The red face: Flushing disorders

The Red Face: Flushing Disorders JONATHAN KEITH WILKIN, MD

F lushing is a transient reddening of the face and frequently other areas, including the neck, upper chest, pinnae, and epigastric area.’ Flushing is

A the visible sign of a generalized increase in cutaneous blood flow* despite the limited distribution of the erythema. Because therapy is individualized according to the specific factors causing the flushing, the first step in the management of a patient with a flushing disorder is a specific diagnosis.

Many patients and a few referring physicians may misuse the term flushing. Often these patients will have a drug-induced photosensitivity reaction, lupus erythema- tosus, seborrhea, or other conditions leading to a red face. Thus, it is important at the outset to determine that the patient does, indeed, have a true flushing reactions.

Once it has been established that the patient does have flushing reactions, it is important to examine the patient’s skin carefully (with cosmetics removed) and to take a careful history. I always inform patients at the outset that I have a specific order in which I like to record the information, and I emphasize that early on I will be asking them for their opinion regarding provocative agents and causes.

I begin with the provocative and palliative factors that the patient has identified. In this particular section of the history I record the patient’s theories and understanding about his or her flushing reaction. After cataloguing these provocative and palliative factors, it is important to determine the “morphology” of the reaction, anamnestically, if the patient is not flushing at the time of the visit. The reaction may consist of a single phase, which comes and goes, or there may be discrete phases or stages. The color

From the Division of Dermatology, Ohio State University, Columbus, Ohio.

Address correspondence to: Jonathan Keith Wilkin, Division of Derma- tology, Ohio State University, 456 W Tenth Avenue, Room 4731 UHC, Columbus, OH 43210.

0 1993 by Elsevier Science Publishing Co., Inc. l 0738-081x/93/$6.00

can be patchy or confluent, or it can vary from bright pink to cyanotic. Flushing may be preceded or followed by pallor or cyanosis. It is extremely important to determine whether perspiration accompanies the reaction and, if so, whether it accompanies the erythema, the pallor, or the cyanosis.

Associated findings, when prominent, can be useful in narrowing the differential diagnosis. Bronchospasm, abdominal cramps, diarrhea, headache, urticaria, hypotension, tachycardia, and pruritus can provide important clues. Occasionally, flushing will be associated with multiple vague systemic complaints without a clear physical cause. Anxiety, depression, and somatization disorders must be considered in these patients. Flushing with urticaria and/or pruritus suggests a histamine-mediated reaction. Mastocytosis, mast cell leukemia, or a significant challenge with a direct mast cell-degranulating substance, for example, vancomycin, must be considered.

Finally, the temporal characteristics must be defined for the flushing reaction. These include the onset of the flushing reaction (first time it ever occurred), the original frequency of the reaction, the current frequency of the reaction, the sequential timing and duration of the specific features during each flushing reaction, and the presence of any overall pattern that corresponds to the diur- nal, day-of-the week, monthly, or seasonal patterns. This is usually the least accurate portion of the patient’s history. Data of much better quality can be obtained from a 2-week diary in which the patient records qualitative and quantitative aspects of flushing reactions and lists all exogenous agents, especially food, drugs, physical exertion, alcoholic beverages, emotions, stress, and occupational exposures. This 2-week diary is especially helpful when the cause is not immediately obvious.

Accordingly, if the diagnosis is not apparent at the initial visit, the patient will return in 2 or 3 weeks with the diary. If, after evaluation of the patient’s diary the diagnosis remains obscure, the patient should be given a diet

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eliminating additives and foods high in histamines and various foods and drugs that affect urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) excretion or mea- surement. Other nonspecific factors should similarly be eliminated to isolate the specific provocative factors which will facilitate a specific diagnosis. As menopause exacerbates flushing, vasomotor control should be achieved with estrogen supplementation or with low- dose clonidine therapy. Overheating and alcohol can lower the threshold for flushing and these must be avoided. The consequent reduction in the frequency and intensity of the flushing reactions often facilitates identification of the specific causative factors. Also, the elimi- nation diets prepare the patient for possible urine collec- tions for histamine and 5-HIAA.

Despite the systemic nature of many stimuli that cause flushing, the redness appears limited to the “blush distribution.” Even so, increases in cutaneous blood flow out- side the blush distribution can be discerned.2 The facial color reaction, erythema or cyanosis, depends on the temperature, the superficial vascular capacitance for er- ythrocytes in facial skin, and the visibility of the vasculature just beneath the epidermis. As flushing is a phenomenon of transient vasodilation, it can be considered an abnormality of cutaneous vascular smooth muscle control.

There is dual control of vascular smooth muscle by autonomic nerves and by circulating vasoactive agents.3 The circulating vasoactive agents may be exogenous, for example, calcium channel blocking drugs and nicotinic acid (niacin), or endogenous, for example, histamine and prostaglandins. Flushing reactions may be broadly classi- fied into those resulting from the direct action of vasodilator agents and those mediated by autonomic nerves. Autonomic nerves also control eccrine sweat glands, so that when vasodilation is mediated by autonomic nerves, it is accompanied by eccrine sweating. It is important to emphasize that this rule applies only to perspiration at the firm of erythema. Eccrine sweating during pallor is not specific for the type of flushing reaction but indicates, instead, the severity of the flushing reaction with probable hypotension and compensatory sympathetic reflexes. Agents that act directly on the vascular smooth muscle without neural mediation cause flushing reactions in which there is no increased eccrine sweating.

Thus, the first algorithmic step in diagnosing a flushing reaction is to determine the mechanism: autonomic neural-mediated flushing, which includes eccrine sweating (“wet flush”), versus flushing form agents that act directly on vascular smooth muscle (“dry flush”) (Table 1). The second algorithmic step is to determine whether pain or a burning sensation is associated with the dry flush. If so, then an antidromic sensorineural flushing

Table 1. Classification of Flushing Reactions

I. Autonomic neural-mediated (wet flushes) II. Direct vasodilator-mediated (dry flushes)

A. Antidromic sensory neural-mediated (dysesthesia) B. Circulating vasodilator agent (no dysesthesia)

1. Exogenous (elicited in history) 2. Endogenous (associated features)

reaction must be considered. If the patient has painless dry flushes, then the third algorithmic step is to determine whether the vasoactive agent is endogenous or exogenous. Exogenous, direct-acting vasodilators are discov- ered by asking the patient about foods, drugs, diagnostic tests, and other things. Vasodilator medications must be rigorously sought from the patient’s history. Although drugs such as calcium channel blockers, nitroglycerin, and nicotinic acid may be obvious, other drugs have flushing as a less frequent, but occasionally prominent, side effect. The side effect profile of each drug a patient takes should be reviewed for associations with flushing reactions. If dry flushing cannot be associated with a drug or dietary agent, if a wide variety of agents seem to non- specifically provoke the flushing reaction, or if it occurs spontaneously, and, especially, if there is a significant associated finding, such as diarrhea, headache, or pruritus, then an underlying systemic disease of which flushing may be a manifestation must be considered.

Autonomic Neural-Mediated Flushing

The most common autonomic neural-mediated flushing reactions are the thermoregulatory flushing reactions, both normal and inappropriate varieties. The most common of these are hyperthermia resulting from exercise and hyperthermia resulting from exogenous heat. Only rarely do patients state these as their primary complaints. It is widely recognized that the first physiologic reaction to warm ambient temperature is cutaneous vasomotor.4 Occasionally, patients will be extremely sensitive to these varieties of hyperthermia. Control can often be achieved without drugs, using ice chip therapy. A cold wet towel around the neck and face, or a cooling fan blowing directly on the face. The ice chips should be held in the mouth, not chewed or swallowed, for maximum effec- tiveness. Chilling the oral cavity likely reduces the temperature at the anterior hypothalamus, thus increasing the threshold for hyperthermia.5 The simple ingestion of iced water can lower oral temperatures for periods lasting longer than 30 minutes. 6 Cold water may also stimulate oropharyngeal receptors which lead to physiologic reactions,7 in addition to the countercurrent heat exchange- mediated central cooling.5 It has also been shown that cold air blown on the face and inspired leads to a sympa-

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thetically mediated cutaneous vasoconstiction in the hands and forearms8 This peripheral vasoconstriction would conserve body heat, implying that this “wind reflex” is actually a thermoregulatory response. By employing these nonpharmacologic maneuvers, patients can avoid or lessen the severity of hyperthermia-related flushing.

Oral thermal-induced flushing appears to be a special case of hyperthermia, limited largely to the thermal econ- omy of the head. As mentioned earlier, the ingestion of hot beverages and the resultant increased heat in the oral cavity may cause flushing by a countercurrent heat exchange mechanism. 5 The increased heat in the tissues surrounding the oral cavity increases the temperature of the blood draining this region, thereby raising the temperature of the blood in the internal jugular vein. A countercurrent head exchange provided by the parallel con- tiguous arrangement of the internal jugular vein and common carotid artery would lead to an increase in temperature of the blood flowing via the internal carotid artery to the base of the brain. At this site the body’s thermostat in the anterior hypothalamus reacts to very slight increases in temperature of the arterial blood supply, leading to physiologic heat-dissipating mechanisms, such as flushing and eccrine sweating. Thus, contrary to many textbook accounts, the active agent in hot coffee causing flushing is heat, not caffeine.

As the average temperature of choice for hot drinks is approximately 60”C,9 oral thermal-induced flushing can be avoided simply by allowing hot beverages and foods, such as soups, to cool before ingestion. Alternatively, one may follow a flush-generating entree with a cooling sher- bet in the manner practiced by many of the more elegant restaurants between servings in a multicourse dinner. Al- though purportedly given to cleanse the palate, gastrono- mists may well have long appreciated the utility of this maneuver to avoid flushing or perspiration during such an elegant meal.

Another setting in which thermoregulatory flushing can be intense is immediately following the downsetting of the body’s thermostat at the zenith of a fever. Before the fever is said to have completely broken, significant stores of body heat must be dissipated by cutaneous vasodilation and perspiration, typically most intense on the head and neck. Aspirin and other antipyretic agents can provoke this heat-dissipating reaction, but otherwise these agents do not directly cause the flushing. The severity of the flushing reaction with a breaking fever can be lessened with ice chip therapy, cold compresses to the face, and drinking of cold liquids.

Inappropriate thermoregulatory flushing at the climacteric represents the most common variety of flushing disorder seen among women in my clinic. Although

menopausal flushing is common, there is a male climacteric flushing reaction that is not very common.1° Primary male climacteric flushing that occurs as a result of de- creasing testosterone levels in the normal maturation processes is rare. lo The drop in circulating testosterone must be substantial and acute before climacteric flushing will occur, and this occurs only rarely during aging. Sec- ondary male climacteric flushing is much more common and is due either to surgery or to drug therapy.‘O The two leading surgical causes are orchiectomy, often for advanced prostatic carcinoma, and following bilateral her- nia repair when the vascular supply to the testes is com- promised in the repair. Pharmacologic causes include antiandrogens (eg, flutamide) and gonadotropin-releasing hormone agonists (eg, leuprolide acetate).

Likewise, menopausal hot flashes can be primary, that is, the result of naturally occurring age-associated loss of ovarian function, or secondary. The secondary causes include surgical removal of the ovaries and pharmacotherapy with antiestrogens (eg, tamoxifen) or gonadotropin- releasing agonists (eg, leuprolide acetate).

Although menopausal flushing is associated with the cessation of menses, some women develop menopausal- like symptoms in their thirties while still having cyclic menses. The important clue is that the flushing will occur most frequently during the last week of the cycle, that is, during the 7 days just before the onset of menses. Often, this pattern will not be detected unless the patient records flushing reactions and catamenial data in a diary. The menopausal flushing reactions in women still having cyclic menses are qualitatively identical to those occurring in women with cessation of menses. Hot beverages, physical exertion, and emotional upsets can provoke menopausal flushing. The drenching perspiration that follows the prodromal sensation of intense overheating can be the most distressing component of the reaction. Characteristically, there are waking episodes at night accompanied by sweating.

A variety of drugs cause a “pharmacologic” menopause, including 4-hydroxyandrostenedione, danazol, tamoxifen, clomiphene citrate, decapeptyl, and leuprolide. Menopausal symptoms can also be seen anytime after puberty when there is surgical loss of ovarian function, most commonly by ovariectomy. Bilateral tubal liga- tion can also compromise the vascular supply to the ovaries, possibly resulting in menopausal symptoms.

Hormonal replacement therapy is the most common solution for this variety of flushing. For personal reasons or because of medical contraindications, however, some women will choose a nonhormonal therapy. A combination preparation marketed by Sandoz (Bellergal-S tablets) contains phenobarbital, ergotamine tartrate, and levoro- tatory alkaloids of belladonna. As each tablet contains

214 WILKIN Clinics in Dermatology 1993;11:211-223

40 mg of phenobarbital, this preparation may be habit- forming.

My nonhormonal therapy of choice for menopausal flushing requires some extra effort on the part of the patient. The smallest-dosage form of clonidine hydro- chloride marketed at present is the O.l-mg tablet. The patient should be instructed to crush one tablet (if it is not scored) and to take half of the powder in the morning and the other half in the evening before going to bed. This represents 0.05 mg twice daily and is sufficient for many patients. 11*12 Some patients may require 0.1 mg twice daily. An adequate therapeutic trial requires 5 weeks of treatment. I have seen several patients abandon therapy prematurely after 1 or 2 weeks, only to achieve excellent control when the clonidine was reinstituted for longer periods later. Many patients experience sedation and/or dry mouth during the first week after starting the clonidine or during the first week after increasing the dosage. After a week or two these side effects are no longer a problem for most patients.

The second major category of autonomic neural-mediated flushing reactions comprises those associated with emotions. Erythrophobia represents the most extreme form of blushing in which the pathologic fear of blushing occurs. Even though blushing is not a real source of danger, erythrophobia is often accompanied by an avoidance of a variety of otherwise normal situations because they may provoke blushing. Although many mild blushes seemingly lack accompanying perspiration, sweating does occur with severe blushing.13@g*) A minor blush can precipitate an embarrassed feeling, which will lead to further blushing. Thus, the blushing- thought cycle can intensify the severity of the blushing.13@*3)

It is useful for the physician to determine what type of blusher the patient may be. Psychologically sensitive blushers are shy and overconcentrate on private thoughts and feelings. These are the people who are always won- dering what others are thinking or noticing about them. In my experience these patients benefit most from a clinical psychologist or a psychiatrist. The second group of blushers are the physiologically sensitive. Minor, healthy emotional responses can trigger particularly intense physiologic responses. These patients often identify heart awareness, racing heart, pounding heart, dry mouth, and other symptoms as features associated with the blushing reaction. When such sympathetic features are prominent, the patient often does extremely well with a low-dose, long-acting nonselective beta blocker, such as nadolol, 40 mg every morning,” or the “migraine regimen” of long-acting propranolol. Although the long-acting propranolol is less expensive in the United States, the less lipophilic nadolol seems to be associated with a lower prevalence of depression as a side effect. Patients selected

for beta-blocker therapy must not have contraindications such as asthma and peripheral vascular disease, and they must be informed that the beta blocker will greatly reduce the intensity of the blush, but perhaps not eliminate it completely. The goal of therapy is to reduce the heart rate by approximately 8 to 10 per minute. Most patients achieve this with the lowest dose, and I have never seen a patient respond at a dose of nadolol greater than 80 mg per day if he or she did not respond at a lower dose. The final type of blusher is the individual who is anatomically predisposed. In these patients the reddening is simply more visible because of limited pigmentation and the presence of many blood vessels close to the surface of their skin. These patients often do quite well with a sheer green cosmetic such as Christian Dior No. 327 or Shiseido controlling green. Many other green cosmetics work equally well; however, it is important that the cosmetic be a sheer product, so that is does not appear green after it has been applied to the skin but merely optically extin- guishes the bright red color.

Obviously, only a few blushers fit completely into one of the three types, that is, psychologically sensitive, physiologically sensitive, and anatomically predisposed. Most patients represent a combination of two or three, and the goal of the physician is to determine the propor- tional involvement to select the appropriate management strategy. For those who are psychologically sensitive to a minor degree, especially those unwilling to see a clinical psychologist or a psychiatrist, relaxation exercises can be recommended.15 It should, however, be remembered that most patients with phobic disorders at first regard their condition as physical in origin and seek medical rather than psychiatric help.16

Ekman and co-workers, independently and recently, have advanced our understanding of blushing. Activity in the autonomic nervous system is emotion-specific.17J8 Not only have the cardiovascular components of blushing been characterized, but the gesture function of blushing has also been suggested.19 They view blushing as an appeasement gesture that diffuses the likelihood of an unfavorable evaluation and potential rejection when an individual’s status within a valued group is in jeopardy. As pointed out by Edelmann, blushers are overly con- cerned with the opinions of others and with their stand- ing in groups and relationships.r3 Leary and Meadows view blushing as a nonverbal apology for a perceived breaking of a social rule. l9 Edelmann’s useful book for patients, Coping with Blushing (1990), provides the basis for changing patterns of thinking in erythrophobia.13 In addition to such techniques directed at improving self-es- teem, muscle relaxation techniques, hypnotic control of blushing,20 and biofeedback therapy’l also can be effi- cacious.

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WILKIN 215 FLUSHING DISORDERS

The final category of autonomic neural-mediated flushing reactions are usually accompanied by compel- ling neurologic signs or symptoms. In addition, thermoregulatory flushing or simple blushing is readily distinguished from this category. Central blushing may originate with events anywhere from the vasomotor center in the pons and medulla through the various higher levels of control to the cortex. For example, as a component of anxiety reactions flushing stimuli begin in these higher centers.22

Tumors and other lesions that compress or destroy the walls of the third ventricle frequently cause disturbances of autonomic function. 23 Diencephalic autonomic epilepsy consists of attacks of flushing, salivation, profuse sweating, pilomotor activity, dilation of the pupils, increase in heart rate, spasm of the sphincters, and rise in blood pressure. 23 This rare syndrome of paroxysmal autonomic discharge accompanied by generalized seizures includes high plasma catecholamines at the peak of the reaction.24 Clonidine will block this rise in plasma catecholamines and the autonomic features, including the flushing. Other manifestations, such as olfactory or epigastric aura and the generalized seizures, are not altered by clonidine therapy. Carbamazepine, on the other hand, will eliminate not only the generalized seizures and the epileptic prodrome but also the autonomic features, including the flushing. Diencephalic epilepsy has occurred from a tumor of the choroid plexus in the third ventricles, from a tumor in the wall of the third ventricle, and with acute obstruction of the cerebrospinal circulation.23 Dien- cephalic epilepsy likely results from acute distention of the third ventricle, which activates the autonomic centers residing within its wall. Flushing has been related to tumor involvement (glioblastoma multiforme) of the preoptic area. 25 Flushing has also occurred with a colloid cyst of the third ventricle. 26 An encapsulated tumor that periodically pressed on the thalamus led to epileptic attacks which included flushing.*’

Autonomic hyperreflexia, a syndrome seen with tran- verse spinal cord lesions, includes flushing of the face, neck, and shoulders. The flushing results from vasomotor reflexes induced by stimulation of intact pressor receptors in the aortic arch, carotid sinus, and cerebral vessels caused by neurogenic hypertension.** The triad of headache, hyperhidrosis, and flushing occurs in 85% of these patients.29

Flushing can occur with both idiopathic orthostatic hypotension and orthostatic hypotension with hyperbra- dykininism (Streeten’s syndrome).30 Excessive perspiration and headache can occur with idiopathic orthostatic hypotension. Streeten’s syndrome is characterized by orthostatic lightheadedness, purple discoloration of the legs in the upright posture, facial erythema, flushing (espe-

cially in recumbency), and an excessive fall in pulse pressure and rise in heart rate occurring immediately with orthostasis.

Unilateral facial flushing may occur transiently early in the development of Homer’s syndrome.31 The syndrome described by Homer comprises partial ptosis, miosis with pupillary constriction in response to light, and loss of sweating on the involved side of the face. After the injury leading to Homer’s syndrome, there is absence of sweating and cooler and paler skin on the involved side of the face. The contralateral, normal side will demonstrate flushing with the proper stimuli such as hyperthermia and simple emotional blushing.32

Similarly, after unilateral cervicodorsal ganglionectomy, heating the body causes flushing on the normal side of the face, while the sympathectomized side remains dry and pale. The line of demarcation in the mid- sagittal plane is definite. 33 Not only is hyperthermic flushing limited to the normally innervated side after unilateral cervicodorsal ganglionectomy, but also emotional blushing is liited to the normally innervated side.34 Thus, emotional blushing requires intact sympathetic nerves.

Postganglionic sympathetic sudomotor fibers pass through the periarterial plexus of the external carotid artery or are carried into the cranium via the periarterial plexus of the internal carotid artery to leave with branches of the trigeminal nerve.35 The cervical sympathetic outflow mediates both thermoregulatory and emotional flushing and sweating.36 In fact, during heat stress the times and onset of sweating and active vasodilation are usually nearly simultaneous.37 Loss of these reactions occurs with interruption of the cervical sympathetic neural pathway. Gustatory flushing and sweating are, however, preserved and can become exaggerated in some patients.36

Physiologic gustatory sweating and flushing are sym- metric over the face, even after cervical sympathectomy on one side. The full syndrome consists of sweating, flushing, salivation, lacrimation, and nasal secretion (“salsa snuffles”). This reaction is likely mediated by parasympathetic fibers traveling with the facial or glos- sopharyngeal nerves .36 Lee felt that pain fibers played a major role in the reaction, as the degree of response varied with the degree of burning sensation.38 He emphasized that chewing chiles caused an immediate reaction, whereas substances that stimulate the taste fibers without causing pain do not give rise to gustatory flushing and sweating. Also, there is no evidence for any esophageal or stomach receptors for this reaction. Warming the body facilitates and cooling the body inhibits gustatory flushing and sweating.

In pathologic gustatory sweating and flushing, how-


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ever, taste fibers play a predominant role.38 Postherpetic gustatory flushing and sweating is localized to the scarred areas of the third division of the trigeminal nerve following facial herpes zoster in childhood.39 Any strongly fla- vored, particularly salty or sour, food provokes the flushing and sweating, which lasts 10 to 15 minutes after a latency of a few seconds. As thermoregulatory sweating and flushing were diminished in the scarred area, postherpetic gustatory flushing and sweating appear to be analogous to Frey’s syndrome in which gustatory flushing and sweating follow damage to the auriculotemporal nerve in the region of the parotid gland. It is possible that some of the vasodilation that occurs with pathologic gustatory flushing and sweating results from antidromic im- pulses in the trigeminal nerve releasing vasoactive substances, such as substance I’ and CGRP, in the superficial dermis.

Antidromic Sensorineural Flushing

In addition to the classic autonomic vasodilator system supplying facial skin, there appears to be a nonclassic autonomic vasodilator system of the facial skin originat- ing in the brain stem and leaving directly with the trigeminal nerve.‘O In addition, the trigeminal sensory fibers may directly participate in the production of vasodilation. Facial flushing develops during thermocoagulation of the Gasserian ganglion. 41 There is a close association between the distribution of the facial flush in one or more divisions of the trigeminal nerve and the subsequent distribution of postoperative analgesia. In fact, trigeminal ganglia are connected to cerebral blood vessels by nerve fibers that contain substance P.42 As substance P can dilate arteries, increase vascular permeability, and activate cells that participate in inflammation, such trigeminovascular fibers have been suggested as a mechanism for the pain and vasodilation of migraine. Some patients with migraine will have an associated facial flushing or even “facial migraine” which includes episodic facial neural- gia, flushing, and lacrimation, along with the past history of migraine.43

In contrast, the facial flushing that accompanies cluster headaches appears to result from autonomic dysfunc- tion.” In the full expression of cluster headache flushing there is facial hyperhidrosis, conjunctival injection, tear- ing, nasal stuffiness, and rhinorrhea.

Various other disorders involving autonomic nervous system functions include flushing reactions, inter alia tumors in the posterior fossa, spinal cord lesions, familial dysautonomia (Riley-Day syndrome), and hypothermia in infants. Paroxysmal flushing attacks may also occur in Parkinson’s disease45 although the mechanism is not un- derstood. Diabetic autonomic neuropathy can be asso-

ciated with flushing and facial sweating, and gustatory stimuli may be prominent.

Circulating Vasodilator Flushing

The high-dose nicotinic acid regimen employed in the treatment of hyperlipidemia routinely provokes flushing early in the course of therapy. Those who do not observe flushing after nicotinic acid are usually employing insufficient amounts of nicotinic acid, challenging patients who have already become tolerant to nicotinic acid flushing, or confusing nicotinamide, which rarely provokes flushing, with nicotinic acid. Over a decade ago it was demonstrated that aspirin blocks nicotinic acid-induced flushing. 46 Subsequently, it was shown in a human in vivo local cutaneous model, using the methyl ester of nicotinic acid, that chemically dissimilar cyclooxygenase inhibitors, but not an antihistamine, blocked nicotinate- provoked cutaneous vasodilation.” More recently, it has been shown that nicotinic acid ingestion in normal human volunteers leads to the biosynthesis of substantial amounts of prostaglandin D,.4* As the release of prostaglandin D2 was not accompanied by a release of histamine, the origin of the prostaglandin D, is not likely to be the mast cell. Further, the substantial quantities of prostaglandin D, found during the flush support the view that it is the mediator of the nicotinic acid-induced flushing reaction. Additional studies with the methyl ester of nicotinic acid applied topically to forearm skin demonstrated an increase in the levels of prostaglandin D, in the antecubital venous blood.49 These studies support the view that the cutaneous vasodilation that follows oral administration of niacin or topical administration of methyl nicotinate is due primarily to a biosynthesis of prostaglandins from a niacin-responsive cell that resides in the skin4’ and extend this information by identifying prostaglandin D, as the specific vasodilator prostaglandin involved.

As the vasodilator mediating the nicotinic acid-provoked flushing reaction is a prostaglandin, the severe flushing can be suppressed by aspirin, indomethacin, or other nonsteroidal anti-inflammatory agents. It is important to realize that the inhibition of cyclooxygenase does not reduce the antihyperlipidemic effect! Even so, tolerance will eventually develop in most patients using the high-dose niacin regimen, if they do not skip doses. Stern et al evaluated the mechanism of the tolerance to nicotinic flushing.50 Because tolerance to nicotinic acid flushing could result from alterations in nicotinic acid metabolism, decreased release of prostaglandin D,, or development of tolerance to prostaglandin D,, they measured the development of tolerance using objective indicators of skin blood flow and related skin blood flow changes in plasma


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nicotinic acid and prostaglandin levels. They demonstrated in normal human volunteers that plasma levels of nicotinic acid did not decrease with the development of tolerance; however, plasma levels of 9c~, 1 I/?-prostaglandin F,, a stable metabolite of prostaglandin Dz, became undetectable in most subjects with the development of tolerance. Thus, tolerance was clearly associated with the decreased biosynthesis of the mediator, prostaglandin

D,* Flushing is a side effect of all of the calcium channel

blockers (nifedipine, verapamil, diltiazem, etc). Even quinidine has been associated with flushing. The organic nitrates, such as nitroglycerin, provoke intense flushing particularly during the first weeks of therapy, but this is followed by the development of tolerance. Even a brief drug holiday can lead to a loss of tolerance and subsequent flushing when the drug is reinstituted. Amy1 nitrite and butyl nitrite, both potent vasodilators, are widely used today as recreational drugs by homosexual men. Choline@ flushing is a side effect of a variety of cholinergic drugs, such as metrifonate, an anthelminthic, which is metabolized into the cholinesterase inhibitor dichlor- vos. Tricyclics can produce a central syndrome that includes flushing, dry skin, urinary retention, and memory loss. All ages are affected, but the elderly are predisposed.’

Although flushing can occur during the natural course of parkinsonism, the use of bromocriptine has been accompanied by flushing in these patients.5* Flushing also accounts for more than 10% of all adverse reactions to intravascularly administered contrast media.52 Flushing is a usual side effect of exogenous adenosine 3,5-monophosphate. 53 This may support a role for purinergic nerve mediation for some types of flushing reactions. With carbon monoxide poisoning and during clinical testing of the hypercapnic ventilatory response, typically in patients with obstructive sleep apnea, flushing and headache occur.

Thyrotropin-releasing hormone (TRH) provokes a flushing reaction. 5*,55 Oral triamcinolone provoked flushing reactions in 5 of 17 patients with psoriatic arthri- ti~.~~ In another report a patient had pronounced flushing of the face and chest after intrasynovial corticosteroid injection for psoriatic arthritis, reproducible with as little as 5 mg microcrystalline triamcinolone acetonide given intraarticularly. 57 Flushing is one of the most frequent side effects during the use of high-dose pulse methyl- prednisolone in rheumatoid arthritis.

Flushing is a frequent occurrence during cyclosporine therapy. Flushing occurs during combination anesthesia with isoflurane and fentanyl.5* Finally, although caffeine does not provoke flushing,5 intense flushing may occur in the caffeine withdrawal syndrome.59

Selected cancer chemotherapeutic agents are also associated with flushing reactions: doxorubicin, mithramy- tin, dacarbazine, cisplatin, and cY,-interferon. Also, the antiemetics alizapride and metoclopramide have caused flushing.60

Other drugs that cause flushing include vancomycin, rifampin, and opiates.

Restaurant Flushing Reactions

Spicy foods, especially those containing capsaicin, the active agent in red pepper, routinely provoke flushing in sensitive individuals. Sodium nitrite, found in cured meats, may cause headache and flushing. Sulfites, such as potassium metabisulfite, can cause wheezing and flushing. Other sulfiting agents, often referred to by the restaurant industry as “potato whiteners,” include sodium and potassium bisulfite, sodium metabisulfite, sodium sulfite, and sulfur dioxide. Sulfites can also be components of certain drug formulations.

Although the National Restaurant Association has recommended their discontinuation, sulfiting agents still may be found in settings such as salad bars, where they are used to maintain freshness of foods during prolonged exposure to the atmosphere. Even if a restaurant does not add sulfiting agents, they may already be present in foods purchased from suppliers. The manager of the restaurant may not even be aware of sulfites added by the suppliers. Unless it is known with absolute certainty that sulfites have not been added, it is prudent for the sulfite-sensitive individual to select foods that are not sulfited, such as chicken, eggs, meat, and cheese.61 Further the sulfite content of wine can be relatively high when compared with other alcoholic beverages. The estimated sulfite consumption level per capita in the United States for food is 6 mg per day (expressed in sulfur dioxide equivalents). In comparison, 200 mL of wine contains 30 mg.62 Tartrazine has also been reported to cause flushing in aspirin-sensitive individuals.63

Food poisoning syndromes can also include flushing. Other features are vomiting and headache, with or without diarrhea, and a short incubation. Food contaminated with Bacillus subtilis leads to such a syndrome within 15 minutes to 3 hours of ingestion, suggesting mediation by a toxin.M

Flushing following the ingestion of a fishy food pre- sents a clinical setting in which the physician must be especially well informed ad discerning. Ciguatera fish poisoning must be distinguished from scombroid fish poisoning. Ciguatera is internationally the most common type of serious marine food poisoning.ti Although especially common in the Caribbean and the Pacific, it can occur anywhere fresh fish is marketed by air, as evi-


dented by two cases in Vermont associated with barracuda. Ciguatera fish poisoning can be diagnosed by the characteristic syndrome in a person who ate an ecologi- cally suspect fish, especially when ciguatoxin can be detected in the fish tissues.66

The ciguatera poisoning syndrome typically includes vomiting, diarrhea, abdominal pain, pruritus, flushing, temperature reversal, dysesthesia, diffuse tingling pain, burning of the tongue, gingival and dental dysesthesia, myalgia, weakness, and ataxia.65*66 The syndrome occurs after an incubation period of only a few hours. Although usually self-limiting, the syndrome can run for years. “Sensitization” lasting years can occur in which symptoms recur after ingestion of a variety of foods or alcohol. Treatment is supportive and nonspecific.

Ciguatoxin and related toxins are produced by coral reef dinoflagellate plankton species. Herbivorous fishes consume these dinoflagellates while foraging on coral reefs. Disturbances in the ecology of coral reefs often precede ciguatera outbreaks. Storms, heavy rains, tidal waves, earthquakes, dredging, explosions, construction works, and nuclear test explosions have been specifically cited.65 The highest concentrations of toxins are found in large carnivorous fish that feed on the herbivorous fish, and these predacious reef fish are most likely to be toxic.66 Cooking does not destroy the toxin, as it is heat stable.

An immunoassay test is available for detecting ciguatoxin in fish tissues.67 If ciguatera poisoning is suspected, public health authorities should be consulted immediately to prevent additional cases and to determine the source of the suspected fish. A wide variety of coral reef fish have been implicated: barracuda, grouper, red snap- per, amberjack, surgeonfish, and sea bass.66

Scombroid fish poisoning, like ciguatera poisoning, is more common in coastal areas, but it can also occur anywhere fish is shipped, even such centrally isolated loca- tions as Indiana.68 The incubation period of 10 to 30 minutes is much shorter than for ciguatera and often the fish is described as having a tangy, bitter, hot spicy, peppery, “Cajun”, or sharp taste. As is the case with ciguatera, cooking does not destroy the heat-stable toxins.

The clinical presentation of scombroid fish poisoning is sufficiently characteristic to suggest the diagnosis. Headache, nausea, facial flushing, sweating, oral burning, abdominal pain, diarrhea, vomiting, and urticaria are common findings. Flushing appears to be more frequent with scombroid fish poisoning than with ciguatera poisoning. Urticaria (when present), the absence of sensory and motor neurologic disturbances, the shorter incubation period, and the distinctive taste of the fish help make the clinical diagnosis of scombroid fish poisoning.69,70 The syndrome is self-limiting, with symptoms lasting less than 8 hours.

Although the causative agent has been referred to as scombrotoxin, histamine formed in fish muscle has a significant causative role. Histamine production by the action of bacterial decarboxylases on the naturally occurring histidine in the fish muscle has been considered the likely scenario since the 194O~.~l-~~ Histamine can be present without obvious signs of spoilage, and free histamine levels of 1.0 mg/lOO g of fish muscle may accumu- late in 24 hours in improperly refrigerated fish.73 Further- more, histamine is not destroyed by cooking. Finally, the symptoms usually respond promptly after parenteral antihistamine therapy. 74 The symptoms are often mild and self-limiting, however, minimizing the importance of this piece of evidence supporting the primacy of histamine in scombroid fish poisoning.

Considerable doubt exists over whether histamine is both necessary and sufficient to cause scombrotoxism. The chief objection has been the inability to reproduce the toxic state by administering histamine by mouth to healthy volunteers in quantities comparable to those obtained by eating spoiled fish.75,76 Histamine may be only poorly absorbed from the gastrointestinal tract or the intestinal, and/or hepatic metabolism of histamine might be sufficient to prevent similar reactions from oral histamine.76 This notion has led to the search for other substances in spoiled fish that potentiate the activity of hist- maine by enhancing its absorption or suppressing its metabolism.77 Also, other thermostable substances, such as saurine,78 might act in an additive manner with histamine to produce scombrotoxism.

Recently, it has been shown convincingly that scombroid fish poisoning is associated with increases in the urinary excretion of histamine well above levels required to produce toxicity. 79 Because the increases in the excretion of both histamine and N-methylhistamine were of similar magnitude in scombrotoxic patients, potentiation of histamine toxicity as a result of the suppression of its catabolism by histamine N-methyltransferase did not occur. Also, the absence of evidence for increased endogenous release of prostaglandin D, suggests that the large quantities of histamine are not of mast cell origin.79 The most probable source of the excess histamine is the spoiled fish; however, inhibitors of diamine oxidase, en- hancers of histamine absorption, and other potentiators of histamine toxicity still may be necessary cause(s) of scombrotoxism. Histamine seems to be a necessary, but insufficient, cause.

The dark-meat fishes, especially of the scombrid and scomberesocid families, are particularly high in histidine. Insufficient refrigeration before consumption has led to the acute syndrome in both scombroid mackerel-like fish, such as tuna, skipjack, bonito, albacore, and mackerel, and nonscombroid fish, such as herring, sardine, pil-

Clinics in Dermatology 1993:11:211-223

WILKIN 219

FLUSHING DISORDERS

chard, anchovy, mahimahi, bluefish, marlin, amberjack, yellowtail, kahala, kahawai, and the Japanese saury.

When the clinical presentation is characteristic and the syndrome follows ingestion of a dark-meat fish, especially one of the varieties listed, a presumptive diagnosis of scombrotoxism can be made. Given the important role of histamine, parenteral antihistamine therapy can be recommended along with general supportive measures for those patients with severe symptoms, especially within the first 2 hours of the syndrome. Rapid resolution is expected, so that overtreatment is to be avoided in mild cases.

Alcohol-Provoked Flushing Reactions

The mechanisms for alcohol-provoked flushing are quite complex. First, other vasoactive pharmacologic agents found in alcoholic beverages, especially the fermented alcoholic beverages, may be important. Tyramine, histamine, sulfites, and long-chain alcohols and aldehydes can be important. Tyramine is found not only in red wines, but also in aged cheeses. Cheese and red wine led to flushing in a patient taking isoniazid,W presumably because of the inhibition of monoamine oxidase by isoniazid, leading to a tyramine-provoked pheochromocytoma-like reaction.81*82 Red wine varieties that have a negligible tyramine content can still routinely provoke migraine attacks, whereas vodka does not.83 The probable active agents in red wine with neglible tyramine content are the phenolic flavonoids, including catechins and anthocyanins. These substances likely have direct effects on blood vessels, inhibit phenol sulfotransferase (PST), or both. In fact, phenolic substances are usually the most plentiful constituents in dry red wine after alcohol, tar- taric acid, and unfermentable sugars.84 It has suggested that patients with dietary migraine may have a deficit of l?ST.85 Some people may already have deficient activity, and flavonoid phenols in red wine which are potent inhibitors could put them at significant risk.86 PST conjugates low concentrations of phenol and a variety of exogenous phenolic compounds. 87 Potentially toxic compounds generated by the gut flora, and normally conjugated by PST, could lead to toxic reactions after certain dietary exposure. 88 Although a role for PST and phenolic substances in headache and flushing, both disorders of vasodilation, remains to be conclusively characterized, it is prudent for patients who are sensitive to food- and beverage-provoked flushing to avoid aged cheeses and red wines.

Heavy red wines, bitter chocolate, and mature cheese also contain 2-phenylethylamine.8 2-Phenylethylamine is structurally similar to phenylpropanolamin, ephedrine, and amphetamine. Neurologic complications of phenyl-

propanolamine and related agents can lead to a headache of acute onset with blood pressure elevationgo In fact, as little as 3 mg of phenylethylamine can provoke migraine in chocolate-sensitive migraine patients.91 These authors emphasize that although cheese and tyramine-containing foods and beverages are frequently implicated in migraine attacks (which are vasodilator in nature), the most common dietary trigger is chocolate that does not contain tyramine but does contain large amounts of phenylethylamine.91 In contrast to serotonin, norepinephrine, and tyramine, phenylethylamine is capable of readily cross- ing the blood-brain barrier.92

Monoamines normally do not gain access to the circulation from the gut, because they are oxidized by monoamine oxidase (MAO) in the intestinal mucosa. Insuffi- cient enzyme activity in the gut may predispose the affected individual to a variety of vasoactive conditions and sequelae, such as migraine, flushing, and rosacea. Unless MAO is inhibited, the effects of administered phenylethylamine are fleeting. Phenylethylamine is unique among the amines in exerting amphetamine-like effects. Brain levels of phenylethylamine are increased approximately fourfold in animals by alcohol and A9-te- trahydrocannabinol. 93 Both of these mood-elevating agents cause flushing in humans. Phenylethylamine is probably the major mediator for the reticular activating system, serving as humoral substrate for attention.93

Thus, red wine appears to be a hopeless pharmacopeia of tyramine, phenylethamine, long-chain alcohol, and aldehydes, along with ethanol. Although the pharmacologic mechanisms are far from clear, Kaufman has shown that the cyclooxygenase inhibitors ibuprofen and aspirin, when given prophylactically, will inhibit the red wine- provoked headache. 94 Similarly, I have found that nonsteroidals given prophylactically will also lessen the severity of the red wine-provoked flushing reaction. Further, the combination of an H,-antihistamine along with a nonsteroidal given prophylactically appears to give the best protection from red wine flushing. The obvious disadvantages are that nonsteroidals can worsen the alcohol-provoked gastritis and the H, -antihistamine can enhance the alcohol-induced drowsiness. Further, in a study evaluating the opioid mediator theory of alcohol- provoked flushing, we found that pretreatment with naltrexone, an opiate antagonist, did not lessen the severity of the alcohol-provoked flushing reaction.95

It is well known that sensitivity to ethanol-induced flushing varies among individuals, with increased sensitivity frequent among a variety of mongoloid popula- tions, especially Chinese and Japanese, and a few North American Indian groups, This ethnic predisposition to alcohol-provoked flushing correlates with significantly higher levels of circulating acetaldehyde, which is a vaso-


active agent. The biochemical defect may be an increased conversion of the alcohol to the aldehyde, a decreased catabolism of the aldehyde, or, most probably, a combination of both. As in the case of oral nicotinic acid and the local in vivo human cutaneous model using methyl.nicotinate, a cognate paradigm of the systemic reaction to alcohol can be observed in human forearm skin. In this model, we have demonstrated that it is really the aldehydes, not the lower aliphatic alcohols, that are primarily responsible for the vasodilator reaction.96*97

In a biochemically related phenomenon, a variety of drugs and occupational exposures will predispose otherwise normal individuals to the alcohol-provoked flushing reaction. Disulfiram exerts its principal effect by the non- competitive inhibition of aldehyde dehydrogenase, the enzyme that degrades acetaldehyde. This leads to acetaldehyde accumulation. A similar reaction occurs when alcohol is taken after other drugs, such as calcium carba- mide, phentolamine, griseofulvin, metronidazole, ketoconazole,98 oral hypoglycemic agents, and/?-lactams with a methyltetrazolethiol side chain.

Exposure to various industrial agents can also predispose to the alcohol-provoked flush. Such agents include tricholoroethylene, N-dimethylformamide, and N-butyr- aldoxime. Carmofur, an anticancer drug, also causes a disulfiram-like reaction.99 Some people appear to be especially susceptible to combined ethanol and xylene exposure and may develop flushing.‘OO Occupational “de- greaser” flushing occurs in workmen drinking beer after exposure to a variety of industrial solvents, and carbon disulfide has been associated with a disulfiram-like effect. Also, ingestion of certain types of mushrooms (Co- prims) can predispose to the alcohol-provoked flush. Fi- nally, it should be pointed out that alcohol can provoke flushing in a variety of settings such as carcinoidosis, mastocytosis, Hodgkin’s disease, and the climacteric (menopause).

Fallacious Flushing Reactions

Monosodium glutamate (MSG) is widely regarded as a cause of flushing in the Chinese restaurant syndrome; however, a true MSG-induced flushing reaction must be extremely rare, if it occurs at all.‘O’ MSG is certainly found in a wide variety of non-Chinese restaurants today, and many Chinese restaurants have actually eliminated MSG from their recipes. Patients should be encouraged to look beyond MSG toward other dietary agents, such as red pepper (capsaicin), other spices, nitrites, sulfites, thermally hot foods and beverages, and alcoholic beverages.

Although the term rosacea flushing has been used, there is no evidence to date to suggest that flushing in

rosacea is qualitatively different from flushing in the general population. Quantitative differences based on such factors as the reactivity of the vasculature, the visibility of the vasculature, and the enhanced release of endogenous mediators are, however, quite likely.’

Finally, the notion that chlorpropamide alcohol flushing identifies a discrete subset of patients with diabetes mellitus has been discredited.102

Strategies for the Management of the Flushing

As described earlier, the hrst algorithmic step is to distin- guish between autonomic neural-mediated and direct vasodilator-mediated flushing. If the patient has one of the former conditions that causes “wet flushing,” then specific therapy depends on specifically characterizing the abnormality. These conditions and their therapies have been described in this review. The patients who have “dry flushing” must be subdivided into two groups: those with prominent dysesthesia and those without. A dry flush with dysesthesia implicates an antidromic sensorineural-mediated reaction. Both flushing and migraine may respond to either the low-dose clonidine regimen recommended earlier for climacteric flushing or the low-dose nadolol therapy recommended earlier for emotional flushing (blushing). When the dysesthesia is particularly prominent and does not respond to clonidine or nadolol, then amitriptyline 10 mg per day can be considered. I increase the daily dosage by 10 mg every 2 weeks up to a total daily dosage of 50 mg. If the side effects are minimal but there is still no response, then low doses of carbamazepine can be added and gradually increased. Most of these patients will benefit greatly from the partic- ipation of a neurologist in their care.

Those 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. Pa- tient diaries listing all food, beverages, medications, activities, and so on, can be extremely helpful not only to document the agent, but to convince the patient of its role. The usual strategy for most exogenous vasodilator agents is simply avoidance of the agent. Many vasodilator drugs will rapidly produce a significant tolerance, permitting the patient to continue therapy without flushing or the need for pretreatment; however, aspirin pretreatment is often required for high-dose nicotinic acid therapy for patients with hyperlipidemia.

The combination of aspirin and an H,-antihistamine given 1 or 2 hours before an alcoholic beverage will greatly reduce the intensity of the flushing reaction. Aspirin, however, increases the risk of gastritis and anti- histamines increase the risk for sedation and drowsiness.



Such a pretreatment regimen should be avoided, except in rare instances, such as an annual religious observance that may require a red wine to which the patient is inordi- nately sensitive.

Finally, endogenous circulating vasodilator agents, typically from underlying neoplasias, are suggested by multiple stimuli that provoke flushing (rather than one or a few provocative agents) and prominent features associated with the flushing attack. The differential diagnosis is usually generated from the prominent associated fea- ture. Itching or urticaria with flushing suggests circulating mast cell mediators. Examples include systemic mastocytosis and mast cell leukemia. Flushing following an attack of hypertension, pallor, tachycardia, palpations, and sweating suggests pheochromocytoma. Flushing with diarrhea can occur with cholinergic urticaria, cholinergic erythema, anxiety reactions, intolerance to foods, menopausal flushing, the dumping syndrome (a common complication of gastric surgery), diabetes mellitus, pan- creatic cholera (watery diarrhea syndrome, Verner- Morrison syndrome), medullary carcinoma of the thy- roid, pheochromocytoma, multiple endocrine neoplasia syndromes II and III, mastocytosis, and carcinoid syndrome.lo3 As most reference works on flushing reactions concentrate on the rare, but important, systemic disorders that are associated with flushing reactions, especially mastocytosis, carcinoid syndrome, and pheochromocytoma, these conditions are only briefly mentioned in this review so that space can be devoted to the more common, but not as life-threatening, varieties of flushing reactions. Recently, the strategies for diagnosing flushing reactions in the cancer chemotherapy patient have been described.@ All of the accounts emphasize that there is no broad-spectrum antiflushing drug. It is imperative that a specific diagnosis be secured before beginning specific pharmacotherapy for flushing.

Drug Names

amitiptyline aspirin clonidine ibuprofen indomethacin nadolol naltrexone propranolol LA

Elavil Ecotrin Catapres Motrin Indocin Corgard Trexan Inderal LA

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The red face: Flushing disorders

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