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ABSTRACT
Nicolau syndrome (livedoid dermatitis) is a rare adverse reaction of a still largely unidentified pathogenesis at the site of intramuscular drug injection. The typical presentation is pain around the injection site soon after injection, followed by erythema, livedoid patch, haemorrhagic patch, and finally necrosis of skin, subcutaneous fat, and muscle tissue. The phenomenon has been related to the administration of a variety of drugs, including nonsteroidal anti-inflammatory drugs, corticosteroids, and penicillin. We report a case of Nicolau syndrome following an intramuscular injection of diclofenac. The large ulceration over the right buttock was positive for Pseudomonas aeruginosa, and histology revealed subcutaneous fat necrosis and non-specific inflammation with no evidence of malignancy or vasculitis. The lesion required multiple debridements and a partial-thickness skin graft. Subcutaneous injection, rather than intramuscular injection, was found to be a determining factor in this case. Clinicians must be cautious in the use of proper injection procedures, including appropriate needle length, in order to minimise complications.

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Key words: anti-inflammatory agents, non-steroidal; diclofenac; fat necrosis; injections, intramuscular; pseudomonas aeruginosa
INTRODUCTION
Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed as analgesics. Known side-effects include peptic ulcer, bronchospasm, and liver and renal toxicity. The development of skin, subcutaneous, and even muscle tissue necrosis (Nicolau syndrome) are rare but serious complications of the intramuscular injection of NSAIDs.1,2 We report a case with typical features of Nicolau syndrome following diclofenac injection.
CASE REPORT
A 58-year-old moderately obese man had a gouty attack on the right knee and received an intramuscular injection of diclofenac from a general practitioner in August 2004. The injection was made on the upper outer quadrant of the right buttock. The patient complained of intense pain radiating from the right buttock to the calf immediately after the injection and was admitted to the Department of Orthopaedics and Traumatology, Queen Mary Hospital in Hong Kong for treatment. Physical examination revealed only some tenderness around the injection site; radiography and blood results were unremarkable. Two days later, the patient developed a patch of bruising over the injection site. The buttock pain improved slightly with oral analgesia, and the patient was discharged after 5 days of hospitalisation. At 2-week follow-up, a large necrotic skin patch with ulceration measuring 10×7 cm was found over the right buttock (Fig.1), and the patient was readmitted.
Bacteriological culture showed Pseudomonas aeruginosa, and intravenous piperacillin was started. Multiple surgical debridements (5 in total) were performed (Fig. 2). Histology of the ulcer tissue showed fat necrosis and non-specific inflammation, mainly in the subcutaneous layer, with no evidence of malignancy or vasculitis. A partial-thickness skin graft was performed 2 months later; most of the graft was well taken but a large scar resulted (Fig. 3).
DISCUSSION
Nicolau syndrome (livedoid dermatitis) is a well known but rare, adverse reaction involving skin, subcutaneous, and even muscle tissue necrosis at the site of intramuscular drug injection. It was first described in the 1920s as an adverse effect of bismuth salts routinely used for the treatment of syphilis. The phenomenon has been related to the administration of a variety of drugs including NSAIDs, corticosteroids, and penicillin. The typical presentation is blanching and pain around the injection site soon after injection, followed by erythema, livedoid patch, haemorrhagic patch, and finally necrosis. Repetitive cycles of infection and wound breakdown are typical.
The exact pathogenesis is uncertain but there are several hypotheses, including direct damage to the end artery and cytotoxic effects of the particular drug or its additives. Indeed, diclofenac is a cyclooxygenase inhibitor, and it may inhibit prostaglandin synthesis through its vasospasm effect. Subcutaneous injection instead of intramuscular injection was an important contributing factor in the present case. Cockshott et al.3 highlighted the difficulties in administering intramuscular injection. The depth of subcutaneous tissue varies and depends on the sex and weight of the patient. Only 5% of females and 15% of males can receive glueteal intramuscular injection with a standard 3.5-cm-long needle, the rest actually receive subcutaneous injections.4
Adequate debridement is critical to the management of Nicolau syndrome. Computed tomographic scan or magnetic resonance imaging is helpful to define the extent of the lesion. Failure to recognise the extent of fat necrosis and poor perfusion in the wound leads to inadequate debridement and poor wound healing. Additional treatment includes antibiotics, wound dressing, skin graft, and flap reconstruction; extensive scarring is usually inevitable.