Introduction

Nicolau syndrome (NS), also known as embolia cutis medicamentosa, is a rare cutaneous adverse reaction following intramuscular and intra-articular injection of various drugs. It manifests with pain and pallor at the injection site followed by erythema and a livedoid reticular patch that may result in necrotic ulceration and scarring (1). In some cases morbid complications can occur such as limb gangrene, paraplegia, widespread cutaneous necrosis, and death (2). We report herein a case with features of NS after diclofenac injection and discuss some precautions to prevent this complication.

Case report

A 30-year-old man received an intramuscular injec-tion of diclofenac in the upper outer quadrant of the left buttock for postoperative pain 2 days after pilonidal sinus excision. Five days later, he had a complaint that an erythematous lesion had devel-oped at the injection site. It progressed to a necrotic eschar with dimensions of 8 cm by 6 cm within 7 days. Dermatologic examination revealed necrotic, crusted, indurated plaque on the outer quadrant of

the patient’s left buttock (Figure 1). The lesion was tender to light touch.

The patient was otherwise in good health, and the results of routine laboratory investigations, including coagulation profile, were within normal limits. No microorganism grew in the swab culture of the ulcer surface. Magnetic resonance imaging (MRI) scan

Cutaneous and Ocular Toxicology, 2010; 29(1): 70–72

C A S E R E P O R T

Nicolau syndrome and perforator vessels: a new viewpoint for an old problem

Gokhan Okan1 and Halil Ibrahim Canter2

1Medical Park Bahcelievler Hospital, Department of Dermatology, Istanbul, Turkey, and 2Acibadem University Faculty of Medicine, Department of Plastic, Reconstructive & Aesthetic Surgery, Istanbul, Turkey

AbstractNicolau syndrome is rare cutaneous adverse reaction following injection of various drugs. The disease has been associated with almost all classes of medications, such as nonsteroidal anti-inflammatory drugs, local anesthetics, corticosteroids, antibiotics, vitamin B complexes, antihistamines, and vaccines. The most severe cases of this complication occur after injection of nonsteroidal anti-inflammatory drugs. Subcutaneous injec-tion is an important factor in the pathogenesis of the syndrome. We report a case of Nicolau syndrome result-ing from intramuscular injection of diclofenac and discuss some precautions to prevent this complication.

Keywords: Nicolau syndrome; diclofenac; perforator vessels

Address for Correspondence: Dr. Gokhan Okan, Dermatologist, Medical Park Bahcelievler Hospital, Dermatology, Medical Park Bahcelievler, Kultur Sokak No: 1 E-Uzeri, Bahcelievler, Istanbul, 34160 Turkey. Tel. :+90 (212 ) 444 44 84; Fax : +90 (212) 484 17 77. E-mail: gokhanokan8@hotmail.com

(Received 25 October 2009; revised 16 November 2009; accepted 17 November 2009)

ISSN 1556-9527 print/ISSN 1556-9535 online © 2010 Informa UK LtdDOI: 10.3109/15569520903496753 http://www.informahealthcare.com/cot

Cutaneous and Ocular Toxicology

1

2010

70

29

72

1556-95271556-9535© 2010 Informa UK Ltd10.3109/15569520903496753

25 October 200917 November 200916 November 2009

COT

450093Figure 1. The necrotic, crusted, indurated plaque on the outer quadrant of the patient’s left buttock.

Cut

aneo

us a

nd O

cula

r T

oxic

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Auc

klan

d on

11/

03/1

4Fo

r pe

rson

al u

se o

nly.

Nicolau syndrome and perforator vessels 71

demonstrated only diffuse infiltration in the adipose tissue at the injection site. The muscle was spared and there was no liquid collected under the eschar tissue.

The lesion was treated initially with debridement, mupirocin ointment, and occlusive dressing. The lesion progressed to full-thickness skin loss despite these conservative treatment measures; the patient was then referred to the plastic surgery department. Surgical management was done with surgical debridement and closure of the defect with split-thickness skin grafts. The recovery period was uneventful and the defect healed completely without any sequelae.

Discussion

NS has been recognized for many years as an adverse drug reaction at the site of intramuscular injection. It was first described in 1925 as an adverse effect of bismuth salts, used for the treatment of syphilis (3). The disease has been associated with almost all classes of medica-tions, such as nonsteroidal anti-inflammatory drugs, local anesthetics, corticosteroids, antibiotics, vitamin B complexes, antihistamines, and vaccines (1).

The pathogenesis of NS is obscure, but the most common hypothesis is that of vascular orgin with arte-rial vasospasm and skin ischemia-mediated livedoid pattern. Histopathologic examination reveals dermal and subcutaneous necrosis with focal thrombosis and inflammation.

Knowledge of the cutaneous arteries and veins is fundamental not only to the design of skin flaps and incisions, but also to understand the pathophysiology of some of the ischemic events in the body. The body is divided anatomically into 3-dimensional vascular territories, named angiosomes after the total-body studies of the blood supply to the skin and the underly-ing deep tissues (4,5). These 3-dimensional anatomic territories are supplied by a source (segmental or distributing) artery and its accompanying vein(s) that span the tissue between the skin and the bone. These composite blocks of skin, bone, muscle, and other soft tissue fit together like the pieces of an intricate jigsaw puzzle. Each angiosome is linked to its neighbor, in each tissue, by fringe true (simple) anastomotic arter-ies without change in caliber or by reduced-caliber choke (retiform) anastomotic vessels. On the venous side avalvular (bidirectional or oscillating) veins often match the anastomotic arteries and define the bound-aries of the angiosome, especially in the deep tissues.

By definition, a cutaneous perforator is any vessel that perforates the outer layer of the deep fascia to sup-ply the overlying subcutaneous fat and the skin (6). These cutaneous perforators, whether arterial or venous, large or small, are derived ultimately from,

or return to, underlying source or segmental vessels that usually course parallel to the bony skeleton. In a broad sense, cutaneous perforator vessels look like the handle of an umbrella and supply the overlying skin in a reticular pattern. Therefore, direct injection of a cuta-neous perforator vessel with an occlusive or vasocon-strictive agent may disturb the cutaneous circulation not only by cessation of the main blood supply through the perforator vessel, but also by occluding the anasto-motic arteries, both true (simple) and reduced-caliber choke (retiform) anastomotic arteries.

The physical and chemical properties of drugs and the injection speed are not associated with develop-ment of the disease. In the case reported here, NS followed an intramuscular injection of diclofenac. Diclofenac itself may cause vasoconstriction by inhib-iting the synthesis of prostaglandin as a cyclooxyge-nase inhibitor. The developed necrotic area fits the angiosome territories of the superior gluteal artery as the source artery (7,8).

There is no specific treatment for the disease once it develops. Treatment alternatives include antibiotics, wound dressings, skin grafting, and flap reconstruction (9). An atrophic scar generally develops. Because our patient’s necrosis proceeded in spite of conservative therapy, surgical recon-struction was preferred.

Subcutaneous injection is an important factor in the pathogenesis of NS. In this case given the immediate report of pain, it is possible that the injection was perivascular. Clinicians must take care to use proper injection procedures and to aspirate before injections. If the patient experiences intense pain, the clinician should stop the procedure (10). It is highly recommended that the medical staff in charge of subcutaneous injections be taught the locations of perforator vessels at the injection sites to prevent such complications.

Acknowledgement

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References

1. Senel E, Ada S, Gulec AT, Caglar B. Nicolau syndrome aggravated by cold application after i.m. diclofenac. J Dermatol 2008;35:18–20.

Cut

aneo

us a

nd O

cula

r T

oxic

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Auc

klan

d on

11/

03/1

4Fo

r pe

rson

al u

se o

nly.

72 Gokhan Okan and Halil Ibrahim Canter

2. Luton K, Garcia C, Poletti E, Koester G. Nicolau syndrome: three cases and review. Int J Dermatol 2006;45:1326–28.

3. Sarifakioglu E. Nicolau syndrome after diclofenac injection. J Eur Acad Dermatol 2007;21:266–7.

4. Taylor GI, Palmer JH. The vascular territories (angiosomes) of the body: experimental study and clinical applications. Br J Plast Surg 1987;40:113–41.

5. Taylor GI. The blood supply of the skin. In:Thorne CH, eds. Grabb and Smith’s Plastic Surgery; Philadelphia, PA: Lippincott Williams & Wilkins. 2007:33–41.

6. Taylor GI. The angiosomes of the body and their supply to perforator flaps. Clin Plast Surg 2003;30:331–42.

7. Pan WR, Taylor GI. The angiosomes of the thigh and buttock. Plast Reconstr Surg 2009;123:236–49.

8. Blondeel PN, Van Landuyt K, Hamdi M, Monstrey SJ. Soft tissue reconstruction with the superior gluteal artery perforator flap. Clin Plast Surg 2003;30: 371–82.

9. Panariello L, Ayala F. Nicolau syndrome folowing intramuscular diclofenac injection: a case report. Dermatol Ther 2008;21(suppl 1):S10-S12.

10. Lee DP, Bae GY, Lee MW, Choi JH, Moon KC, Koh JK. Nicolau syndrome caused by piroxicam. Int J Dermatol 2005;44:1069–70.

Cut

aneo

us a

nd O

cula

r T

oxic

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Auc

klan

d on

11/

03/1

4Fo

r pe

rson

al u

se o

nly.