Approach to flushing in adults

INTRODUCTION — Flushing, a common problem encountered in the practice of medicine, has a broad differential diagnosis. A detailed history including associated symptoms, duration, tempo, and environmental exposure is important to determine the underlying etiology and to formulate a management plan.

This topic reviews the pathogenesis, differential diagnosis, evaluation, and treatment of flushing. The management of benign excessive sweating as well as the approach to the patient with night sweats are discussed separately. (See "Primary focal hyperhidrosis" and "Evaluation of the patient with night sweats or generalized hyperhidrosis".)

DEFINITION — Flushing is a sensation of warmth accompanied by transient erythema that most commonly occurs on the face but may also involve the neck, ears, chest, epigastrium, and arms or other areas [1]. The predilection for specific anatomical areas is likely to relate to the volume of visible superficial vessels and differences in the relative amount of cutaneous blood flow compared with other body areas [2].

It is important to differentiate "true flushing" from other disorders that lead to facial erythema, such as the butterfly rash associated with systemic lupus erythematosus or photosensitivity reactions [3]. It is also important to distinguish flushing from excess sweating alone.

PATHOGENESIS — Flushing is a consequence of increased cutaneous blood flow secondary to vasodilation and represents part of a synchronized physiologic response of cutaneous vascular smooth muscle to a variety of autonomic or vasodilator stimuli. Flushing may be episodic, transient, or constant, depending on the etiology.

The appearance of a patient with flushing varies depending on the skin color, temperature, visibility of blood vessels beneath the skin, and capacitance of those vessels for erythrocytes [1]. A fixed degree of facial erythema and telangiectasias may be seen in patients who have experienced flushing over many years [4].

Vascular smooth muscle responds to both autonomic innervation and circulating vasoactive agents; changes in either of these factors can lead to a flushing response. Autonomic nerves also innervate eccrine sweat glands. Thus, disorders of the autonomic nervous system tend to cause vasodilation accompanied by sweating, whereas vasoactive substances, either endogenous or exogenous, tend to cause flushing reactions alone. Autonomic-mediated flushing is often referred to as a "wet" flush, whereas vasoactive-mediated flushing is referred to as a "dry" flush [1].

Vasomotor innervation of specific cutaneous vessels involves either vasoconstrictor or vasodilator fibers; in most areas of the body, one will predominate over the other. Cutaneous vessels in the face are primarily innervated by vasodilator fibers that originate in the brainstem and exit with the trigeminal nerve [5].

ETIOLOGY — The differential diagnosis of flushing is broad (table 1). Neural (autonomic) mediated flushing syndromes can be classified as thermoregulatory flushing, emotional flushing, and flushing related to a disorder of the central nervous system. Direct vasodilator-mediated flushing syndromes result from exposure to a variety of exogenous substances that have a direct effect on the vascular smooth muscle or a number of systemic disorders associated with overproduction of vasoactive agents.

An approach to the evaluation of patients with flushing is shown in an algorithm (algorithm 1) and discussed below. (See 'Evaluation' below.)

The most common etiologies of flushing are [2]:

●Fever

●Hyperthermia

●Menopause

●Emotional blushing

●Rosacea

Autonomic mediated flushing

Thermoregulatory flushing — All forms of thermoregulatory flushing are associated with diaphoresis, which is the body's attempt to bring the core body temperature back to baseline. Thermoregulatory flushing can be caused by:

●Fever

●Exercise

●Heat exposure: ambient or ingested hot beverage

Fever is readily diagnosed by an elevated temperature and may be caused by a variety of infectious and noninfectious etiologies. An increase in body temperature, either by exposure (ie, a very hot day) or exercise will induce a similar response.

The ingestion of a hot beverage appears to induce flushing by a countercurrent heat exchange between the internal jugular vein and the carotid artery [6]. Transmission of heat via the carotid to the anterior hypothalamus, which is exquisitely sensitive to temperature, causes a rapid flushing and sweating response. Thermoregulatory flushing can typically be avoided by allowing a hot drink to cool slightly prior to ingestion and mitigated by consuming a cold beverage or ice.

Menopause — A particularly common and uncomfortable form of thermoregulatory flushing is seen around the time of menopause and is secondary to decreasing levels of circulating estrogen. The flushing reaction is best known as a "hot flash." (See "Menopausal hot flashes".)

Symptoms related to hot flashes characteristically consist of episodic sensations of heat, intense sweating, and flushing [7]. An estimated 50 to 80 percent of women over the age of 45 suffer from these symptoms. Surgically induced menopause tends to cause more severe symptoms, particularly in the first year [8]. Typical episodes last from three to five minutes and may occur up to 20 times per day [9]. They are often very uncomfortable and anxiety-provoking, and they can interfere with sleep as well as normal daily functioning.

The decrease in circulating estrogen appears to stimulate a sudden downward resetting of the body's thermostat in the hypothalamus that precedes the hot flash via unclear mechanisms. The alternation in set point causes a sensation of extreme heat and concomitant activation of both physiologic and behavioral heat loss responses [8]. Central adrenergic pathways may contribute to the reaction, as evidenced by the relief that many women gain from use of an alpha-2 agonist [1,4].

Emotional flushing — Emotional flushing may be a significant source of discomfort for a patient and is more common in women than men. The exact etiology of the heightened vascular response has not been determined.

It has been suggested that blushers are particularly concerned with how others perceive them [10]. These patients often exhibit other heightened physiological reactions to stress, including palpitations, dry mouth, and a sense of cognitive dysfunction. The flushing reaction may be triggered by even minor healthy emotional responses.

Neurologic disorders — Lesions that disturb autonomic function anywhere along the nervous system can lead to flushing. Neurologic disorders that may cause autonomic instability and flushing include:

●Tumors or masses that compress the third ventricle.

●Diencephalic autonomic epilepsy – Generalized seizures accompanied by sympathetic and parasympathetic discharge that results in sweating, flushing, piloerection, salivation, tachycardia, and hypertension.

●Cluster headache – Characterized by hemifacial sweating, lacrimation, rhinorrhea, and Horner syndrome [11]. (See "Cluster headache: Epidemiology, clinical features, and diagnosis".)

●Spinal cord injuries – Cause autonomic hyperreflexia [12]. (See "Chronic complications of spinal cord injury and disease", section on 'Thermoregulatory dysfunction'.)

●Parkinson disease. (See "Clinical manifestations of Parkinson disease", section on 'Autonomic dysfunction'.)

●Multiple sclerosis.

●Autonomic hyperreflexia and orthostatic hypotension [2]. (See "Mechanisms, causes, and evaluation of orthostatic hypotension", section on 'Baroreflex dysfunction'.)

●Auriculotemporal (Frey) syndrome – Recurrent episodes of gustatory flushing and/or sweating in the cutaneous distribution of the auriculotemporal nerve. This is believed to result from misdirection of regenerated parasympathetic nerve fibers [2] and can occur after parotid surgery or injury, perinatal birth injury, or facial trauma in childhood [13]. (See "Primary focal hyperhidrosis".)

●Trigeminal neuralgia and migraine headache – May cause unilateral flushing, described as "antidromic sensorineural flushing" [1]. This is mediated by a nonclassic autonomic vasodilator system that originates in the brainstem and is not associated with eccrine sweat gland activation.

●Harlequin syndrome – Rare autonomic disorder involving unilateral hyperhidrosis and flushing of the head and neck. It is felt to be secondary to compression or a lesion of the sympathetic regulatory neurons. Flushing is often brought on by exercise or heat [14].

Vasodilator mediated flushing

Rosacea — Acne rosacea is a common inflammatory dermatologic disorder primarily affecting the face. The typical age of onset is between age 40 and 60, though earlier onset is not uncommon. (See "Rosacea: Pathogenesis, clinical features, and diagnosis".)

Rosacea characteristically is associated with telangiectasias as well as papules and pustules. Flushing is one of the earliest reported symptoms, and some have suggested that frequent flushing may be part of the pathogenesis of the disorder [5]. Flushing may be stimulated by emotion, heat or cold, exercise, spicy or hot foods, and alcohol. Patients often complain of a burning sensation. Xerosis, edema, and plaque formation may all occur.

Diagnosis is purely clinical, with persistent facial erythema lasting greater than three months and frequent flushing episodes.

Medications — Many medications cause flushing [2]. The mechanisms responsible include vasodilation, increased prostacyclin synthesis, release of mast cell mediators, and release of other vasoactive mediators [2].

●Vasodilators - Vasodilators, including calcium channel blockers, nitroglycerin, and phosphodiesterase 5 inhibitors (sildenafil, vardenafil, and tadalafil), are the most common medications associated with flushing.

Among calcium channel blockers, dihydropyridine agents (eg, nifedipine, nisoldipine, amlodipine) are more commonly associated with flushing than nondihydropyridine agents (eg, diltiazem and verapamil). Among the dihydropyridine agents, nifedipine is the most commonly associated with flushing [15]. (See "Major side effects and safety of calcium channel blockers".)

●Nicotinic acid - Flushing associated with nicotinic acid therapy is caused by an increase in prostacyclin, which is a potent vasodilator. The flushing response is antagonized by concomitant aspirin administration. Newer slow-release formulations tend to mitigate this effect. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors".)

The selective prostaglandin D2 receptor antagonist laropiprant has been shown to decrease flushing associated with extended-release niacin, but long-term safety data are absent, and it is not clear that the benefit is greater than that achieved by aspirin [16]. This medication is not available in the United States.

●Other medications - Other medications that may produce flushing include [2]:

•Antihypertensives – Beta-blockers and angiotensin-converting enzyme (ACE) inhibitors

•Hormonal therapies – Calcitonin, calcitonin gene-related peptide, thyrotropin-releasing hormone, leuprolide, cyproterone acetate

•Glucocorticoids – High-dose intravenous methylprednisolone, oral triamcinolone, intrasynovial triamcinolone

•Antimicrobials – Vancomycin and amphotericin B (see "Vancomycin hypersensitivity", section on 'Vancomycin infusion reaction')

•Chemotherapy agents – Cyclosporine, doxorubicin, cisplatin, interferon alfa-2, tamoxifen, mithramycin, dacarbazine, and flutamide

•Opiates and related drugs – Morphine and other narcotics, enkephalin analogs

•Metoclopramide

•Gold

•Induction of anesthesia (especially the combination of isoflurane and fentanyl) [17]

•Contrast media

•Nonsteroidal antiinflammatory drugs (NSAIDs)

•Bromocriptine

•Catecholamines

There are also several medications that can cause flushing when taken in combination with alcohol. (See 'Alcohol' below.)

Food ingestion — A variety of foods or their additives may be responsible for flushing. Spicy foods are often implicated, particularly those containing capsaicin, which is derived from red peppers [1]. Other examples include foods containing sodium nitrate (eg, cured meats) and sulfites (used to maintain freshness).

Certain toxins can produce a flushing reaction, believed to be mediated by histamine [1]. Scombroid fish poisoning is commonly associated with flushing and also causes headache, nausea, oral burning, sweating, and diarrhea. Ciguatera fish poisoning is characterized by abdominal pain, nausea and vomiting, diarrhea, flushing, pruritus, dysesthesias, and muscle weakness. (See "Overview of shellfish, pufferfish, and other marine toxin poisoning".)

Monosodium glutamate (MSG) in Chinese food has long been purported to cause a flushing reaction as part of the "MSG syndrome." However, randomized placebo-controlled studies raise questions as to whether MSG reproducibly causes symptoms in most individuals who believe they react to this additive [18,19]. When MSG is ingested in large doses, however, it causes an increase in an acetylcholine-like substance that may result in flushing in susceptible individuals [1]. (See "Allergic and asthmatic reactions to food additives".)

Alcohol — Alcohol (ethanol) ingestion may cause flushing by direct vasodilation of blood vessels in the skin, either due to the alcohol or its metabolite, acetaldehyde. Acetaldehyde triggers catecholamine release from the adrenal medulla and sympathetic nerves [20]. Further, some alcoholic beverages such as wine contain vasoactive substances (such as tyramine, histamine, and sulfites) that contribute to the flushing response [1].

Alcohol is oxidized to acetaldehyde in the liver by alcohol dehydrogenase (ADH), and the rate of this reaction is a key factor in determining whether flushing will occur [21]. In addition, aldehyde dehydrogenase (ALDH) enzymes are also involved in alcohol metabolism and are responsible for the break down acetaldehyde; ALDH-2 deficiency, seen frequently in individuals of Asian descent, results in severe flushing after alcohol ingestion due to a buildup of acetaldehyde [22]. Of note, several studies have suggested that such polymorphisms in ALDH may increase an individual’s susceptibility to esophageal cancer as well as oropharyngeal cancer [23,24].

Many medications, when combined with alcohol, can intensify the flushing response. Disulfiram inhibits ADH and may cause severe flushing, nausea, vomiting, and hypotension. Co-administration of sulfonylurea medication (particularly chlorpropamide, where available) with alcohol is well known to cause flushing that typically begins around the eyes and spreads to the forehead [25]. Other medications that may cause flushing with concomitant alcohol administration include metronidazole, ketoconazole, griseofulvin, cephalosporins, antimalarials [2], and topical calcineurin inhibitors [26].

Additionally, patients with underlying rhinitis or aspirin-sensitive respiratory disease may experience flushing and severe nasal congestion when drinking alcohol. (See "An overview of rhinitis", section on 'Nonallergic rhinitis' and "Aspirin-exacerbated respiratory disease", section on 'Reactions to alcoholic beverages'.)

Carcinoid syndrome — The classic carcinoid syndrome is characterized by flushing and secretory diarrhea; additional symptoms may include profuse sweating, abdominal pain, and bronchospasm. Patients with longstanding carcinoid syndrome may develop valvular heart disease (especially right-sided) and facial telangiectasias. However, only a small subset of patients with carcinoid tumors will experience symptoms of carcinoid syndrome (see "Clinical features of carcinoid syndrome"):

●The carcinoid syndrome is primarily associated with metastatic tumors originating in the distal small intestine and proximal colon (midgut). Since the liver normally inactivates these hormones, there needs to be enough tumor burden downstream of normally functioning hepatic tissue for the mediators to enter the systemic circulation and cause symptoms [4].

The typical flush associated with midgut carcinoids (jejunum, ileum, cecum, appendix) begins suddenly and lasts from 30 seconds to as long as 30 minutes. It primarily involves the face, neck, and upper chest, which become red to violaceous or purple, and is associated with a mild burning sensation (picture 1). Patients often develop a drop in blood pressure as well as tachycardia during a typical flushing episode.

●By contrast, bronchial, gastric, appendiceal and rectal carcinoid tumors (ie, those arising from the foregut and hindgut) can produce the carcinoid syndrome in the absence of metastatic disease because of their direct access to the systemic circulation, but this is rare overall (table 2).

When they occur, the flushes associated with gastric carcinoid tumors are atypical and tend to be red-brown hue, patchy, sharply demarcated, and serpiginous; they are also intensely pruritic. (See "Clinical features of carcinoid syndrome", section on 'Gastric NET variant syndrome'.)

In patients with the bronchial carcinoid variant, the flushes can be very severe and prolonged, lasting hours to days [27]. They may be associated with disorientation, anxiety, and tremor. (See "Clinical features of carcinoid syndrome", section on 'Lung NET variant syndrome'.)

A variety of stimuli may trigger flushing in patients with carcinoid syndrome, including alcohol, chocolate, and ingestion of beef. It is postulated that alcohol and chocolate may release a catecholamine with direct activity on the tumor. The secretion of gastrin may also play a role, particularly in tumors of stomach or foregut origin. Alcohol and beef consumption are known to enhance gastrin secretion, which is one proposed mechanism for their mediating a carcinoid flush [1].

Potential flushing mediators include substance P, histamine, kallikrein, and kinins, although it is not absolutely clear which vasoactive hormone is responsible for symptoms. (See "Clinical features of carcinoid syndrome", section on 'Pathophysiology'.)

The diagnosis of carcinoid syndrome may be made by measurement of 24-hour urine for 5-hydroxyindoleoacetic acid (5-HIAA), a metabolite of serotonin. Diagnosis and tumor localization are discussed in detail elsewhere. (See "Diagnosis of carcinoid syndrome and tumor localization".)

Mastocytosis — Mastocytosis is a rare disorder of mast cell proliferation leading to tissue infiltration. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

Mastocytosis in the pediatric population is typically associated with a skin rash characterized by red-brown papules, macules, or plaques that become urticarial with topical pressure (Darier sign) (picture 2) [28]. Systemic symptoms and abnormalities in the peripheral blood smear are more common in adults. Systemic symptoms are caused by the release of mast cell mediators such as histamine and prostaglandin, which cause vasodilation, flushing, hypotension, tachycardia, and anaphylaxis. Patients may also have abdominal cramping, diarrhea, nausea, vomiting, and fever.

Systemic symptoms may be triggered by narcotic analgesics, as well as by agents that trigger allergic reactions such as intravenous contrast [4]. Other known precipitants include anesthetic agents, aspirin, and other NSAIDs [2].

Two related disorders (ie, idiopathic and monoclonal mast cell activation syndromes) are felt to be distinct from mastocytosis. Patients with these disorders typically present with abdominal pain, dermatographism, and flushing, and they may also report headache, diarrhea, and memory or concentration difficulties. (See "Mast cell disorders: An overview".)

Pheochromocytoma — Pheochromocytoma is a neoplasia of chromaffin cells. The tumor is typically derived from the adrenal medulla and is associated with a release of catecholamines episodically into the systemic circulation.

Headaches, sweating, and tachycardia and hypertension are common; 60 percent of patients have sustained hypertension or labile blood pressure, and 40 percent experience blood pressure elevation only during attacks [2]. Patients may experience either pallor or flushing, though flushing characteristically occurs following, rather than during, a typical attack. A feeling of apprehension is not uncommon, and patients often experience nausea, vomiting, and chest or abdominal pain. Episodes are paroxysmal in nature and last between minutes to hours.

Catecholamine-induced flushing is felt to be regulated by innervation of sympathetic vasodilator fibers of the face, as well as related to increased cardiac output. Diagnosis is made by measuring urinary catecholamine and fractionated metanephrine levels. The clinical presentation and evaluation of pheochromocytoma is reviewed in detail elsewhere. (See "Clinical presentation and diagnosis of pheochromocytoma".)

Medullary thyroid carcinoma — Medullary thyroid carcinoma is a malignant tumor of parafollicular thyroid cells. Tumor cells produce calcitonin, as well as biogenic amines, adrenocorticotropic hormone (ACTH), and corticotropin-releasing hormone [7]. Presentation typically involves facial and upper-extremity flushing, as well as telangiectasias. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging".)

Serotonin syndrome — The serotonin syndrome, associated with increased serotonergic activity in the central nervous system, is most often related to medication side effects and interactions. It is characterized by mental status changes, autonomic hyperreactivity, and neuromuscular hyperreactivity. Diaphoresis and hyperthermia are characteristic autonomic manifestations that may present as flushing. (See "Serotonin syndrome (serotonin toxicity)".)

Anaphylaxis — It is important to consider anaphylaxis in the differential diagnosis of flushing. Flushing occurs commonly with anaphylaxis but generally in conjunction with other symptoms such as hypotension, stridor, hives, and abdominal pain; flushing in isolation is rare [2]. Flushing is seen in almost 50 percent of anaphylactic allergic reactions to medications [29].

Flushing is caused by the release of mast cell as well as basophil vasoactive substances into the circulation. Diagnosis is typically based on clinical presentation, and prompt treatment is imperative. (See "Anaphylaxis: Acute diagnosis", section on 'Symptoms and signs'.)

Pancreatic tumor/VIPoma — Vasoactive intestinal polypeptide (VIP) tumors are non-beta islet cell neoplasms that secrete VIP, prostaglandins, gastric inhibitory peptides, and pancreatic peptides [2]. Typical presentation includes watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome) [7]. Flushing occurs in 20 percent of patients and is attributable to the vasodilator action of VIP. (See "VIPoma: Clinical manifestations, diagnosis, and management".)

Other — A number of less common causes of flushing should be considered in a broad differential diagnosis. These include:

●Dumping syndrome or short-gut syndrome – Tachycardia, flushing, sweating, dizziness, and hypotension related to rapid gut transit.

●Sarcoidosis – Associated with facial flushing due to vasodilation caused by granuloma infiltration of blood vessels in the skin, especially in the lupus pernio variant. (See "Clinical manifestations and diagnosis of sarcoidosis".)

●Hyperthyroidism. (See "Overview of the clinical manifestations of hyperthyroidism in adults", section on 'Skin'.)

●Bronchogenic carcinoma.

●Androgen deficiency in men.

●Renal cell carcinoma – Renal cell carcinoma most often presents with hematuria. The classic triad of gross hematuria, palpable abdominal mass, and flank pain is present in less than 10 percent of cases. Patients may also have fatigue, weight loss, fever, and anemia. Flushing, when it occurs, is felt to be due to the production of gonadotropin-like hormones from the tumor that cause a downregulation of the pituitary gland. (See "Clinical manifestations, evaluation, and staging of renal cell carcinoma".)

●Superior vena cava syndrome [30].

Additionally, other conditions that cause facial erythema may be mistaken for a flushing reaction. Conditions to be considered are:

●Mitral stenosis – Can cause a chronic malar flush associated with cyanosis [4]

●Systemic lupus erythematosus — The classic malar or "butterfly rash" over the cheeks and nose may be confused with flushing

●Photosensitivity reactions

EVALUATION — A summary of an approach to evaluating a patient with flushing is presented in an algorithm (algorithm 1).

A detailed history and physical examination are important in evaluating the patient with flushing. The presence of sweating associated with flushing suggests an autonomic mediated etiology of flushing and distinguishes this from a direct vasodilator etiology.

Patients should be advised to keep a diary of flushing reactions for two weeks, recording associations with food or medication, exertion, or emotional stress as well as symptoms including headache, bronchospasm, abdominal pain, diarrhea, and urticaria [2].

Most systemic disorders that include flushing are distinguished by typical associated symptoms. When history and physical do not yield a probable diagnosis, the patient should undergo assessment for carcinoid syndrome, mastocytosis, and pheochromocytoma, as these are the most common systemic disorders to cause flushing. Initial laboratory evaluation should include a complete blood count and liver function tests, a 24-hour urine for 5-hydroxyindoleoacetic acid (5-HIAA; carcinoid syndrome), serum tryptase (mastocytosis), and a 24-hour urine for catecholamines and fractionated metanephrines (pheochromocytoma). (See "Diagnosis of carcinoid syndrome and tumor localization" and "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis" and "Clinical presentation and diagnosis of pheochromocytoma".)

If initial studies are negative, referral to an endocrinologist is warranted to continue evaluation for etiologies such as a VIPoma, medullary thyroid carcinoma, and other conditions as noted above.

TREATMENT — Treatment is typically tailored to the underlying condition or predisposing factor. Flushing that is a consequence of an exogenous agent is readily treated by removal of the identified offending agent.

Anaphylaxis must be immediately recognized and treated. Patients with flushing as a consequence of a systemic illness should be treated appropriately for the underlying condition. (See "Anaphylaxis: Emergency treatment" and "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors" and "Advanced systemic mastocytosis: Management and prognosis" and "Treatment of pheochromocytoma in adults".)

Other specific conditions may respond to tailored treatment for flushing. For example:

●Menopausal-related hot flashes may respond to a variety of agents [31,32]; the treatment in reviewed elsewhere. (See "Menopausal hot flashes", section on 'Management'.)

●Flushing related to nicotinic acid can be prevented by administration of aspirin prior to a dose of nicotinic acid and by use of longer-acting formulations of nicotinic acid. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Side effects'.)

●Alcohol-induced flushing can be prevented by avoiding alcohol consumption. In addition, in a trial including East Asian participants, application of topical brimonidine (0.33% gel) to the face 30 minutes prior to alcohol consumption decreased facial flushing [33]. Although aspirin and antihistamines have also been reported to prevent flushing, this is not supported by high-quality data [34-37].

●Patients may develop tolerance to calcium channel blocker flushing over time.

●Flushing associated with rosacea has been treated with only minimal success [38,39] and is reviewed in detail elsewhere. (See "Management of rosacea", section on 'Avoidance of flushing'.)

For most benign etiologies, there are no agents that easily and readily eliminate the flushing response. Emotional flushing or blushing may respond to the use of a nonselective beta blocker, particularly when associated with other prominent sympathetic nervous system features such as tachycardia, palpitations, and dry mouth [1]. Individuals who are predisposed to blushing secondary to skin type may find that use of cosmetics with a green tint can offset the redness [1].

Botulinum toxin A has been used with success to treat neck and anterior chest wall flushing [40]. Endoscopic transthoracic sympathectomy has been reported to have short-term effectiveness for severe cases of flushing associated with social phobia [41]. The potential side effects of such procedures must be weighed against possible benefits, and in general we do not recommend either botulinum toxin or sympathectomy for management of flushing.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Rosacea (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Etiologies – The most common etiologies of flushing are fever, hyperthermia, menopause, emotional blushing, or rosacea. Flushing may be categorized as autonomic-mediated or vasodilator-mediated flushing. Autonomic flushing syndromes include thermoregulatory flushing, emotional flushing, and flushing related to a central nervous system disorder. Vasodilator flushing may be caused by exogenous agents (drugs, alcohol, food) or endogenous hormones resulting from systemic disease (table 1). (See 'Etiology' above.)

●Evaluation: History and physical examination – A thorough history and physical is important. Patients should maintain a diary for at least two weeks that documents each flushing episode along with associated activity, food intake, emotional state, and medication use (algorithm 1). Although many conditions that are associated with flushing have nonspecific or no physical examination findings, the presence of other skin lesions, hypertension, thyroid nodule, or abdominal mass may suggest specific etiologies. (See 'Evaluation' above.)

●Laboratory evaluation when cause remains uncertain – Most systemic disorders that include flushing are distinguished by typical associated symptoms. When history and physical do not yield a probable diagnosis, the patient should undergo assessment for carcinoid syndrome, mastocytosis, and pheochromocytoma, as these are the most common systemic disorders to cause flushing. Initial laboratory evaluation should include a complete blood count and liver function tests, and a 24-hour urine for 5-hydroxyindoleoacetic acid (5-HIAA; carcinoid syndrome), serum tryptase (mastocytosis), and catecholamines and fractionated metanephrines (pheochromocytoma) (algorithm 1). (See 'Evaluation' above.)

●Treat underlying cause – Treatment is tailored to the underlying condition or predisposing factor. Avoidance of hot beverages, spicy foods, cured meats, and alcohol may be helpful for those individuals who are predisposed to flushing episodes. (See 'Treatment' above.)