Amiodarone-induced blue man syndrome: a case report

Abstract

Background
Amiodarone is one of the most commonly used and effective antiarrhythmic drugs to treat ventricular and supraventricular arrhythmias. Besides its advantages, this drug has side effects like liver, digestive, pulmonary, thyroid, neural, skin, optical, hematologic, psychiatric, and cardiac complications. Blue-gray cutaneous discoloration, also known as blue man syndrome, is an undesirable and unusual side-effect of chronic amiodarone therapy in less than 3% of patients.

Case presentation
This report presents a 51-year-old Caucasian man treated for the past 3 years with amiodarone and implantable cardioverter defibrillators due to his ventricular arrhythmia and cardiomyopathy, without any follow-up visit to his doctor. He was referred to the medical center for blue-gray discoloration on his nose and cheeks, which had started to appear in the last 3 weeks.

Conclusion
Considering the findings obtained in this report and the numerous side effects of amiodarone, the blue-man syndrome is a rare yet important finding of this drug which may influence the patient’s daily life. It is recommended that all patients under treatment with this drug be notified about its side effects and visit their doctors regularly. Regarding the high therapeutic value of this drug, the lack of any association between blue man syndrome and other complications, and the related aesthetic problems, the role of the caregiver becomes much more critical in the prescription of amiodarone.

Full text

SamadiTakaldanietal.
Journal of Medical Case Reports (2023) 17:248
https://doi.org/10.1186/s13256-023-03954-6
CASE REPORT Open Access
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Journal of
Medical Case Reports
Amiodarone-induced blue man syndrome:
acase report
Ali Hossein Samadi Takaldani1, Mohammad Negaresh2* , Maryam Salimi2 and Nima Javanshir3
Abstract
Background Amiodarone is one of the most commonly used and effective antiarrhythmic drugs to treat ventricular
and supraventricular arrhythmias. Besides its advantages, this drug has side effects like liver, digestive, pulmonary,
thyroid, neural, skin, optical, hematologic, psychiatric, and cardiac complications. Blue-gray cutaneous discoloration,
also known as blue man syndrome, is an undesirable and unusual side-effect of chronic amiodarone therapy in less
than 3% of patients.
Case presentation This report presents a 51-year-old Caucasian man treated for the past 3 years with amiodarone
and implantable cardioverter defibrillators due to his ventricular arrhythmia and cardiomyopathy, without any follow-
up visit to his doctor. He was referred to the medical center for blue-gray discoloration on his nose and cheeks, which
had started to appear in the last 3 weeks.
Conclusion Considering the findings obtained in this report and the numerous side effects of amiodarone, the
blue-man syndrome is a rare yet important finding of this drug which may influence the patient’s daily life. It is rec-
ommended that all patients under treatment with this drug be notified about its side effects and visit their doctors
regularly. Regarding the high therapeutic value of this drug, the lack of any association between blue man syndrome
and other complications, and the related aesthetic problems, the role of the caregiver becomes much more critical in
the prescription of amiodarone.
Keywords Amiodarone, Blue man syndrome, Skin toxicity
Introduction
Amiodarone is one of the most commonly used and
effective antiarrhythmic drugs to treat ventricular and
supraventricular arrhythmias. However, amiodarone has
the electrophysiological properties of all four classes of
antiarrhythmic drugs [1]. Most of its effects are catego-
rized under Class III. is drug exerts its antiarrhythmic
effect by prolonging phase 3 of the cardiac action poten-
tial. Besides its advantages, this drug has side effects such
as liver, digestive, pulmonary, thyroid, neural, skin, opti-
cal, hematologic, psychiatric, and cardiac complications
[2, 3].
Blue-gray cutaneous discoloration, also called blue
man syndrome, is an uncommon side-effect of amiodar-
one therapy [2]. It results from the accumulation of sil-
ver chemical compounds in the patient’s skin and has no
proven relationship with the other side effects of ami-
odarone therapy [3, 4]. Blue man syndrome occurs in
only 1% to 3% of patients. It is an undesirable yet benign
side-effect; however, the affected patients feel stressed
due to changes in the observable areas of their bodies [3].
e blue-gray discoloration of the skin is not specific to
amiodarone therapy, other drugs, such as minocycline,
*Correspondence:
Mohammad Negaresh
mohamad.negaresh@gmail.com
1 Department of Internal Medicine (Pulmonology Division), School
of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
2 Department of Internal Medicine, School of Medicine, Ardabil University
of Medical Sciences, Ardabil, Iran
3 Faculty of Medicine, School of Medicine, Ardabil University of Medical
Sciences, Ardabil, Iran
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SamadiTakaldanietal. Journal of Medical Case Reports (2023) 17:248
chlorpromazine, chloroquine, and hydroxychloroquine,
may also cause some level of blue-gray discoloration. Fur-
thermore, it has also been observed in argyrosis, methe-
moglobinemia, and ochronosis [5].
Case presentation
e patient was a 51-year-old Caucasian man referred
to the medical center with chief complaints of short-
ness of breath and cutaneous lesions on his cheeks and
nose (Fig.1). Shortness of breath had begun 3years ago
with the severity of modified medical research council
(mMRC) II, but the severity had increased to mMRC III
in the previous week, and dry coughs had also emerged.
In the physical examination, a generalized wheeze was
auscultated. He had no organomegaly and was not
edematous.
e patient mentioned no familial or psychosocial
history. He had a history of hospitalization 3 years
before due to palpitation and dyspnea without chest
pain. He was also diagnosed with ventricular tachycar-
dia (VT) and ventricular fibrillation (VF). In addition,
he was diagnosed with hypertension (HTN) due to a
blood pressure of 180/100. His echocardiography pre-
sented an ejection fraction (EF) of 20%, severe global
hypokinesia, and mild mitral regurgitation (MR). How-
ever, angiography indicated no severe coronary dis-
ease in that hospitalization. Considering the patient’s
VF and the diagnosis of cardiomyopathy, implantable
cardioverter defibrillators (ICD) were implanted. After
being discharged from that cardiac center, amiodarone
with a dose of 200mg twice daily, furosemide tab 20mg
twice daily, spironolactone tab 25mg twice daily, carve-
dilol tab 6.25mg twice daily, losartan tab 25mg once
daily, rosuvastatin tab 10mg once daily, and acetylsali-
cylic acid (ASA) tab 80mg once daily was prescribed.
Since that day, he did not refer to any medical center
for follow-up and has continued using amiodarone with
a daily dose of 400mg and a cumulative dose of about
438 g. e physical examinations revealed that upon
referral to the medical center, his oxygen saturation
(SpO2) was 96%, blood pressure was 100/70 mmHg,
body temperature was 36.5, and heart rate was 80bpm.
e patient reported smoking (20 p/y) since he was 19.
However, he stopped it 10years ago.
e skin lesions had started to appear in the last
3weeks. e lesions were in the form of blue-gray dis-
colorations in the skin of the nose and cheeks.
After admission, amiodarone was discontinued and
replaced with mexiletine cap 200mg thrice daily due
to skin lesions. ICD analysis revealed a VT episode ter-
minated by a 20J shock that lasted 38min. e results
of thyroid function tests were normal. In the 12-lead
electrocardiography (ECG) obtained from the patient,
P pulmonale and left anterior hemiblock were detected.
Moreover, in precordial leads, evidence of incomplete
right hemiblock was observed. e serial troponin
assay (× 3) and polymerase chain reaction (PCR) test
for coronavirus disease 2019 (COVID-19) showed neg-
ative results. e lung images indicated air trapping
(Fig.2), and the results obtained from the pulmonary
function test showed signs of obstructive lung disease,
both in favor of pulmonary emphysema. e patient
was discharged after a week with mexiletine cap 200mg
thrice daily, ipratropium bromide spray four puffs four
times daily, and fluticasone/salmeterol 250/50mg two
puffs twice daily.
Discussion andconclusion
is case presents a rare adverse effect of amiodarone,
which, despite the cosmetic impact, does not detract
from the value of amiodarone treatment. e patient
mentioned no history of consuming silver-containing
drugs or substances for argyrosis diagnosis [6]. Methe-
moglobinemia is also another differential diagnosis. It is
diagnosed by the presence of cyanosis and unexplained
hypoxemia in the patient. Further findings such as pal-
lor, fatigue, headache, cyanosis, weakness, dysrhythmias,
depression of the central nervous system, metabolic
acidosis, seizures, coma, and death may be evident in
patients with methemoglobinemia [7]. None of these
Fig. 1 Blue man syndrome. Blue-gray discoloration on cheek and nose (yellow arrow)
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SamadiTakaldanietal. Journal of Medical Case Reports (2023) 17:248
symptoms were available in our patient. Also, our patient
expressed no other drug usage that could cause this blue-
gray discoloration.
e US Food and Drug Administration (FDA) has
confirmed amiodarone for treating life-threatening and
recurrent ventricular arrhythmias such as ventricu-
lar fibrillation or ventricular tachycardia. Furthermore,
prospective trials have indicated that using amiodarone
increases the chance of survival and improves the health
status of patients suffering from myocardial infarc-
tion with left ventricular systolic dysfunction and heart
failure up to class III, in terms of the New York Heart
Association (NYHA) classification. Despite many favora-
ble advantages of amiodarone, it has numerous adverse
effects, of which skin reactions are one of the less dan-
gerous side effects. e most common skin reaction is
photosensitivity, with a 24%–57% prevalence among the
patients. e mechanism of skin photosensitivity seems
to be related to the active metabolites produced by ultra-
violet rays and oxygen free radicals. After consuming a
cumulative dose of at least 40g of amiodarone, erythe-
matous or eczematous skin lesions might emerge. ey
are itchy and are mainly observed in areas of the body
that are exposed to sunlight, that is, hands, face, and
neck. In rare cases, other side effects include alopecia,
toxic epidermal necrolysis, exfoliative dermatitis, vas-
culitis, polyserositis, bullous dermatosis, and pustular
psoriasis [2]. In amiodarone-induced skin lesions, the
appearance of blue-gray discoloration is an undesirable
and uncommon side-effect of this therapy [8]. e biopsy
of the discolored skin indicated dense bodies attached to
the lysosomal membrane, similar to lipofuscin [9]. Ami-
odarone might accelerate normal cellular autophagocyto-
sis and lead to an increase in the production of lipofuscin,
which is then accumulated in lysosomes. Phototoxic
lesions explain the distribution of discolorations in body
areas exposed to sunlight [10]. Discoloration might also
result from drug deposition in the skin cells of these sun-
light-receiving body parts [11].
Due to its pharmacokinetics and metabolism, oral ami-
odarone has a slow absorption rate with a bioavailability
of about 40%. Its effects emerge a few days or weeks after
starting the consumption of the drug, and the highest
level of plasma is achieved after 3–7weeks. is drug is
highly lipophilic and has a long half-life (35–100days).
Bioavailability might be inhibited or intensified under
the effect of age, liver disease, or interaction with other
drugs. Amiodarone mainly accumulates in adipose tis-
sue, liver, lung, and skin because of its lipophilic nature.
Furthermore, it is mainly expelled via biliary excretion in
the digestive system. A smaller amount of it is also dis-
charged via urinary excretion [1, 12].
ere seems to be a threshold dose for the skin side
effects of amiodarone to emerge. If the daily dose is
reduced to 200 mg or lower and sufficient protection
against sunlight is secured, those side effects are revers-
ible [13]. It is recommended that patients who are photo-
sensitive or have developed blue-gray discoloration avoid
exposure to sunlight, wear clothes that protect them
against sunlight, and use sunscreens. Although other
undesirable effects of amiodarone must be monitored
and controlled, there is no relationship between them
and the blue-gray cutaneous discoloration [14].
Considering the findings obtained in this report and
the numerous side effects of amiodarone, the blue-man
syndrome is a rare yet important finding of this drug
which may influence the patient’s daily life. It is recom-
mended that all patients under treatment with this drug
be notified about its side effects and visit their doctors
regularly. Regarding the high therapeutic value of this
drug, the lack of any association between blue man syn-
drome and other complications, and the related aesthetic
problems, the role of the caregiver becomes much more
critical in the prescription of amiodarone.
Abbreviations
mMRC Modified medical research council
VT Ventricular tachycardia
VF Ventricular fibrillation
HTN Hypertension
EF Ejection fraction
Fig. 2 Chest imaging indicated air trapping in favor of emphysema.
The red arrow shows the patient’s Implantable cardioverter
defibrillators (ICD)
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SamadiTakaldanietal. Journal of Medical Case Reports (2023) 17:248
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MR Mitral regurgitation
ICD Implantable cardioverter defibrillators
SpO2 Oxygen saturation
p/y Pack/year
ECG Electrocardiography
PCR Polymerase chain reaction
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FDA The US Food and Drug Administration
NYHA The New York Heart Association
ACC The American College of Cardiology
AHA American Heart Association
HRS Heart Rhythm Society
AF Atrial fibrillation
HF Heart failure
Acknowledgements
Not applicable.
Author contributions
AHST performed the medical management of the patient, and checked and
revised the manuscript, MN drafted, reviewed, and revised the manuscript,
MS drafted the manuscript, NJ drafted the manuscript. All authors read and
approved the final manuscript.
Funding
This article was prepared without any support or funding.
Availability of data and materials
The datasets used and analyzed during the current study are available from
the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of
this case report and any accompanying images. A copy of the written consent
is available for review from the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interest to disclose.
Received: 26 December 2022 Accepted: 26 April 2023
References
1. Martino E, Bar talena L, Bogazzi F, Braverman LE. The effects of amiodar-
one on the thyroid. Endocr Rev. 2001;22(2):240–54.
2. Biancatelli RMC, Congedo V, Calvosa L, Ciacciarelli M, Polidoro A, Iuliano L.
Adverse reactions of amiodarone. J Geriatr Cardiol. 2019;16(7):552.
3. Jolly U, Klein G. Blue man syndrome. CMAJ. 2016;188(8):604.
4. Jain SA, Rao MS, Mahesh AR. Blue in dermatology. 2022.
5. Bracey NA, Zipursky JS, Juurlink DN. Argyria caused by chronic ingestion
of silver. CMAJ. 2018;190(5):E139.
6. Steininger H, Langer E, Stömmer P. Generalized argyrosis. Dtsch Med
Wochenschr. 1990;115(17):657–62.
7. Iolascon A, Bianchi P, Andolfo I, Russo R, Barcellini W, Fermo E, et al. Rec-
ommendations for diagnosis and treatment of methemoglobinemia. Am
J Hematol. 2021;96(12):1666–78.
8. Enseleit F, Wyss CA, Duru F, Noll G, Ruschitzka F. The blue man: amiodar-
one-induced skin discoloration. Circulation. 2006;113(5):e63.
9. Delage C, Lagace R, Huard J. Pseudocyanotic pigmentation of the skin
induced by amiodarone: a light and electron microscopic study. Can Med
Assoc J. 1975;112(10):1205.
10. Alinovi A, Reverberi C, Melissari M, Gabrielli M. Cutaneous hyperpig-
mentation induced by amiodarone hydrochloride. J Am Acad Dermatol.
1985;12(3):563–6.
11. Ammoury A, Michaud S, Paul C, Prost-Squarcioni C, Alvarez F, Lamant L,
et al. Photodistribution of blue-gray hyperpigmentation after amiodarone
treatment: molecular characterization of amiodarone in the skin. Arch
Dermatol. 2008;144(1):92–6.
12. Vyskocilova EH, Grundmann M, Duricova J, Kacirova I. Therapeutic
monitoring of amiodarone: pharmacokinetics and evaluation of the
relationship between effect and dose/concentration. Biomed Pap Med
Fac Palacky Univ Olomouc. 2017;161(2):134.
13. Kounis NG, Frangides C, Papadaki PJ, Zavras GM, Goudevenos J. Dose-
dependent appearance and disappearance of amiodarone-induced skin
pigmentation. Clin Cardiol. 1996;19(7):592–4.
14. Epstein AE, Olshansky B, Naccarelli GV, Kennedy JI Jr, Murphy EJ, Gold-
schlager N. Practical management guide for clinicians who treat patients
with amiodarone. Am J Med. 2016;129(5):468–75.
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