Nicolau syndrome treated with triple therapy of enoxaparin, steroids, and pentoxifylline and monitored using infrared thermography

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Nicolau syndrome is a rare complication of intramuscular injection that can lead to skin necrosis.^1,2 Patients present with intense burning or stabbing pain at the site of injection and retiform purpura with tissue necrosis. Here, we describe a case of a 57-year-old male who developed Nicolau syndrome following an intramuscular diclofenac injection in the buttock but responded to treatment with enoxaparin, prednisolone, and pentoxifylline.

A 57-year-old man with no known comorbidities presented with complaints of severe burning pain and reddish-blue discolouration on the right buttock for 4 days. The symptoms started immediately after an intramuscular injection of diclofenac in the right buttock for a low backache. There was no history of fever, trauma, bites, or topical or any other systemic medications. Physical examination revealed a well-defined, tender, purpuric plaque with retiform margins on the right gluteal region [Figure 1a]. Bilateral lower limb pulses were well felt. Nikolsky’s sign was negative. Complete blood count, renal and liver function tests, and urine examination were normal except for iron deficiency anaemia, for which the patient was started on iron supplements. Coagulation parameters, including prothrombin time, bleeding time, and clotting time, were also within normal limits. Antinuclear and anticardiolipin antibodies were not detected. The skin tissue culture did not yield any microbial growth; therefore, antibiotics were not administered. The skin biopsy showed epidermal necrosis, inconspicuous dermal inflammation, and thin-walled dermal vessels occluded by thrombi. Considering the typical history, temporal association with the administration of an intramuscular injection and development of a characteristic cutaneous lesion, Nicolau syndrome was diagnosed. Naranjo’s causality assessment score was 3 (possible). He was treated with a one-week course of tablet prednisolone (0.5 mg/kg/day), daily subcutaneous enoxaparin (40 mg), thrice daily tablet pentoxifylline (400 mg), analgesics, and daily dressings. Following the initiation of the treatment, skin lesions stopped progressing, and there was a significant decrease in pain [Figures 1b and 1c]. The response was monitored using serial infrared thermography images. We observed a reduction in the size of the cold spot over seven days of therapy [Figures 2a and 2b]. He did not develop any complications like secondary infection, compartment syndrome, hypoesthesia, or lower limb paralysis during his stay in the hospital. He was discharged with a prescription of tablet pentoxifylline (400 mg) three times a day. On a follow-up visit after 2 months, a well-demarcated eschar was noted at the centre, which was debrided, and the ulcer was allowed to heal by secondary intention. The defect was smaller than the purpuric plaque noted at the initial presentation.

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Figure 1a:

Purpuric plaque with retiform margin on the right buttock prior to initiation of therapy.

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Figure 1b:

Superficial necrosis and peeling on day 7 of triple therapy.

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Figure 1c:

Follow-up after 2 months. The necrotic area at the centre of the plaque has become well-demarcated with eschar.

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Figure 2a:

Thermographic image of the right buttock on day 3 of triple therapy showing a cold spot (red to dark blue) (temperature gradient- 4.2°C)

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Figure 2b:

Thermography on day 7 showed a decrease in the size of the cold spot (temperature gradient- 1.59°C)

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Nicolau syndrome is commonly reported with intramuscular injection of drugs like non-steroidal anti-inflammatory drugs, penicillin, corticosteroids, and vaccinations.^1,2 There are no specific diagnostic criteria for Nicolau syndrome, nor any specific diagnostic modalities. Early institution of therapy is required to prevent or limit tissue necrosis by establishing reperfusion. Analgesics, antibiotics, wound debridement, and dressings are the mainstays once necrosis is established. The widely accepted hypothesis regarding the pathogenesis of Nicolau syndrome involves vasospasm, thromboembolic occlusion, or inflammation of vessels following a peri- or intravascular injection. In view of vascular pathology, heparin, systemic steroids, hyperbaric oxygen, and pentoxifylline have been used as monotherapy or in combination with variable results.^2-5 Triple therapy with prednisolone, enoxaparin, and pentoxifylline in Nicolau syndrome has not been previously documented. The anti-inflammatory action of prednisolone relieves vascular inflammation, while heparin reverses thromboembolic occlusion, and pentoxifylline relieves vasospasm by inhibition of phosphodiesterase. Nicolau syndrome progresses in three distinct phases: initial phase (days 0-3), acute phase (days 5-10), and necrotic phase. Research has shown that anticoagulants and corticosteroids can help alleviate occlusion and inflammation during the acute stage. Based on this evidence, we initiated treatment with steroids and anticoagulants on day four to address these issues effectively. Pentoxifylline was added to the treatment regimen of steroids and anticoagulants, as it has been shown to relieve vasospasm and accelerate the recovery of necrosis.^1-5 We felt that early institution of these drugs in combination, especially in the acute phase, may help restore perfusion and prevent progression to necrosis in areas with reversible ischaemic changes, as suggested by the improvement in serial thermography in this case.³ The early institution of therapy may limit the extent of tissue necrosis, preventing the need for skin grafting and flap-reconstruction surgeries.¹ Sequential infrared thermography can be used to assess the efficacy of therapy in the acute phase and to delineate the extent of necrosis. Gluteal injections must be given in the upper outer quadrant to avoid the neuro-vascular structures. When injecting larger volumes, it must be split between multiple sites. Aspiration before injections prevents intravascular injections.² Z-track technique to prevent drug leakage into the subcutaneous tissue is another strategy proposed. As this is a single case report, it does not confirm the efficacy of triple therapy, and larger studies or trials are warranted to prove the same.