Pharyngeal haematoma and partial airway obstruction caused by interaction between warfarin and topical miconazole gel

Background

There are many known interactions between warfarin, a commonly used anticoagulant, and common drugs and food products, which are listed in the British National Formulary (BNF).1 Miconazole, an ergosterol inhibitor used as an antifungal, is one of these medications, documented as having a ‘severe study’ interaction with warfarin. This means the result of this interaction may be severe or life-threatening, which has been based on formal study. The Medicines and Healthcare products Regulatory Agency2 (MHRA) advises to avoid prescribing miconazole with warfarin, unless international normalised ratio (INR) and signs of bleeding can be closely monitored. The mechanism of interaction is understood to be inhibition by miconazole of the CYP2C9 enzyme (from the cytochrome p450 enzyme group), resulting in reduced warfarin metabolism and clearance, and an enhanced anticoagulation effect.

Some may assume that the use of oral miconazole gel with warfarin poses a low risk due to the lower bioavailability of a topical medication compared with one that is ingested or given intravenously, however, there have been multiple reports of interactions from oral miconazole gel and warfarin, resulting in elevated INR levels.3–7 Most of these papers detail an elevation in INR without significant clinical consequences. There are a few cases in the literature describing clinical consequences, including a haematoma on the arm and epistaxis,8 haematuria and bleeding gums9 and retroperitoneal haematoma and small bowel haematoma,10 all of which were treated with little resulting harm to the patient. However, there have been three reported deaths where the interaction between miconazole and warfarin has been implicated.11 This case describes a potentially life-threatening consequence of the interaction between topical miconazole and warfarin, and should serve as a reminder and warning about the risk of coprescribing them.

Case presentation

A retired man in his 70s presented to the emergency department (ED) at 14.00, having a feeling of something ‘stuck’ in his throat since the previous night. He denied any cough, fever, coryzal symptoms, shortness of breath or difficulty swallowing. His medical history included atrial fibrillation, an implantable cardioverter defibrillator for broad complex tachycardia, dilated cardiomyopathy and hypertension but despite this, he was fully independent, symptom-free from a cardiac perspective and enjoyed dancing. His regular medications included warfarin, bisoprolol, furosemide, ramipril and simvastatin. His initial observations showed a heart rate of 74, blood pressure of 167/114, a respiratory rate of 24, oxygen saturations of 97% on air and a temperature of 37.4°C. On examination, it was documented that his throat was red and inflamed and he was prescribed a course of penicillin-V for pharyngitis and discharged home. He reached the car park and returned to the ED at 17.30 after coughing up blood. He described this as small flecks of blood mixed with sputum. He was reassessed and an INR sent to the lab, who were unable to process the sample. He was then discharged and advised to continue antibiotics and see his general practitioner for a repeat INR sample. It was unclear from the notes why the lab were unable to process the INR sample.

At 08.00 the following day, the man attended ED for a third time, complaining of swelling to the neck, shortness of breath and difficulty swallowing food and fluids. There had been no trauma to the neck or mouth. His heart rate was 91, blood pressure 156/112, respiratory rate 20, oxygen saturations 95% on air and temperature 36.1°C. He was seen immediately by a different doctor, who noted on examination that he had a high-pitched unusual-sounding voice (which the patient said was not normal for him), and left-sided soft non-tender neck swelling with no evidence of inflammation or infection inside the throat. They also noted a new bruise on his hard palate and on his arm, which had appeared that morning.

Investigations

Blood tests including a full blood count, urea and electrolytes, an INR and a group and save were taken on the third attendance, which revealed: haemoglobin 157 g/L, white cell count (WCC) 10.1×10⁹/L, platelets 143×10⁹/L and an INR >20 (the maximum possible reading). An initial INR sample was sent on the second attendance but the laboratory were unable to process it. There was a delay of about an hour for the laboratory to process the second INR, who again initially reported it as unreadable, and only found the reading to be >20 once they reprocessed it.

An X-ray of the neck and chest were performed looking for any evidence of foreign bodies, aspiration, infection or soft-tissue swelling. These were all reported by the radiologist as normal (figure 1).

Differential diagnosis

The ED doctor on the third attendance was the first person to be concerned about a haematoma in the neck, due to the new bruising and localised swelling, the patient being on warfarin and in the absence of any tenderness to the neck or infective symptoms. The swelling did not clinically appear as an inflamed lymph node, abscess or gland (it was non-tender, not hot, red or mobile). The tonsils did not appear inflamed or red, and there was no exudate present. The patient was apyrexial, with a normal WCC and no clinical signs of infection, which led towards an alternative diagnosis.

The patient was started on oxygen, taken to the resuscitation area and the anaesthetist and ear, nose and throat (ENT) surgeons called for assistance due to the risk of impending airway compromise. The anaesthetist assessed his airway, noting a large swelling in the neck that was pushing up the base of his tongue, giving him a Mallampati score of 4. They also suspected this to be a haematoma. With the voice changes, they declared the airway partially obstructed due to worstening swelling, at risk of complete obstruction.

At this point, the INR result was returned as >20, which confirmed the suspected coagulopathy.

The ENT surgeon performed a nasal endoscopy in the ED, which revealed swelling of the pharynx and fresh blood in the oropharynx. They were unable to visualise the vocal cords due to the swelling. The diagnosis of a spontaneous pharyngeal haematoma was confirmed.

While the patient was being managed, the patient’s history was reviewed further to try to establish what had caused the significantly raised INR. The patient’s normal INR range was 2–3 and his levels had previously been well-controlled and monitored every 3 months. His last INR had been 3.0, 17 days before he presented with the haematoma. The patient’s warfarin dosing and compliance was examined, in addition to any new over the counter, herbal or illicit drugs, significant changes in diet or alcohol intake and recent medication changes. The only new significant finding was that he said the dentist had prescribed him miconazole oromucosal gel (24 mg/mL), two weeks ago for oral candidiasis. He had been applying this topically to his mouth twice daily since then (the usual prescription is 2.5 mL four times per day). He thought that he had given a list of his medications to the dentist at the time of prescription. There were no other triggers or causes found for the elevation in INR so it was concluded that the interaction between the miconazole gel and warfarin was the cause of this spontaneous haematoma.

Treatment

A multidisciplinary treatment plan was made between the emergency physicians, anaesthetists, ENT surgeons and the haematologists. The patient’s airway was partially obstructed, but he was still maintaining oxygen saturations above 94% on oxygen and based on the time course in which the haematoma was expanding, it was decided that it would be safer to manage him conservatively rather than intubating and attempting surgery to evacuate the haematoma. This was due to the high chance of difficult intubation and bleeding around the airway.

After consultation with the haematologists, 5 mg intravenous vitamin K was given immediately, in addition to 30 mL/kg dried prothrombin complex concentrate (Octaplex), which can used for rapid reversal of coagulopathy caused by warfarin and other vitamin K-antagonists. It contains those clotting factors inhibited by warfarin.

Outcome and follow-up

The patient was transferred to the intensive care unit in case of further airway compromise, where he was closely monitored. The haematoma and airway obstruction gradually resolved over the next few days. His INR reduced from >20 at 09.40 that morning to 1.1 by 17.20. He was stepped down to a medical ward by day 3 and his warfarin restarted. He had regular input from the speech and language therapy and dietician daily due to difficulty swallowing; he was initially nil by mouth, restarted fluids by day 3 and by day 7 was able to restart solid foods. He was discharged home on day 8 and made a full recovery.