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PHYSICAL FINDINGSThomas J. Marrie, MD, Section Editor 

Pseudocyanosis: Drug-Induced Skin HyperpigmentationCan Mimic Cyanosis Jason Weatherald, BSc,a Thomas J. Marrie, MDb

a Department of Medicine, University of Alberta, Edmonton; bFaculty of Medicine and Dentistry, Walter C. Mackenzie Health Sciences

Center, University of Alberta, Edmonton, Alberta, Canada.

Cyanosis is an important manifestation of cardiovascular or

pulmonary dysfunction that is defined as a blue or grayish

discoloration of the skin or mucous membranes. It is caused

by an increased amount of reduced hemoglobin circulating

in the blood.1

While there are many different causes of bothcentral and peripheral cyanosis,2  it is important for the

clinician to be aware that several drugs and heavy metals

can result in a bluish or slate-gray pigmentation of the skin

that can be confused with cyanosis. This drug-induced skin

discoloration is sometimes referred to as pseudocyanosis, as

it must be distinguished from true cyanosis.1  This article

will briefly review some of the most commonly implicated

drugs causing pseudocyanotic skin pigmentation.

CLINICAL SCENARIOThe patient, a 70-year-old white man was admitted to the

neurosurgery service for investigation of headaches. The ad-

mitting physician noted bluish discoloration of the skin of his

face and hands (Figure) and made a diagnosis of cyanosis. The

examination of the heart and lungs was normal. The lips were

not cyanotic. It also was noted that only sun-exposed areas of 

skin had a bluish discoloration. Oxygen saturation as deter-

mined by pulse oximetry was normal. Further history revealed

that the patient had been treated with chlorpromazine daily for

the past 20 years. At this point, a diagnosis of chloroproma-

zine-induced skin discoloration was made.

DRUGS THAT CAN CAUSE SKIN PIGMENTATIONRESEMBLING CYANOSIS

ChlorpromazineChlorpromazine was the first and one of the most widely used

conventional antipsychotic drug for treating schizophrenia be-

fore the advent of newer atypical antipsychotic drugs.3 Among

the many reported side effects of prolonged high-dose admin-

istration of chlorpromazine is a diffuse violaceous or purplish

grey discoloration of sun-exposed areas of the face, neck, and

the dorsum of the hands that occurs almost exclusively inwomen,4 but can occur in men, as illustrated by our patient.

Deposition of golden-brown pigment granules around capillar-

ies in the dermis have been shown to be responsible for chlor-

promazine-induced hyperpigmentation.4

AmiodaroneAmiodarone is an antiarrhythmic and a coronary vasodilator

that commonly causes photosensitivity and can, in some

instances, cause a slate gray or purplish pigmentation of the

face.5 This discoloration appears on sun-exposed surfaces

and may be confused with cyanosis when occurring on the

hands, or around the mouth or lips.

MinocyclineThis commonly used antibiotic of the tetracycline family is

a well-documented cause of skin discoloration in several

distributions, including a pseudocyanotic blue-black pig-

mentation of the shins, ankles, and arms (Type II distribu-

tion). It also can cause a bluish discoloration of the oral

cavity, particularly of the bones underlying the oral mucosa.

In some rarer cases, the oral mucosa itself may discolor,

making it even more difficult to discern between pseudo-

cyanosis and true cyanosis.6 Because of the widespread use

of minocycline, it is important to be aware of this side effectand include a thorough drug history so as not to confuse this

pigmentation with cyanotic changes.

HEAVY METALS THAT CAN CAUSEPSEUDOCYANOSIS

Silver (Argyria)Historically, silver salts were used in the treatment of epilepsy

but now are used only for local cutaneous or ocular treatment,

Requests for reprints should be addressed to Thomas J. Marrie, MD,

Faculty of Medicine and Dentistry, 2J2.01 Walter C. Mackenzie Health

Sciences Center, 8440 112 Street, Edmonton, AB T6G 2R7, Canada.

E-mail address: tom.marrie@ualberta.ca

0002-9343/$ -see front matter © 2008 Elsevier Inc. All rights reserved.

doi:10.1016/j.amjmed.2008.01.029

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although application to mucous membranes may result in suf-

ficient absorption to cause side effects such as argyria.7 This

hyperpigmentation caused by systemic silver ingestion is usu-

ally blue to slate-gray, occurring in sun-exposed areas and

occasionally in the sclera, nails, and mucous membranes.8

Despite the decrease in the use of silver in medications, a

recent article noted that the use of colloidal silver in some

alternative health products may lead to a ‘cyanotic’ blue-gray

appearance of the cheeks and nose.9

Gold (Chrysiasis)

Gold salts are used as treatment in several common condi-tions such as rheumatoid or psoriatic arthritis.10 Gold is

deposited permanently in the dermis of light-exposed skin

and, with increasing cumulative dose, may eventually lead

to blue or slate-gray pigmentation of the face and neck.

Chrysiasis is common and under-recognized in patients re-

ceiving gold treatment and, although benign, may be mis-

diagnosed as cyanosis.11

APPROACH TO PSEUDOCYANOSISWhen cyanosis is suspected, the gold standard for eval-

uation is arterial blood gas measurement with co-oxim-

etry. The presence of normal PaO2 and normal hemoglo-

bin concentrat ions suggests abnormal hemoglobin or

abnormal skin pigmentation, as in pseudocyanosis. Clin-

ically, pseudocyanosis also can be distinguished from

cyanosis as it does not blanch with pressure, whereas

cyanotic skin does.1

References1. Stapczynski JS. Respiratory diseases: Cyanosis. In: Tintinalli JE,

Kelen GD, Stapczynski JS, eds. Emergency Medicine: A Comprehen-

sive Study Guide, 6th edn. New York, NY: McGraw-Hill, Medical

Publishing Division; 2004:443-444.

2. Kasper DL, Braunwald E, Hauser S, et al.  Harrison’s Principles of 

 Internal Medicine, 16th edn. New York, NY: McGraw-Hill, Medical

Publication Division; 2005.

3. Bhatara VS, López-Muñoz F, Gupta S. Guest editorial: celebrating the

50th anniversary of the introduction of chlorpromazine in North Amer-

ica and the advent of the psychopharmacology revolution.  Ann Clin

Psychiatry. 2005;17:109-111.

4. Greiner AC, Berry K. Skin pigmentation and corneal and lens opacities

with prolonged chlorpromazine therapy. Can Med Assoc J . 1964;90:663-665.

5. Harris L, McKenna WJ, Rowland E, et al. Side effects of long-term

amiodarone therapy. Circulation. 1983;67:45-51.

6. Eisen D, Hakim MD. Minocycline-induced pigmentation. Incidence,

prevention and management.  Drug Saf . 1998;18:431-440.

7. Levantine A, Almeyda J. Drug induced changes in pigmentation. Br J 

 Dermatol. 1973;89:105-112.

8. Hendrix JD Jr, Greer KE. Cutaneous hyperpigmentation caused by

systemic drugs. Int J Dermatol. 1992;31:458-466.

9. Chang AL, Khosravi V, Egbert B. A case of argyria after colloidal

silver ingestion. J Cutan Pathol. 2006;33:809-811.

10. Dereure O. Drug-induced skin pigmentation. Epidemiology, diagnosis

and treatment.  Am J Clin Dermatol. 2001;2:253-262.

11. Smith RW, Leppard B, Barnett NL, et al. Chrysiasis revisited: a

clinical and pathological study. Br J Dermatol. 1995;133:671-678.

Figure The patient shows signs of chlorpromazine-induced

pseudocyanosis.

386 The American Journal of Medicine, Vol 121, No 5, May 2008