Methylene Blue–Induced Serotonin Toxicity: Case Files of the Medical Toxicology Fellowship at the New York City Poison Control Center

Case Presentation

A 46-year-old female presented to the Emergency Department (ED) via Emergency Medical Services (EMS) due to syncope. Per the EMS report, the patient independently ambulated to a crossing guard, asked for help, and collapsed. On arrival, EMS found the patient lethargic but arousable with bradycardia and hypotension. They administered a 10-µg intravenous (IV) push of epinephrine and transported the patient to the ED.

In triage, the patient was found to be altered with a blood pressure of 74/46 mmHg, heart rate of 91 bpm, and SpO₂ of 100% on room air. Her finger-stick glucose was 88 mg/dL. She was unable to provide any additional history. The patient was put on a cardiac monitor, additional IV access was obtained, and an IV fluid bolus of 2 L was administered without improvement in her blood pressure.

Chart review revealed that the patient had been seen by psychiatry several days prior to this presentation for anxiety, and at that time, she denied any suicidal ideation. Her medication list included amlodipine (a dihydropyridine calcium channel blocker [CCB]) and lisinopril (an angiotensin-converting enzyme inhibitor [ACE-I]) for hypertension and sertraline (a selective serotonin reuptake inhibitor [SSRI]) and buspirone for anxiety. She had no history of suicide attempts or previous hospitalizations related to mental health illness.

As the patient remained persistently hypotensive and the providers became increasingly concerned about the possibility of multi-drug ingestion, vasopressors were started, and an arterial line was placed. Poison control was contacted due to a concern for an overdose involving amlodipine, lisinopril, and sertraline. The patient was initially started on norepinephrine, and treatment escalated to include vasopressin, phenylephrine, and epinephrine. On point-of-care ultrasound, the patient had hyperkinetic left ventricular function with no signs of cardiogenic shock. A consultation for extracorporeal membrane oxygenation was placed, but was denied given the patient had retained adequate left ventricular contractility. Due to concern for possible dihydropyridine CCB overdose, an initial 2-g calcium gluconate bolus was given followed by a subsequent 4-g bolus; however, there was no improvement in blood pressure or mean arterial pressure (MAP). High-dose insulin (HDI) was not started due to concern for exacerbation of vasoplegic shock from endothelial nitric oxide synthase activation from insulin. A trial of naloxone 1.2 mg was used for possible ACE-I toxicity, with no improvement in MAP or mental status. As the patient’s MAP remained below 60 mmHg, the decision was made to start methylene blue as an adjunct vasopressor.

What is the Role for Naloxone in ACE-I Toxicity?

The evidence for use of naloxone to reverse ACE-I toxicity is highlighted in case reports [1–4]. The proposed mechanism is that ACE-Is antagonize enkephalinase leading to an increase in enkephalins [1]. Enkephalins are a class of endogenous opioids which act throughout the nervous system and have been shown to have physiologic effects on blood pressure regulation [5]. Theoretically, an increase in enkaphalins leads to vasodepression and decreased sympathetic tone [1]. Haluska et al. report an improvement in blood pressure from 75/40 to 94/63 mmHg 1 min after administration of 0.4 mg naloxone without requirement of a continuous infusion [2]. Some cases highlight resolution of hypotension after multiple bolus doses [4] whereas other cases report the requirement for a naloxone infusion for over 24 h prior to achieving resolution of hypotension [1, 3]. Bolus doses of naloxone ranged from 0.4 to 2 mg, with infusions ranging from weight-based doses of 0.04 mg/kg/h to non-weight based doses of 200 µg/h. Naloxone is a low-risk intervention that might help improve hypotension due to ACE-I toxicity by reversing the effects of increased endogenous enkephalins [2].

How Does Methylene Blue Act as a Vasopressor?

Methylene blue increases systemic vascular resistance by scavenging nitric oxide and inhibiting endothelial nitric oxide synthase (eNOS) and guanylate cyclase [6, 7]. eNOS produces nitric oxide in blood vessels and can be activated by several stimuli, including pharmacological agents that increase intracellular Ca²⁺ [8]. Nitric oxide is also produced by inducible nitric oxide synthase in vascular smooth muscle and cardiac myocytes. Nitric oxide activates guanylyl cyclase which increases production of cyclic guanosine monophosphate (cGMP). Increased cGMP leads to relaxation of myocardial and vascular smooth muscle. Jang et al. report a blood pressure improvement to 90/75 mmHg from 75/40 mmHg 1 h after administration of methylene blue. The patient had been hypotensive and tachycardic for 16 h following an overdose of amlodipine prior to initiation of methylene blue [6]. The patient had been given a 2 mg/kg bolus dose of methylene blue over 20 min followed by an infusion of 1 mg/kg/h [6]. A subsequent review found that methylene blue was also effective at improving blood pressure in patients with distributive shock due to sepsis or anaphylaxis [9]. Fisher et al. provide evidence of a multi-drug ingestion that did not involve a CCB or beta-blocker in which the patient demonstrated refractory vasoplegic shock that resolved with methylene blue. The patient’s blood pressure was 88/40 mmHg 12 h post-ingestion despite use of 4 L of IV fluids and four vasopressors [10]. The blood pressure improved to 90/40 mmHg 1 h following a loading dose of 1.5 mg/kg of methylene blue and an infusion at a rate of 1.5 mg/kg/h [10]. The authors report that the vasopressor requirements decreased 1 h after initiation of methylene blue, and the patient only required norepinephrine to maintain hemodynamic stability [10]. However, a more recent randomized trial using a porcine model of amlodipine toxicity found no difference in survival time when methylene blue was compared to norepinephrine [11].

Case Continuation

After a 1 mg/kg bolus dose of methylene blue, a pulmonary artery catheter was used to confirm vasoplegic shock. The patient had a mean pulmonary artery pressure of 29 mmHg (reference range: 9–16 mmHg), a central venous pressure of 13 mmHg (8–12 mmHg), a cardiac index of 5.58 L/min/m² (2–4 L/min/m²), a systemic vascular resistance of 380 dyne s/cm⁵ (900–1600 dyne s/cm⁵), and a systemic vascular resistance index of 688 dyne·s·m²/cm⁵ (1600–2400 dyne·s·m²/cm⁵). This confirmed the patient was in vasoplegic shock with adequate cardiac contractility. Initial labs came back with an ethanol level of 35.8 mg/dL and negative for salicylate or acetaminophen. The patient was admitted to the intensive care unit (ICU) and intubated for airway protection. As the patient’s MAP continued to remain below 60 mmHg despite use of four vasopressors and a methylene blue bolus, the treatment team continued with a methylene blue infusion at 1 mg/kg/h. Overnight, the patient developed an up trending temperature rising from 37.9 to 39.5 °C within 4 h. On exam in the morning of hospital day 2, the patient had hyperreflexia in her knees and continuous inducible clonus in her lower extremities bilaterally.

What is the Mechanism of Methylene Blue–Induced Serotonin Toxicity?

Methylene blue is a monoamine oxidase inhibitor (MOAI) [12, 13]. At therapeutic doses, methylene blue is a potent MOA-A inhibitor and partial MOA-B inhibitor [13]. The MOAI properties of methylene blue alone are unlikely to lead to serotonin toxicity. However, when combined with a xenobiotic that has serotonin reuptake inhibiting (SRI) properties, use of methylene blue creates a risk for serotonin toxicity [12].

What is the History of Methylene Blue-Induced Serotonin Toxicity?

The first record of methylene blue leading to serotonin toxicity was in 1999 [14]. The authors noted a patient developed altered mental status, brisk reflexes, ankle clonus, hypertension, and hyperthermia following administration of methylene blue during a parathyroidectomy [14, 15]. More recently, two retrospective surgical case reviews of patients receiving methylene blue as surgical dye for parathyroidectomy highlighted that out of 280 patients, any reported symptoms consistent with serotonin toxicity only occurred among patients being treated with an SRI and none who had not been treated with an SRI [16, 17]. Serotonin toxicity has also been reported from use of methylene blue as a vasopressor [18, 19]. Chan et al. report a patient with refractory vasoplegic shock from a multi-drug ingestion that developed serotonin toxicity after initiation of methylene blue. Similar to prior cases, the authors report the patient’s MAP improved from 48 to 70 mmHg following a 1.5 mg/kg bolus and 1.5 mg/kg/h infusion; however, the patient developed hyperthermia, increased tone, and rigidity in their lower extremities bilaterally with sustained clonus 5.5 h after administration of the methylene blue bolus [18]. Serotonin toxicity has also been reported outside of the ED for other surgeries as well. Schumacher et al. report serotonin toxicity after giving a patient methylene blue 0.5 mg/kg/h as a vasopressor due to persistent hypotension following a routine left ventricular assist device (LVAD) placement [19]. They also highlight their case to be 1 of 14 in the cardiology literature implicating serotonin toxicity after use of methylene blue. In 13 of the 14 cases, the authors discuss, patients had used an SRI prior to hospitalization [19].

Case Conclusion

Early in the morning on hospital day 2, the methylene blue infusion was stopped, and the patient was given midazolam 4 mg IV push followed by diazepam 20 mg IV about 2.5 h later. The patient’s workup did not yield evidence that the vasoplegia was due to sepsis. The patient’s temperature continuously rose over the course of 13 h, from 37.8 °C at the end of hospital day 1 to a peak of 39.4 °C on hospital day 2 before starting to downtrend. The hyperthermia was likely due to serotonin toxicity as the first hyperthermic temperature of 38.2 °C was recorded 12.5 h after initiation of methylene blue, and resolution of hyperthermia occurred ~ 11.5 h after cessation of methylene blue and administration of midazolam 4 mg IV push. The patient’s creatine kinase was normal on hospital day 1 and started to rise 8 h after the temperature started to increase, peaking at 9332 IU/L on hospital day 2 with no evidence of kidney injury. The hyperreflexia and clonus had resolved by hospital day 3 with no subsequent administration of benzodiazepines. The patient’s MAP started to improve on hospital day 2 with a decrease in vasopressor requirements. Upon extubation, the patient reported an intentional ingestion of amlodipine, lisinopril, sertraline, and buspirone with alcohol. On hospital day 6 the patient was downgraded from the ICU to the psychiatric unit for further treatment.

Does the Dosage or Timing of Methylene Blue Contribute to the Risk of Serotonin Toxicity?

There is evidence that methylene blue will inhibit MAO-A at doses as low as 1 mg/kg [12, 15]. According to the manufacturer’s package insert, the half-life of methylene blue is 24 h; however, Walter-Sack et al. report the half-life to be 14 h in plasma whereas Peter et al. report the half-life to be 5.5 h [20–22]. In vivo studies showed that maximum plasma concentrations were achieved approximately 30 min after administration of intravenous methylene blue [20]. As such, the typical doses used for methemoglobinemia or vasoplegic shock (1 mg/kg) appear to be sufficient to cause serotonin toxicity. Based on the above pharmacokinetic and pharmacodynamic data, we would expect the onset of symptoms to be within several hours and lasting up to 24–48 from after cessation of methylene blue administration.

Is Vasoplegic Shock or Cardiogenic Shock More Common in Patients with Amlodipine Toxicity?

In contrast to non-dihydropyridine CCBs, dihydropyridine CCBs (such as amlodipine) have a stronger affinity for Ca²⁺ channels at a less negative membrane potential and therefore prefer to bind to L-type Ca²⁺channels in peripheral vascular smooth muscle (− 70 mV) instead of cardiac muscle (− 90 mV) [23]. As such, dihydropyridine CCBs preferentially antagonize Ca²⁺ channels in the peripheral vasculature and lead to vasoplegic shock with a reflex tachycardia [23]. Therefore, amlodipine is more likely to cause vasoplegic shock than cardiogenic shock. However, in overdose, receptor selectivity can be lost, and cardiogenic shock should be considered with amlodipine overdose — particularly if the patient is bradycardic [24].

High-Dose Insulin Therapy Can Be Used to Treat Shock from CCBs: Why Was It Not Used in This Case?

High-dose insulin (HDI) is a generally accepted treatment for CCB toxicity [24]. However, there is a distinction between the cardiovascular effects of non-dihydropyridine CCB versus dihydropyridine CCB. Whereas non-dihydropyridine CCBs lead to reduced cardiac contractility and depressed myocardial conduction systems, dihydropyridine CCBs more commonly result in peripheral vasodilation and tend to result in reflex tachycardia [25]. Furthermore, amlodipine causes vasodilation through an additional mechanism of directly activating eNOS, which is also activated by insulin [25]. As such, use of HDI is expected to work better for non-dihydropyridine CCB than for dihydropyridine CCB toxicity. Some case reports showed that patients with amlodipine toxicity had favorable outcomes with treatment of HDI and vasopressors [26, 27]. Koliastasis et al. provide a case of patient in refractory hypotension attributed to amlodipine overdose who had a systolic blood pressure of 65 mmHg that improved to 95 mmHg 30 min after initiation of HDI. In contrast, a retrospective study showed that patients with amlodipine toxicity treated with HDI experienced more vasoplegia than patients with non-dihydropyridine toxicity [25]. Cole et al. conclude that it is possible the stimulation of eNOS by both amlodipine and HDI could theoretically lead to worsening vasoplegia. In the case presented here, the patient was confirmed to have vasoplegic shock with preserved cardiac contractility, and the decision was made to not use HDI due to concern for exacerbation of vasoplegia.

Is There a Synergistic Effect from Dihydropyridine CCB Toxicity Combined with ACE-I Toxicity That could have Led to This Degree of Vasoplegic Shock?

Profound vasoplegic shock from CCB combined with ACE-I or angiotensin-II receptor blocker (ARB) toxicity has been documented in case reports [28, 29]. A recent case series found that overdoses of dihydropyridine CCBs with an ACEI or ARB were associated with more hypotension and bradycardia than overdoses with dihydropyridine CCBs alone [30]. Huang et al. also found that combined CCB and ACEI/ARB overdoses required more hemodynamic support versus CCB overdose without an ACEI/ARB. The potential synergism between CCBs with ACEI/ARB leading to vasoplegic shock is likely due to widespread peripheral vasodilation without physiologic capability to compensate. Once a CCB overdose leads to widespread peripheral vasodilation, the physiologic counter-regulatory mechanism through activation of the renin–angiotensin–aldosterone system is inhibited by the concurrent ACEI/ARB overdose.

If a Patient on a Therapeutic SRI Develops Acute Methemoglobinemia, Should Methylene Blue Be Withheld Due to Concern for Serotonin Toxicity?

Methylene blue should not be withheld if indicated to treat methemoglobinemia. While there may be a risk of serotonin toxicity if the patient is on SRI therapy, methylene blue is a potentially lifesaving treatment and therefore should not be withheld. If a patient taking an SRI presents with methemoglobinemia requiring methylene blue administration, they should be closely monitored for the development of serotonin toxicity until resolution of their symptoms.

Funding

None.

Declarations

Conflicts of Interest

None.