Neurological sequelae following methylene blue injection for parathyroidectomy

Intra-operative staining of the parathyroid glands with intravenously administered methylene blue is well described and has been demonstrated as an effective and safe method to facilitate parathyroidectomy [1, 2]. However, we report a case of a 60-year-old woman who had an adverse neurological event following the use of intravenous methylene blue. This patient, scheduled for a parathyroidectomy, had symptomatic hypercalcaemia secondary to a parathyroid adenoma, and a history of anxiety and depression. Her only medications were fluoxetine, coproxamol and beclamethasone nasal spray. She had no known allergies and had undergone one previous general anaesthetic for tonsillectomy with no adverse effects. Pre-operatively, she was administered a methylene blue infusion of 7.5 mg.kg−1. She vomited once during its administration and, on arrival in the anaesthetic room, looked very blue but showed no abnormal behaviour. Surgery was carried out uneventfully under general anaesthesia during which all her vital signs remained within the normal range. At the end of the procedure, the patient was extubated and transferred to the recovery room. Shortly after arrival in recovery, she was noted to have rotational nystagmus and dilated pupils that were unreactive to light. Thirty minutes later, she began to display rigid, jerky movements of all four limbs and remained very agitated over the subsequent 2 h with a fluctuating Glasgow Coma Scale (GCS) of 7–10. She had increased tone in all four limbs, bilateral up-going plantar reflexes, was noted to be sweating profusely and flushed above the shoulders, yet remained haemodynamically stable. An arterial blood gas revealed a respiratory acidosis with a Pco2 of 60.1 mmHg, Pco2 103 mmHg and an ionised calcium level of 1.49 mmol.l−1. It was decided to transfer her to the intensive care unit for closer observation where she appeared to improve initially, but became more agitated and aggressive overnight. The maximum methaemoglobin level in arterial blood gases reached 0.7% on admission to the ICU. A methylene blue blood level obtained from blood taken 6 h postoperatively was reported as very low but the validity of the result could not be guaranteed. Information from the regional poisons unit suggested that plasma levels are not known to be clinically useful. The patient was re-intubated the following morning in order to facilitate a CT head scan, which was normal. On the second postoperative morning, the sedation was stopped and the patient extubated without incident. She remained intensely blue-stained and had dark blue urine for 3 days. Her corrected calcium stayed within the normal range, and her haemoglobin dropped from a pre-operative value of 14.7 to 9.7 g.dl−1, which was attributed to haemodilution. There was no evidence of haemolysis. Over the following 2 days her speech and neurological status returned to normal. After a normal MRI scan on the fourth day, she made a full recovery, and was discharged to the ward before returning home. Despite many years of apparent innocuous use of intravenous methylene blue, it has definite toxic effects. Nadler et al.[3] found that intravenous methylene blue excited the individual, and by its rapid elimination into the stomach and urine produced transitory gastrointestinal and urinary irritation. The most frequent toxic symptoms observed were restlessness, paraesthesia, burning sensation and chest pain, all of which subsided in 24–48 h. A number of individuals also complained of dizziness, headache and mental confusion, all of which completely resolved. The UK National Poisons Information Service (Cardiff Centre) recommend an intravenous dose not exceeding 4 mg.kg−1 of a 1% solution and list similar potential signs and symptoms of toxicity, namely nausea and vomiting, abdominal pain, precordial pain, headache, hypertension, profuse sweating, restlessness and confusion. They also state that methylene blue itself may cause methaemoglobinaemia (up to 7%) when given in very large doses, but that this amount of methaemoglobin (MHb) is clinically insignificant. Another authority reports that if methylene blue intravenous dosage exceeds 7 mg.kg−1, the same adverse symptoms may result [4]. Yet staining abnormal parathyroid glands with 7.5 mg.kg−1 of intravenously administered methylene blue is common practice among surgeons and we have been unable to find reports of toxicity in the literature associated with this dose. The picture presented could be explained by the hypoxaemia caused by methaemoglobinaemia. However, it is unusual for MHb levels of less than 20% to be associated with hypoxic symptoms such as confusion, and in individuals with normal amounts of haemoglobin (Hb), an MHb level of less than 20% usually only causes cyanosis [5]. Our patient had a pre-operative Hb of 14.7 g.dl−1 and the maximum MHb present at the height of symptoms was only 0.7%. We are therefore led to conclude that the observed decrease in Hb was not proportional to the intensity of the symptoms, unless it could be argued that the reversibility of this reaction is almost immediate. Indeed, the reconversion rate of MHb to haemoglobin in normal individuals is about 15% per hour, assuming no ongoing MHb production [6]. Furthermore, if this clinical picture was brought about by acute hypoxaemia, we would have expected to see a more marked effect on respiration and circulation, whereas the primary effect seemed to be a neurological one. We are led to conclude that the harmful effects of methylene blue may not be associated primarily with methaemoglobin, but rather attributed to the direct action of the drug itself. A further possible explanation might be a neuroexcitatory response to propofol. There are a number of reported cases of hypertonia, opisthotonus, jerky movements and seizures occurring in otherwise healthy individuals after an anaesthetic involving intravenous propofol [7]. Whilst some of the features seen in this case would be consistent with an adverse response to propofol, it would not explain the profuse sweating and sense of apprehension seen in this patient. Furthermore, the patient was sedated with propofol on the intensive care unit for 24 h, during which time her symptoms improved. Thus, although we cannot give conclusive evidence that this patient's symptoms were wholly a result of the high dose of methylene blue, it remains the most likely cause. In summary, it is important to remember that no dye or drug given to a patient either intra-operatively or postoperatively should be regarded as inconsequential, and indiscriminate use of methylene blue in doses above those recommended may produce unpleasant results and may be dangerous to the patient.