Journal of Dermatology 2010; 37: 488–492
doi: 10.1111/j.1346-8138.2010.00864.x
CASE REPORT
Three cases of embolia cutis medicamentosa (Nicolau’s syndrome) Giovanni Francesco MARANGI, Pierluigi GIGLIOFIORITO, Vito TOTO, Marika LANGELLA, Tiziano PALLARA, Paolo PERSICHETTI Plastic and Reconstructive Surgery, ‘‘Campus Bio-Medico di Roma’’ University, Rome, Italy
ABSTRACT Embolia cutis medicamentosa, also known as Nicolau’s syndrome, is a rare complication due to i.m. injections. Its real incidence is actually underestimated. Many drugs have been associated with it, but at the time only a few studies showed a related pathogenetic mechanism. Symptoms consist of immediate local pain, edema and cutaneous, subcutaneous and even muscular necrosis occurring in the first 48 h. The type of treatment depends mostly on time of diagnosis. A medical resolution can be achieved through heparin and cortisone injections within the first 48 h. Surgical debridement has to be considered as the main treatment in case of late diagnosis. We present three cases of Nicolau’s syndrome presenting to us in a short period of time that we treated with surgical debridement. Key words: embolia cutis medicamentosa, i.m. injection, Nicolau’s syndrome.
INTRODUCTION
CASE REPORTS
Nicolau’s syndrome is a rare but well-known complication occurring after i.m. injection of many drugs. It consists of local symptoms represented by extreme local pain, cutaneous erythematous rash, livedoid plaque, local edema followed by cutaneous–subcutaneous–adipose–muscular necrosis up to systemic symptoms such as disseminated ischemic complications and neurological onsets such as hyposensitivity, paraplegia and sphincterial deficits.1 Treatment consists of medical and surgical therapies depending on the timing of the diagnosis. Medical resolution is obtained through heparin s.c. injections plus i.v. cortisones. Marked improvements are achieved within 48–56 h. Surgical debridement represents the solution in cases of late diagnosis. We present three cases of patients affected by Nicolau’s syndrome presenting to us from January to June 2008.
Patient 1 A dialyzed 70-year-old white female patient, affected by nephrotic syndrome, was admitted with a 5 cm · 4.5 cm painful, necrotic cutaneous ulcer which occurred 2 weeks after an i.m. injection of ketorolac on the upper outer quadrant of the right buttock. The patient did not receive any kind of therapy until she presented to us. She was successfully treated through wound surgical debridement. The wound closed by second intention. Histology showed steatonecrosis and tissue inflammation. Patient 2 A 66-year-old white female patient with negative anamnesis of cardiovascular diseases, presented with a painful ulcer that had appeared 10 days after an i.m. injection of diclofenac sodium.
Correspondence: Giovanni Francesco Marangi, M.D., Division of Plastic Surgery, Campus Bio-Medico University, Via A. del Portillo, 200-00100 Rome, Italy. Email:
[email protected] Received 7 April 2009; accepted 23 January 2010.
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Figure 1. Preoperative view: 8 cm · 6 cm necrotic spot in the outer upper quadrant of the left buttock.
Figure 3. Intraoperative view: the middle cut shows the cutaneous and subcutaneous necrosis.
mirabilis and Corynebacterium spp. infection treated with piperacillin–tazobactam and amikacin sulfate combined therapy. Treatment with surgical debridement and excision was successful. Drainage of wound was performed for 12 weeks. First intention suture was followed for the wound healing. Histological examination revealed steatonecrosis.
DISCUSSION
Figure 2. Intraoperative view: the thrombotic vessel is clearly visible from a lateral view.
She had a 8 cm · 6 cm painful necrotic spot, located in the upper outer quadrant of the left buttock that we resolved with surgical debridement (Figs 1–3). Primary suture was necessary. Histological examination revealed inflammation and tissue hemorrhagic necrosis. Patient 3 A 60-year-old woman was admitted with an 8 cm · 6 cm indolent necrotic spot which developed into a loss of substance approximately 1 week after a diclofenac i.m. injection. She developed a Proteus
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The first scientific descriptions of Nicolau’s syndrome date back to late 1924 by Nicolau and Freudenthal as a collateral effect of bismuth salts, used for the treatment of syphilis. Nicolau’s syndrome is a complication following i.m. drug administration which may be split into two different chapters:1,2 (i) cytotoxic effects, depending on the drug’s composition, injection zone and personal skin sensitivity; and (ii) mechanical effects, namely, vascular lesions (which probably represents the main cause of mechanical effects), intra-arterial ⁄ venous accidental injections and peripheral sensory nerve lesions. Even if many drugs have been associated with Nicolau’s syndrome, only in a few of these cases it was possible to understand the pathogenetic mechanisms. For example, some studies show the possible role of non-steroidal anti-inflammatory drugs (diclofenac sodium) through a vasospastic effect3 and a
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cyclooxygenase inhibition with following inhibition of prostaglandin synthesis resulting in a vasoconstrictive phenomenon. Further studies are needed to explain the possible involvement of anesthetics (lidocaine hydrochloride), antihistamines (diphenhydramine), corticosteroids (triamcinolone acetonide),4 B vitamins (cyanocobalamin), antibiotics (penicillin, sulfamidic acid),5 anti-epileptics (phenobarbital, chlorpromazine), vaccines,6 thiocolchicoside,7 glatiramer acetate,8 b-interferon injection9 and a-interferon.10 Presently, Nicolau’s syndrome’s pathogenesis has not been totally resolved. The main hypothesis is that a vascular mechanism could be involved. Six different theories may explain its development: (i) a vascular or perivascular injection followed by inflammation and progressive necrosis of the intima; (ii) a periarterial injection with arterial wall perforation and thrombosis ⁄ necrosis; (iii) an inadvertent intra-arterial injection
with embolic occlusion of small arteries; (iv) an intraarterial, periarterial or perinervous injection with muscular ⁄ cutaneous ischemic necrosis after sympathetic vasospasm; (v) crystal precipitation during injection of drugs into aqueous solutions; and (vi) iodine sclerosing substances and saphenofemoral arteriovenous shunts.11–13 All these mechanisms contribute to peripheral arterial stenosis in different ways: either through true emboli or through vessel damage and then occlusion.14 Discussing differential diagnosis in Nicolau’s syndrome may appear useless because of its rarity. Left atrial myxoma emboli, cholesterol emboli and Hoigne’s syndrome (acute direct i.v. injection) need to be considered first. Conservative treatment with advanced local therapy (i.e. dressings), debridement and pain control
Classic injection
Derma Epidermid
Higher risk of skin drug’s reflux
Muscle Hypoderma
Z-track injection
Tracking the skin
Releasing the skin
Lower risk of skin drug’s reflux
Figure 4. Z-track injection.
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are the mainstay of therapy. Therapy ranges from topical corticosteroids and heparin (within the first 36 h after injection) to surgical excision. Considering the presumed vascular pathogenesis, vasoactive medication may also be beneficial.15 Additional treatment includes antibiotics, skin graft and flap reconstruction. In our case, all patients described a substantially similar evolution of their lesion: immediate pain right after needle entry which increased after the injection, swelling at injection site, edema at injection site, discoloration at injection site (erythema comes after a primary white ischemic spot) were noticed, followed by a subsequent cutaneous, subcutaneous and even muscular necrosis with a pale marble-like livedoid pattern. No evidence of regional lymphadenopathy was found. Complete hemogram including bleeding time, clotting time and urine examinations were normal. Chest X-ray, blood urea, serum creatinine, liver function tests and creatine kinase were normal.16 We actually think a vasculitic process was involved, leading to a necrotic process. The hypersensitivity reaction was first excluded because our patients were chronic users of those medicaments and some of them had approximately one injection a day for many years. The intraoperative found was a necrotic vascular pedicle (Figs 2–3). As clearly visible in these images, the thrombotic perforator vessel could possibly represent the primum movens. Our theory is also confirmed by the fact that two of our patients are still using those drugs, and up to now they have not presented any other reactions. Prevention has also to be considered as a mainstay. We suggest practice of Z-track injections, a method of injecting medication into a large muscle using a needle and syringe. This method seals the medication deeply within the muscle and allows no exit path back into the subcutaneous tissue and skin. This is accomplished by displacing the skin and subcutaneous tissue 1–1.5 inches (2.5–3.75 cm), laterally, prior to injection and releasing the tissue immediately after the injection (Fig. 4). The site should be checked at least once more a short time after the injection to ensure that no bleeding, swelling or any other signs of reaction to the medication are present. The patient should be monitored for other signs of side-effects, especially if it is the first time the patient is receiving the medication. The injection site should
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be aspirated (while syringe and needle are within the muscle) by holding the barrel of the syringe with the non-dominant hand and pulling back on the syringe plunger with the dominant hand. If blood appears in the syringe, it shows that a blood vessel may have been punctured. The needle and syringe should be immediately withdrawn and a new injection prepared. If no blood is aspirated, continue by slowly injecting the medication at a constant rate until all medication has been delivered.17,18.To avoid the risks of s.c. injection, attention must be paid to needle choice. Depending on which muscle has to be injected and the patient’s weight, we suggest different needles. For example, a 2-inch needle may be suitable for 90 kg patient as a 1.25-inch needle is suitable for a 50 kg patient. We suggest to decide on a case-bycase basis whether the injection of drugs should be followed by the application of a cool-pack to avoid additional local vasospasm. If more than one injection has to be given simultaneously, it is preferable to administrate each at a different anatomical site. If this is not possible, then the thigh is usually a preferred site and the two injections should be sufficiently (1–2 inches) separated.19 In conclusion, timing of diagnosis and treatment must be considered the most important factors. It is possible to recognize two different phases that request minimal (e.g. cortisones and heparin) or invasive solutions (e.g. surgical debridement). Up to now, the risk factors of this pathology have not yet been clarified. We found few connections between these three patients. They all had a long history of i.m. injections and were connected by a long history of vasculopathy such as venous insufficiency.
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5 Ocak S, Ekici B, Cam H, Tas¸ tan Y. Nicolau syndrome after intramuscular benzathine penicillin treatment. Pediatr Infect Dis J 2006; 25: 749. 6 Nagore E, Torrelo A, Gonza´lez-Mediero I, Zambrano A. Livedoid skin necrosis (Nicolau syndrome) due to triple vaccine (DTP) injection. Br J Dermatol 1997; 137: 1030–1031. 7 Guarneri C, Polimeni G, Guarneri F, Cuzzocrea S. Embolia cutis medicamentosa following thiocolchicoside injection. J Eur Acad Dermatol Venereol 2008; 22: 1005–1006. 8 Harde V, Schwarz T. Embolia cutis medicamentosa following subcutaneous injection of glatiramer acetate. J Dtsch Dermatol Ges 2007; 5: 1122–1123. 9 Koontz D, Alshekhlee A. Embolia cutis medicamentosa following interferon beta injection. Mult Scler 2007; 13: 1203–1204. 10 Sonntag M, Hodzic-Avdagic N, Bruch-Gerharz D, Neumann NJ. Embolia cutis medicamentosa after subcutaneous injection of pegylated interferon-alpha. Hautarzt 2005; 56: 968–969. 11 Faucher L, Marcoux D. What syndrome is this? Nicolau syndrome. Pediatric Dermatol 1995; 12: 187–190.
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12 Ruffieux Ph, Salomon D, Saurat J. Livedo-like dermatitis (Nicolau’s Syndrome) a review of three cases. Dermatolog 1996; 193: 368–371. 13 Corazza M, Capozzi O, Virgili A. Five cases of livedo-like dermatitis (Nicolau’s syndrome) due to bismuth salts and various other non-steroidal anti-inflammatory drugs. J Euracad Dermatol Venereol 2001; 15: 585–588. 14 Stiehl P, Weissbach G, Schroter K. Das Nicolau-Syndrome. Schweiz Med Wochenshr 1971; 99: 266–269. 15 Ruffieux P, Salomon D, Saurat JH. Livedo-like dermatitis (Nicolau’s syndrome): a review of three cases. Dermatology 1996; 163: 368–371. 16 Murthy C, Siddalingappa K, Suresh T. Department of Dermatology and Venereology. Vijayanagara Institute of Medical Sciences, Bellary, Karnataka, India. 17 Elkin MK, Perry AG, Potter PA Nursing Interventions and Clinical Skills. Mosby-Year Book, Inc., Missouri 1996. 18 Kozier B et al. Techniques in Clinical Nursing. AddisonWesley Nursing, Canada 1993. 19 CDC. Vaccine Administration. In: William LA, Larry P, Benjamin S, Bruce W, eds. General recommendations on Immunisation. John lskander, John Watson, Atlanta, USA. MMWR 2002; 51(RR02): 11–14.
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