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Nicolau syndrom
Introduction
Nicolau Syndrome (NS) also know as livedo like dermatitis and embolia cutis medicamentosa is a rare cutaneous adverse reaction at the site of intramuscular injection of particular drugs.
It is clinically characterized by severe pain immediately after the injection, followed by an erythematous, reticular patch that may result in a necrotic ulcer and scarring at the injection site
NS was first described by Freudenthal in 1924 and Nicolau in 1925 in patients treated for syphilis with bismuth salts. Nicolau suggested the term “livedoid dermatitis” for the patients with the disease. NS has been reported with the administration of various other drugs such as penicillins, non-steroidal anti-inflammatory drugs, local anesthetics, and
corticosteroids in the literature. Table 1 summarizes
causative drugs reported in the literature.
Table 1. Review of causative drugs associated with Nicolau syndrome reported in the literature.
Non-steroidal anti-inflammatory drugs diclofenac,piroxicam, ketoprofen, ibuprofen, phenylbutazone
Antibiotics penicillin derivates,tetracycline, sulfapyridine,streptomycin, gentamicin
Corticosteroids dexamethasone, triamcinolone,hydrocortisone
Antipsychotics and antiepileptics phenobarbital, chlorpromazine
Vaccinations diphtheria-tetanus-pertussis
Antihistamines diphenhydramine, hydroxyzine,
Local anesthetics lidocaine
Miscellaneous interferon alpha, cyanocobalamin, bismuth, vitamin K
Pathogenesis
The pathogenesis of NS has not been clarified yet but in the past it was suggested to be due to accidental intraarterial injections. In 1977 Brachtel and Meinertz performed experiments on the rabbit ear lobe to clarify
the pathogenesis of local skin necrosis after intramuscular
injection in NS. Phenylbutazone solution was injected to paraarterial, intraarterial and paraarterial areas after perforation of the vessel. They detected that the drug produced violent inflammation with all kinds of application. The histological examinations of all three types of application in these cases showed massive destruction of the inner arterial wall.
McGee and Davison reported skin necrosis following non-steroidal antiinflammatory injection,
with histopathology revealing dermal and subcutaneous necrosis with focal thrombosis and inflammation.
Another suggested mechanism involves damage to an end artery, sympathetic stimulation and subsequent vascular spasm from periarterial or perineural injection
The result of all these mechanisms either singularly or acting in combination is end organ damage of the cutaneous and subcutaneous tissues and muscle.
It was reported that cold application for local pain relief caused rapid skin necrosis by increasing acute local vasospastic effects in a case with NS.
Clinical Features
The typical presentation of NS is extremely severe pain around the injection site of the drug immediately after injection, followed by rapid development of erythema, livedoid reticular patch or haemorrhagic patch.
Finally an ulcer or necrosis of skin, subcutaneous fat, and muscle tissue develops and then heals with scar formation (Fig. 1). Various neurological complications such as hypoesthesia, or paraplegia were reported in one-third of the patients. The necrotic ulcer usually heals in several months with an atrophic scar.
Histopathology
Histopathological examination reveals necrosis of the epidermis, dermis, subcutaneous tissue and muscle with focal thrombosis of small and medium blood vessels in NS.
Differential Diagnosis
The differential diagnosis of NS includes cutaneous cholesterol emboli, vasculitis and cutaneous embolization of cardiac myxoma. Cutaneous cholesterol
embolia is a disease of elderly with severe atherosclerotic disease. Skin manifestations in patients with a left atrial myxoma are frequent, usually on acral sites and accompanied by cardiopulmonary symptoms.15
Treatment
There is no specific therapy for NS. Treatment of NS depends on the extent of the necrosis and ranges from topical to surgical. Conservative treatment with debridement, pain control (analgesics) and dressingsis the mainstay of therapy especially for limited cases.
Tissue damage may be reversible in the acute phase
of NS. Use of vasoactive agents such as subcutaneous heparin and oral pentoxifylline has been recognized as beneficial. Topical steroids may be worth trying.
Surgical intervention is rarely required.
Prevention
Nicolau syndrome is an avoidable complication. The Z-track injection is a method of intramuscular injection into large muscle using a needle and syringe and it can minimize or prevent Nicolau syndrome. Health care
personnel should take these precautions:
1. A long (enough to reach muscle) needle should be used. A 90-kg patient requires a 2 or 3-inch (5–7.5 cm) needle and a 45-kg patient requires a1.25 or 1.45-inch needle.
2. Injection should be applied in the upper outer quadrant of the buttock.
3. Aspirating the needle before injecting the medication should be performed to be sure not to hit a blood vessel.
4. The health care personnel should never inject more than 5 ml of medication at a time when using the Z-track injection method.
5. If more than one injection or larger dose is required or ordered, different sites should be chosen.
