patients with difficult-to-treat hypertension. In 2008, the American Heart Association defined resistant hypertension as blood pressure uncontrolled with 3 medications, but controlled with ≥4 medications.[3] The lack of a similar codified definition of refractory hypertension has led to some discrepancy in terminology. Status angiotensus and refractory hypertensive state are usually used as synonyms for refractory hypertension and RfHTN, however sometimes they can describe a sudden acute hypertensive crisis arising from refractory hypertension.

See also

References
  1. Artinian B (January 2010). "A third status". The Ulster Medical Journal. 79 (1): 32. PMC 2938992. PMID 20844733.
  2. Acelajado MC, Hughes ZH, Oparil S, Calhoun DA (March 2019). "Treatment of Resistant and Refractory Hypertension". Circulation Research. 124 (7): 1061–1070. doi:10.1161/CIRCRESAHA.118.312156. PMC 6469348. PMID 30920924.
  3. Dudenbostel T, Siddiqui M, Oparil S, Calhoun DA (June 2016). "Refractory Hypertension: A Novel Phenotype of Antihypertensive Treatment Failure". Hypertension. 67 (6): 1085–92. doi:10.1161/HYPERTENSIONAHA.116.06587. PMC 5425297. PMID 27091893.
  4. Van Dyne JR (June 1960). "Iproniazid in the treatment of resistant hypertension. A preliminary report on twenty intractable cases". Journal of the American Geriatrics Society. 8 (6): 454–62. doi:10.1111/j.1532-5415.1960.tb00410.x. PMID 13841056. S2CID 70416945.
  5. Grigoryan L, Pavlik VN, Hyman DJ (November 2013). "Characteristics, drug combinations and dosages of primary care patients with uncontrolled ambulatory blood pressure and high medication adherence". Journal of the American Society of Hypertension. 7 (6): 471–6. doi:10.1016/j.jash.2013.06.004. PMC 3883386. PMID 23890931.
  6. Modolo R, de Faria AP, Sabbatini AR, Barbaro NR, Ritter AM, Moreno H (May 2015). "Refractory and resistant hypertension: characteristics and differences observed in a specialized clinic". Journal of the American Society of Hypertension. 9 (5): 397–402. doi:10.1016/j.jash.2015.03.005. PMID 25979412.
  7. Irvin MR, Booth JN, Shimbo D, Lackland DT, Oparil S, Howard G, et al. (June 2014). "Apparent treatment-resistant hypertension and risk for stroke, coronary heart disease, and all-cause mortality". Journal of the American Society of Hypertension. 8 (6): 405–13. doi:10.1016/j.jash.2014.03.003. PMC 4120268. PMID 24952653.
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