Flushing

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Flushing

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

image

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.

Management strategy

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.

Specific investigations

Serotonin, catecholamines, histamine, and their metabolites in urine, platelets, and tumor tissue of patients with carcinoid tumors.

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.

First-line therapies

imageIce chips B
imageAspirin B
imageHormone replacement A

Second-line therapies

imageH1 and H2 antihistamines C
imageClonidine A
imageSelective serotonin reuptake inhibitors A
imageSerotonin–norepinephrine reuptake inhibitors A

Histamine receptor antagonism of intolerance to alcohol in the Oriental population.

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.

Third-line therapies

imageSomatostatin analogs E
imageExcision for carcinoid tumors D
imageSympathectomy for severe, refractory blushing B
imageβ-Blockers D
imageTopical oxymetazoline E

Treatment of type II gastric carcinoid tumors with somatostatin analogues.

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.

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Flushing

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

image

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.

Management strategy

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.

Specific investigations

Serotonin, catecholamines, histamine, and their metabolites in urine, platelets, and tumor tissue of patients with carcinoid tumors.

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.

Comparison of clinical trials with sildenafil, vardenifil and tadalafil in erectile dysfunction.

Doggrell SA. Expert Opin Pharmacother 2005; 6: 75–84.

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