Skin necrosis following injection of non-steroidal anti-inflammatory drug

A. M. McGee* and P. M. Davison

Department of Plastic Surgery, North Staffordshire NHS Trust Hospital, Hartshill, Stoke-on-Trent, UK*Corresponding author

Accepted for publication: August 3, 2001


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We report two patients who developed skin necrosis following an intramuscular injection of non-steroidal anti-inflammatory drug into the anteriolateral area of their thigh. Both patients required further multiple operations and one developed life threatening septicaemia. They were left with disfiguring scars. Skin necrosis, although rare, is a recognized adverse reaction to intramuscular non-steroidal anti-inflammatory injections. It is likely that the injections were, unwittingly, administered subcutaneously. It is important to ensure intra-muscular administration, with an appropriate needle length.

Br J Anaesthesia 2002; 88: 139–40

Keywords: analgesic techniques, i.m.; analgesics, non-steroidal anti-inflammatory drugs; complications, skin necrosis


    Introduction
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Non-steroidal anti-inflammatory drugs (NSAID) are frequently prescribed analgesics in the postoperative period. Well-known side effects include gastric or duodenal ulceration, skin rashes, as well as renal and liver toxicity, and bronchospasm, especially in asthmatics.1 2 Tissue necrosis is recognized as a rare but serious consequence of NSAID injection,3 potentially leaving the patient with life-long disfigurement. We present two patients who developed this complication.


    Case 1
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A 35-yr-old man underwent an arthroscopy of his knee under general anaesthesia. For postoperative pain relief he received an i.m. injection of ketoprofen (Oruvail) in the anteriolateral aspect of his thigh whilst under anaesthesia. In the recovery room, he complained of pain and a red rash on his thigh. This was thought, at the time, to be a mild reaction to the drug. He was reassured and discharged home.

The patient was seen 12 days later in outpatients. He explained that the initial erythematous rash had turned a deep purple colour over the initial 24 h and then over the following days had faded. He was now getting more pain from this area than from his knee. On examination the patient looked unwell and was pyrexial. The rash had developed into a necrotic lesion measuring 10x10 cm with a sloughy green surface.

He was admitted to hospital, started on i.v. antibiotics, and he underwent wound debridement with daily dressings until the wound was clean enough to accept a skin graft. Although only a 90% skin graft take was achieved; the remaining raw areas were allowed to heal conservatively, leaving a very obvious indented scar. He also had an area of anaesthesia distal to the site of injury.

Histology of the necrotic tissue showed full dermal necrosis and necrosis of the subcutaneous fat. There was associated focal thrombosis within vessels and a marked acute inflammatory infiltrate.


    Case 2
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A 33-yr-old, moderately obese woman, underwent arthroscopy of her left knee. In the anaesthetic room diclofenac (Voltarol) was injected into the left upper outer thigh. A tourniquet was applied over this area. The arthroscopy lasted 25 min. Postoperatively the patient complained of intense itching around the injection site, which was noted to have a red discolouration. This area of inflammation subsequently necrosed over the next 2 days.

The wound management was complicated by development of severe cellulitis affecting the whole leg a week after the operation. This responded well to i.v. antibiotics. The wound was gradually desloughed with local dressings over the next month. This created a defect measuring 4 cm in diameter and 5 cm in depth. An attempt at delayed primary closure failed because of infection and further dressings were required.

A further attempt at wide local excision and primary closure was undertaken 4 months after her original surgery. This did not heal and a sinus developed with an underlying abscess, which required incision and drainage. Gentamicin beads were inserted into the defect. The patient again developed severe cellulitis and septicaemia that required intensive care support for 2 weeks.

A year after the original operation, the patient still had a large and painful wound on her thigh that required daily packing. The vicious circle of sepsis and wound breakdown was finally stopped by the patient undergoing a wide excision of the soft tissue 10 cm in diameter taken down to the fascia. The wound was skin grafted and it healed without further complications. Histology confirmed wide-spread fat necrosis with chronic inflammatory changes.

The patient was so unhappy with the cosmetic result that she eventually underwent tissue expansion of the surrounding skin, allowing advancement flaps and a linear wound closure.


    Discussion
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The term Nicolau Syndrome (synonym: embolia cutis medicamentosa) has been coined to describe skin necrosis following i.m. injections.4 5 Soon after the injection there is pallor of skin around the injection site with associated pain. This is followed by erythema that evolves into a lividoid violaceous patch. The involved area subsequently becomes haemorrhagic and then necroses. Scarring is an inevitable outcome.

The pathogenesis explaining the cause of skin necrosis is uncertain. However, the most common hypothesis is damage to an end artery.3 5 The other causes to consider, especially with tissue necrosis, are the cytotoxic effect of the drug or the additives in the injectate.

These two cases highlight the potentially serious consequences of tissue necrosis following injections of NSAID. They demonstrate that the area of tissue damage with diminished vascularity often extends beyond the visible area of necrosis. Failure to recognize the extent of fat necrosis and poor tissue perfusion in the wounds leads to inadequate debridement and poor wound healing. They are then prone to repetitive cycles of infection and wound breakdown, resulting in multiple surgical procedures. Both patients were left with extensive scarring, soft tissue indentation and unsightly skin grafts.

Cockshott and colleagues6 have highlighted the difficulties in administering an intramuscular injection. They showed that there was a variable depth of subcutaneous tissue dependent on the sex and weight of the patient. They demonstrated that only 5% of females and 15% of males would receive a gluteal i.m. injection with a standard 3.5 cm long needle (19 gauge green needle) and that the rest would receive a subcutaneous injection. It is almost certain that these two patients received subcutaneous injections, as clinically and histologically there was no muscle necrosis.

The authors believe that the information given in the advisory sheets accompanying NSAID injections is not explicit enough with respect to this potentially serious complication. For instance, the drug information sheet of ketoprofen warns that pain or a burning sensation may occur around the injection site. It advises that the injection should be given by deep intragluteal injection in the upper outer quadrant of the buttock. If more than one injection is required then alternative sites should be used. This would obviously include the upper outer thigh, which was the site involved in both cases. The potential for subcutaneous injection and consequent subcutaneous tissue necrosis is not mentioned. Only in the more commonly used Voltarol injection is there a warning that there is a rare incidence of local pain and induration and, in isolated cases, you may get abscess and local necrosis.

NSAID are effective analgesic agents and i.m. injections are an accepted means of administration. Unfortunately, there is a relatively high chance that the injection will be administered, unwittingly, into the subcutaneous tissue. Even though subsequent skin and soft tissue necrosis remains a rare complication, it can occur. Specific warnings should be added to the drug information sheet.


    References
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1 Alhava E. Reported adverse drug reactions and consumption of non-steroidal anti-inflammatory drugs. Pharmacol Toxicol 1994; 75 [Suppl. 2]: 37–43

2 Carson JL, Willett LR. Toxicity of nonsteroidal anti-inflammatory drugs. An overview of the epidemiological evidence. Drugs 1993; 46 [Suppl.1]: 243–8

3 Pillans PI, O’Connor N. Tissue necrosis and necrotizing fasciitis after intramuscular administration of diclofenac. Ann Pharmacother 1995; 29: 264–6

4 Bork K. Cutaneous Side Effects of Drugs. Philadelphia: WB Saunders, 1988; 364–9

5 Faucher L, Marcoux D. What syndrome is this? Nicolau syndrome. Pediatr Dermatol 1995; 12: 187–90

6 Cockshott WP, Thompson GT, Howlett LJ, Seeley ET. Intramuscular or intralipomatous injections? N Engl J Med 1982; 307: 356–8





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