Refractory Hypertension, also known as a refractory hypertensive state, RfHTN, or status angiotensus, is a

hypertensive Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

condition which can occur, for no apparent reason, in patients with previously well-managed

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

. Refractory hypertension is characterized by a

blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...

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 A thiazide-like diuretic is a sulfonamide diuretic that has similar physiological properties to a thiazide diuretic, but does not have the chemical properties of a thiazide, lacking the benzothiadiazine molecular structure. Examples include metolaz ...

(such as

chlorthalidone Chlortalidone, also known as chlorthalidone, is a thiazide-like diuretic drug used to treat hypertension, high blood pressure, edema, swelling including that due to heart failure, liver failure, and nephrotic syndrome, diabetes insipidus, and re ...

) and

spironolactone Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure ...

. Patients with refractory hypertension typically exhibit increased sympathetic nervous system activity. 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. Observational studies suggest that RfHTN is rare, affecting <5% of patients.

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. These phenomena are well understood in resistant hypertension, but not in refractory hypertension. 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. Specifically, none of the studies of refractory hypertension has reported adherence based on measurement of drug or drug metabolite levels in serum or

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra. Cel ...

Cause

Transthoracic impedance cardiography, combined with assessment of

arterial stiffness Arterial stiffness occurs as a consequence of biological aging and arteriosclerosis. Inflammation plays a major role in arteriosclerosis development, and consequently it is a major contributor in large arteries stiffening. Increased arterial stiff ...

, 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.

Risk Factors

Risk factors for RfHTN overlap with those for resistant hypertension including

black race Black is a racialized classification of people, usually a political and skin color-based category for specific populations with a mid to dark brown complexion. Not all people considered "black" have dark skin; in certain countries, often in s ...

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...

diabetes mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

, and

chronic kidney disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...

. However, patients with refractory hypertension tend to be younger and more often women than those with resistant hypertension.

Treatment

By definition, refractory hypertension cannot be effectively treated. RfHTN does not respond to

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...

calcium channel blocker Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium () through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as ...

ACE An ace is a playing card, Dice, die or domino with a single Pip (counting), pip. In the standard French deck, an ace has a single suit (cards), suit symbol (a heart, diamond, spade, or club) located in the middle of the card, sometimes large a ...

, or

renin Renin (etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin–angiotensin–aldosterone system (RAAS)—also known as the r ...

inhibitors; endothelium receptor blockers;

Angiotensin II Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adre ...

Adrenergic Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine in ...

Aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...

, or

Alpha-2 adrenergic receptor The alpha-2 (α2) adrenergic receptor (or adrenoceptor) is a G protein-coupled receptor (GPCR) associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Som ...

agonists; or

Vasodilators Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...

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 The American Heart Association (AHA) is a nonprofit organization in the United States that funds cardiovascular medical research, educates consumers on healthy living and fosters appropriate cardiac care in an effort to reduce disability and death ...

defined resistant hypertension as blood pressure uncontrolled with 3 medications, but controlled with ≥4 medications. 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.

References