Anticholinergic Toxidrome as a Possible Explanation for Methylene Blue Toxicity

Background

Methylene blue has multiple uses in medicine. It is generally used to treat refractory vasoplegia [1], and methemoglobin toxicity [2], or as a dye to localize the parathyroid glands intraoperatively [3]. In refractory vasoplegia, methylene blue inhibits endothelial nitric oxide and guanylate cyclase, causing vasoconstriction and potentially stabilizing blood pressure [1]. Multiple complications have been associated with the use of methylene blue. These are related to either the sole effect of methylene blue [4] or the combined effect of methylene blue and certain antidepressants, such as selective serotonin reup-take inhibitors (SSRIs) [5]. However, the mechanisms underlying methylene blue toxicity have yet to be fully elucidated. Studies have revealed that methylene blue blocks muscarinic receptors in the central nervous system [6]. Furthermore, the neurological toxicity of methylene blue observed after parathyroidectomy, excluding serotonin syndrome, has been linked to the anticholinergic effects of methylene blue [4]. To the best of our knowledge, in the setting of post-cardiac surgery vasoplegia, there have been no reports of neurological toxicity from methylene blue in the absence of SSRI use. In this case, we describe the anticholinergic manifestations associated with the use of methylene blue in post-cardiac surgery vasoplegia. This case report is presented after obtaining consent for publication from the participant.

Case Report

A man in his mid-sixties with mitral valve regurgitation (MVR), which had been repaired with artificial neo-chordae, presented with dyspnea related to repair failure and severe MVR. The patient had stopped smoking 10 years prior to admission and denied using alcohol, antidepressants, antipsychotics, or amphetamines. The patient had undergone elective mitral valve replacement with a mechanical valve and implantation of an intra-aortic balloon pump (IABP). Upon arrival at the critical care unit, the patient was hypotensive and tachycardic, requiring high doses of vasopressors and inotropes. Arterial blood gases exhibited a pH of 7.18 and a lactic acid concentration of 8.8 mmol/L. Transesophageal echocardiography (TEE) was performed and revealed diffuse left ventricular (LV) hypokinesia with an ejection fraction of 25%, LV wall hypertrophy, moderate right ventricular (RV) dysfunction, and a normally functioning mitral valve prosthesis. The patient received crystalloids and colloids to augment the preload and inhaled nitric oxide (NO) to support RV systolic function and oxygenation. While the patient was still on IABP, there was no plan to escalate the ventricular support by using other mechanical circulatory support devices. Two hours after arrival at the critical care unit, the vasopressors and inotrope requirements continued to increase (vasopressin at 0.06 units/min, epinephrine at 0.05 mcg/kg/min, and norepinephrine at 0.3 mcg/kg/min). The decision was made to administer a methylene blue bolus of 1.5 mg/kg, followed by a continuous infusion at 1 mg/ kg/h. Initially, the patient’s blood pressure responded well to the methylene blue and the infusion was reduced to 0.6 mg/ kg/h; however, 8 hours later, hypotension worsened, and the patient became severely oliguric. The dose of methylene blue infusion was then increased to 0.8 mg/kg/h and the patient was still hypotensive. Eighteen hours after the first methylene blue bolus, another bolus of methylene blue at 1 mg/kg was administered. Promptly, the patient became anuric and hyperthermic, with a temperature of 42°C, and presented with bilateral mydriasis and lactic acidosis (lactic acid concentration of 13 mmol/L).

Internal cooling was initiated through a nasogastric tube and Foley catheter. Internal cooling was stopped after the patient’s temperature decreased to 38°C. The patient became normothermic 5 h after reaching peak temperature. At this point, the mydriasis had resolved. Antibiotics (piperacillin/tazobactam and vancomycin) were administered and blood cultures were obtained. Continuous renal replacement therapy (CRRT) was initiated. Within the next 2 hours after starting CRRT, the doses of vasopressors were reduced, and blood pressure had stabilized. Twelve hours after starting CRRT, the patient was on minimal doses of vasopressors and the methylene blue was discontinued. However, his lactic acid levels remained high for the following 5 days.

The patient was discharged after 4 months of hospitalization with a permanent catheter for hemodialysis. The patient returned to his preoperative functional status and recovered from the psychiatric complications related to prolonged hospitalization.

Discussion

This report describes a case of profound vasoplegia following cardiac surgery that required treatment with methylene blue in addition to vasopressors and inotropes. This treatment resulted in hyperpyrexia, mucosal dryness, and bilateral dilated pupils. The patient received 2 methylene blue boluses (1.5 mg/kg and 1 mg/kg) and was on methylene blue infusions ranging from 0.6 mg/kg to 1 mg/kg. Methylene blue toxicity was included in the differential diagnosis, as the patient had been exposed to both large doses of methylene blue and fentanyl in the context of multi-organ failure. Serotonin and anticholinergic syndromes are potential causes. Infectious causes were less likely as fever began within 24 h following surgery, and multi-site cultures were negative. Laboratory tests and computed tomography (CT) excluded endocrine and neurological causes. Malignant hyperthermia and neuroleptic malignant syndrome were also excluded as the patient did not present with muscle rigidity.

The use of methylene blue for refractory vasoplegia after cardiac surgery is common, and its early use may reduce mortality and the duration of vasopressor support [7,8]. No previous studies have compared different doses of methylene blue in patients with vasoplegia. The dose is generally the same as that used to treat methemoglobinemia (2 mg/kg) [1]. In our institute, the maximum bolus dose is 1.5 mg/kg. Higher doses have been used in refractory vasoplegia, reaching up to 5.5 mg/kg with no significant complications [8]. The standard doses used to identify the parathyroid gland intraoperatively are generally higher, ranging from 5 mg/kg to 7.5 mg/kg [4,9]. At these doses, there have been reports of neurological toxicity that can be attributed to methylene blue after the exclusion of other causes [4,10,11]. The symptoms include agitation, confusion, nystagmus, aphasia, hyperpyrexia, and seizures [11]. The most reported symptom of methylene blue neurological toxicity is altered mental status in the form of agitation and confusion [4,10–12]. It was difficult to assess the neurological status of the patient presented in this report because he was obtunded, in severe shock and in multi-organ failure. The use of methylene blue as an infusion for septic shock has also been reported, whereby an infusion of 0.5 mg/kg/h was used; however, there were no reports of toxicity at that dose [13–15].

Methylene blue has been described as a potential cause of serotonin toxicity, especially in patients exposed to fentanyl, which is a serotonin agonist [16,17]. It has also been reported that increased doses of methylene blue are more likely to induce serotonin syndrome [18]. Despite the established link between methylene blue and serotonin syndrome, no case of the development of serotonin syndrome has been reported with methylene blue as the sole pharmacological cause. In the present case, the patient did not meet standard diagnostic criteria for serotonin syndrome.

The most probable toxicological process is anticholinergic syndrome. Anticholinergic syndrome occurs when exogenous compounds inhibit sweat glands and muscarinic receptors in the central nervous system [19]. In this case, the patient received methylene blue and fentanyl, both of which have been reported to interact with the cholinergic system [20]. It is also noteworthy that methylene blue contains a phenothiazine pharmacophore, which has been shown to interact with multiple phenothiazine derivatives at various doses in affecting the central muscarinic system [21]. The patient was also exposed to fentanyl, a muscarinic antagonist, the effect of which may have been potentiated by a pharmacokinetic interaction with methylene blue through cytochrome P450 3A4 inhibition and multi-organ failure [22–24]. Within hours of the initiation of these drugs, the patient developed fever, mucosal dryness, anhidrosis, and mydriasis, all of which are manifestations of anticholinergic toxidrome. Detection of other manifestations of anticholinergic toxidrome is limited. Other case reports linking methylene blue toxicity and anticholinergic syndrome reported fewer symptoms [4–15].

Despite the occurrence of the above-mentioned symptoms suggesting anticholinergic syndrome, the treatment team excluded serotonin syndrome and did not consider other methylene blue toxidromes. This explains the 24-hour delay in discontinuing methylene blue. In addition, the patient should not have received another bolus of methylene blue, and the infusion should not have exceeded 0.5 mg/kg/h, especially in the context of acute kidney injury. Treatment of methylene blue toxicity should include urgent discontinuation of the drug, enhanced elimination, and supportive therapy.

Conclusions

Anticholinergic toxidrome can explain the neurological adverse effects associated with high methylene blue doses. Physicians should be cautious when using methylene blue in combination with other anticholinergic drugs in patients with renal failure. The development of methylene blue toxicity warrants urgent discontinuation of methylene blue and early drug elimination.