Published on 19/03/2015 by admin
Filed under Dermatology
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Sarah A. Stechschulte, Calvin O. McCall and Jonathan K. Wilkin
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Flushing is a transient reddening of the face and frequently other areas, including the neck, upper chest, pinna, and epigastric area. Flushing is the visible sign of a generalized increase in cutaneous blood flow despite the limited distribution of the erythema.
The first step in the management of a patient with a flushing disorder is a specific diagnosis, because therapy is individualized according to the specific factors causing the flushing, and there is no broad-spectrum antiflushing treatment. The first algorithmic step is to distinguish between autonomic neural-mediated flushing, in which eccrine sweating occurs at the time of the flushing (‘wet flushing’), and direct vasodilator-mediated flushing, in which there is no accompanying eccrine sweating (‘dry flushing’). The dry flushing reactions are further divided into those with prominent dysesthesia and those without.
Patients with dry flushing and no dysesthesia have circulating vasodilator substances that are either exogenous or endogenous. Exogenous vasodilator agents are almost always elicited from the patient’s history. Patient diaries listing all foods, beverages, medications, activities, etc., can not only pinpoint the inciting agent, but also the temporal relationship can be convincing for both the patient and physician. The usual strategy for most vasodilator agents is simple avoidance of the agent, although niacin (nicotinic acid) therapy for hyperlipidemia and tamoxifen for breast cancer are important exceptions for which antiflushing therapies can permit continued treatment with the offending agent.
Finally, endogenous circulating vasodilator agents, typically from underlying neoplasias, are suggested by both multiple stimuli that provoke flushing and prominent features associated with the flushing attack (e.g., itching, urticaria, hypertension, sweating, and diarrhea.) Prominent features associated with the flushing can occur with cholinergic urticaria, cholinergic erythema, anxiety reactions, intolerance to foods, menopausal flushing, the dumping syndrome, diabetes mellitus, pancreatic cholera, medullary carcinoma of the thyroid, pheochromocytoma, multiple endocrine neoplasia syndromes II and III, mastocytosis, and carcinoid syndrome.
5-Hydroxyindoleacetic acid urine test
Histamine urine test
Serotonin blood/platelet test
Histamine plasma test
Wilkin JK. Clin Dermatol 1993; 11: 211–23.
The first step in diagnosing a flushing reaction is to determine the mechanism: autonomic neural-mediated flushing, which includes eccrine sweating (wet flush), versus flushing from agents that act directly on vascular smooth muscle (dry flush). This review describes the three types of blushing, including the type that responds to a low-dose, long-acting non-selective β-blocker such as nadolol 40 mg every morning. The use of aspirin to block niacin-induced flushing, and amitriptyline to treat facial dysesthesia, is described.
Wilkin JK. Arch Dermatol 1992; 128: 1387–9.
Chemotherapy causes of flushing are reviewed, along with other drugs that cause flushing.
Wilkin JK. In: Rook AJ, Maibach H, eds. Recent Advances in Dermatology. New York: Churchill Livingstone, 1983; 157–87.
This reviews categories of flushing reactions with catalogs of specific causes.
Kema IP, Schellings AM, Meiborg G, Hoppenbrouwers CJ, Muskiet FA. Clin Chem 1992; 38: 1730–6.
Kema IP, de Vries EG, Slooff MJ, Biesma B, Muskiet FA. Clin Chem 1994; 40: 86–95.
The platelet serotonin level has a higher sensitivity for the detection of carcinoid tumors and is more consistently elevated than urinary 5-HIAA (5-hydroxyindoleacetic acid). Also, in contrast to urinary 5-HIAA, platelet serotonin is not influenced by the consumption of a serotonin-rich diet.
The quantitative 24-hour urinary 5-HIAA level is useful in the follow-up of carcinoid tumors with a high serotonin production rate. It is also useful initially for diagnosis, but only when it is positive during a low-serotonin diet. If the urinary 5-HIAA level is not elevated in a patient with flushing and other features characteristic of carcinoid, the platelet or blood serotonin level should be obtained.
Doggrell SA. Expert Opin Pharmacother 2005; 6: 75–84.
Flushing was identified as an adverse effect in the clinical trials of each of these selective phosphodiesterase-5 (PDE-5) inhibitors.
Patients with significant flushing should be aware that PDE-5 inhibitors may worsen their flushing.
Wilkin J. J Invest Dermatol 1981; 76: 15–8.
It is heat, not caffeine, which causes the flushing from drinking hot coffee.
Sucking on ice chips can abort mild menopausal, thermal, or spicy food-induced flushing.
Wilkin JK, Wilkin O, Kapp R, Donachie R, Chernosky ME, Buckner J. Clin Pharmacol Ther 1982; 31: 478–82.
Not only does aspirin block niacin flushing, but other cyclo-oxygenase inhibitors (non-steroidals) also block this prostaglandin-mediated flushing reaction. Importantly, the inhibition of cyclo-oxygenase does not reduce the lipid-lowering effect of niacin.
Although 975 mg of aspirin 1 hour before taking the niacin will greatly suppress the flushing reaction, a substantial number of the patients taking niacin are already taking non-steroidal agents. Generally, all that is needed is to change the time of dosing to 1 hour before the niacin.
Truitt EB, Gaynor CR, Mehl DL. Alcohol 1987; 1: 595–9.
Eight Oriental and three Occidental subjects sensitive to alcohol manifested as facial flushing were given 0.64 g of aspirin 1 hour before orange juice with vodka at levels known to cause flushing. Facial flushing was markedly reduced after aspirin pretreatment.
Bech P, Munk-Jensen N, Obel EB, Ulrich LG, Eiken P, Nielsen SP. Psychother Psychosom 1998; 67: 259–65.
In a double-blind, placebo-controlled study of 105 early postmenopausal women, hormone replacement therapy (HRT) was superior to placebo for many symptoms, including hot flushing.
Although effective for controlling hot flashes, HRT has associated risks and is contraindicated for many women.
Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 2000; 49: 398–400.
Four adults in Pennsylvania had facial flushing, nausea, diarrhea, sweating, headache, metallic taste, and burning sensations in the mouth occurring within 5 minutes to 2 hours after eating tuna. Scombroid fish poisoning has been associated primarily with the consumption of tuna, mahi-mahi, and bluefish.
The association of features of histamine toxicity and the ingestion of fish should alert the physician to the possibility of scombroid fish poisoning. Both H1 and H2 antihistamines may be sufficient symptomatic therapy, and epinephrine and systemic corticosteroids considered for more severe cases.
Miller NS, Goodwin DW, Jones FC, Pardo MP, Anand MM, Gabrielli WF, et al. J Nerv Mental Dis 1987; 175: 661–7.
Each of 17 subjects received placebo, diphenhydramine 50 mg, and cimetidine 300 mg, singly and in combination, 1 hour before drinking ethanol in a soft drink at a level sufficient to produce flushing. Cimetidine given alone blocked the flushing significantly more than diphenhydramine alone or placebo, but less than the combined antihistamines.
Patients should be screened for alcohol abuse, and warned about gastritis and sedation before combination pretreatment consisting of cimetidine and a non-steroidal are prescribed. The author has found that such combination pretreatment greatly reduces the flushing and headache caused by red wine in sensitive subjects.
Burstein HJ, Winer EP. N Engl J Med 2000; 343: 1086–94.
Table 4 of this paper summarizes a variety of non-estrogenic agents used to ameliorate hot flushes. Selective serotonin reuptake inhibitors received the most favorable comments.
Although the focus of this article is on breast cancer survivors, the list of non-estrogenic agents is useful for all women in whom estrogenic agents are contraindicated or not desirable. Clonidine patches are frequently associated with a contact dermatitis, so the author favors oral clonidine.
Lethaby AE, Brown J, Marjoribanks J, et al. Cochrane Database Syst Rev 2007; (4): CD001395.
The current evidence indicates no clinically meaningful effect for phytoestrogens.
Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, et al. JAMA 2006; 295: 2057–71.
In a review of published randomized controlled trials, there was evidence for the effectiveness of selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, clonidine, and gabapentin in controlling menopausal hot flashes. However, the efficacy of these non-hormonal treatments was less than that of estrogen.
Umland EM. J Manag Care Pharm 2008; 14: S14–19.
Non-pharmacologic modalities such as relaxation techniques and ways to avoid overheating are described along with pharmacologic interventions in a review of strategies for reducing hot flashes during the menopausal transition and perimenopause.
Non-hormonal drugs do not provide the full effectiveness provided by HRT; however, non-hormonal drugs coupled with strategies to avoid overheating, sucking on ice chips, and relaxation techniques may be sufficient to avoid resorting to HRT. Clonidine 0.1 mg orally daily may be better accepted by patients than fluoxetine, paroxetine, or venlafaxine, which carry the designation of ‘antidepressant.’
Tomassetti P, Migliori M, Caletti GC, Fusaroli P, Corinaldesi R, Gullo L. N Engl J Med 2000; 343: 551–4.
This is a report of three patients with multiple type II gastric carcinoids treated with lanreotide or octreotide acetate. In all three patients there was a reduction in size and number of the carcinoid tumors after 6 months of somatostatin analog treatment, and complete disappearance of tumors after 1 year. A report of regression of a type III gastric carcinoid with octreotide is also cited.
Although all three types of gastric carcinoid tumor are usually removed surgically, somatostatin analogs, especially the longer-acting octreotide acetate (20 mg intramuscularly every 28 days), provide a successful medical option.
Licht PB, Pilegaard HK. Thorac Surg Clin 2008; 18: 223–8.
Although the title might imply flushing disorders more generally, the specific focus is on the uncontrollable, rapid onset of blushing in response to embarrassment from the attention of others.
Hsu CC, Lee JY. Arch Dermatol 2012; 147: 1258–60.
Although there is a lack of objective laboratory evidence for the direct effects β-blockers have on cutaneous blood vessels during episodes of flushing, fewer symptoms have been observed in patients taking β-blockers.
Low-dose carvedilol may be an effective treatment for severe rosacea flushing.
Craige H, Cohen JB. J Am Acad Dermatol 2005; 53: 881–4.
Eight of nine patients experienced diminished symptoms and flushing episodes while taking various doses of propranolol.
Side effects must be monitored such as hypotension, bradycardia, dizziness, fatigue, somnolence, and sexual dysfunction.
Shanler SD, Ondo AL. Arch Dermatol 2007; 143: 1369–71.
Two patients with treatment-resistant erythematelangectatic rosacea experienced improvement in erythema, decrease of erythematous flares (flushing), and symptomatic relief of burning and stinging with once daily topical oxymetazoline, without rebound flares or tachyphylaxis.
Treatment of Skin Disease Comprehensive Therapeutic Strategies 4e
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Ice chips
Aspirin
Hormone replacement
H1 and H2 antihistamines
Clonidine
Selective serotonin reuptake inhibitors
Serotonin–norepinephrine reuptake inhibitors
Somatostatin analogs
Excision for carcinoid tumors
Sympathectomy for severe, refractory blushing
β-Blockers
Topical oxymetazoline
