Methylene Blue Encephalopathy: A Case Report and Review of Published Cases Ellen Shopes, CRNA, MHS, MSN, CCRN Wayne Gerard, MD Jessica Baughman, CRNA Methylene blue is a cationic thiazine dye useful in staining parathyroid glands during surgical resection. There have been a number of reports of altered neurologic status postoperatively in patients who are taking antidepressant medications when they received methylene blue for their surgery. We present a case report and review 30 additional cases that have been reported in the literature. It has been suggested that in susceptible individuals an interaction occurs between

M

ethylene blue is a cationic thiazine dye. In clinical practice, it is used to treat encephalopathy due to ifosfamide, a chemotherapeutic agent with associated neurotoxicity. Methylene blue improves oxygen-carrying capacity in cases of methemoglobinemia. It is the only dye in common use for staining parathyroid glands during surgical resection.1 In the early 1970s, methylene blue was introduced as a replacement for toluidine blue (which caused cardiotoxicity). Since that time, a number of reports have been published relating perioperative use of methylene blue to postoperative altered mental status. What was initially thought of as a harmless substitute for toluidine blue may, in some patients, induce adverse reactions and sequelae in the postoperative period.

Case Summary A 50-year-old, 103-kg woman presented to our service for an elective parathyroidectomy. Her chief complaint was frequent urination and bladder irritability. Results of laboratory analysis revealed an elevation of calcium and parathyroid hormone (PTH) levels. A gallium scan showed mild diffuse tracer uptake in 4 parathyroid glands, more pronounced in the right inferior gland. The patient’s medical history included obesity (body mass index [BMI] of 40 kg/m2), hypertension, hyperlipidemia, type 2 diabetes, lumbar stenosis with radicular pain, bipolar disorder, and gastroesophageal reflux disease. Her medications included insulin, atenolol, verapamil, levothyroxine (Synthroid), lithium, gabapentin, oxybutynin, lorazepam, simvastatin, carbamazepine, and lamotrigine. On the morning of surgery, she presented in no acute

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methylene blue and serotonergic agents that precipitates serotonin syndrome. Because people with hyperparathyroidism commonly experience depression as part of their illness, anesthesia practitioners should exercise increased vigilance when administering methylene blue to these patients. Keywords: Methylene blue, parathyroidectomy, postoperative encephalopathy, serotonin syndrome.

distress. Vital signs were within normal limits. Nothing had been taken by mouth except for her morning medications. During her 1.5 hours in the preoperative holding area, she urinated twice in the bathroom. Sedation was achieved with midazolam (2 mg) and fentanyl (50 μg). General anesthesia and endotracheal intubation was achieved with fentanyl (100 μg), lidocaine, propofol, and succinylcholine. Anesthesia was maintained throughout the 6-hour case with sevoflurane, fentanyl (250 μg), and morphine (10 mg). Because no right inferior parathyroid gland could be identified, the surgeon requested that methylene blue be administered at a dose of 7.5 mg/kg (750 mg) over a 30-minute period. Two superior parathyroid glands were identified and excised, with subsequent decline of intraoperative PTH levels from 93.6 pg/ mL to 19.1 pg/mL (reference range = 10-55 pg/mL). During infusion of the methylene blue, the patient’s esophageal temperature rose from 37.5°C to 38.5°C. Except for a decline in oxygen saturation, all other vital signs remained unchanged. Arterial blood gases drawn 45 minutes after the start of the infusion were normal (Po2 = 113 mm Hg; Pco2 = 31 mm Hg; pH = 7.47). Intraoperatively the blood glucose level was 133 mg/dL. At the completion of surgery, the patient was extubated and transported to the postanesthesia care unit (PACU). The patient’s tympanic temperature was 37.3°C. Vital signs and oxygen saturation were in the normal range. The patient appeared drowsy with an unfocused gaze. She opened her eyes to gentle stimulation and responded to questions slowly, with poorly articulated yes and no answers. No medications were administered during her time in the PACU. The patient was admitted to the step-down unit. She remained lethargic but arousable for the remainder of the

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Finding Preoperative

Day of surgery

Postop day 1

Postop day 2

Postop day 3

Laboratory values Sodium (mEq/L)

141

140

149

153

163

Potassium (mEq/L)

4.6

4

4.1

3.1

4

BUN (mg/dL)

22

Not measured

18

16

18

Glucose (mg/dL)

161

133

241

257

300

Lithium (mEq/L)

1.1

1.2

1.6

0.7



24-hour intake (mL)

Not measured

3,750

3,390

2,100

4,030

24-hour urinary output (mL)

Not measured

2,885

5,200

3,650

5,436

Neurologic findings

Alert, oriented

Arouses with stimulation, disoriented, follows simple commands, answers yes/no questions

Alternately lethargic or agitated, disoriented, speech difficult to understand

Lethargic or agitated

Lethargic or agitated, had respiratory distress requiring endotracheal intubation

Table 1. Laboratory Values and Neurologic Findings Abbreviations: BUN, serum (blood) urea nitrogen; postop, postoperative.

operative day. She was oriented only to person, and her speech was garbled. She was able to follow simple commands but lapsed into a state of apparent sleep without constant stimulation. She was unaware of her hospitalization and recent surgery. She was able to take sips orally with medications. Glucose measurement obtained by finger stick rose to 226 mg/dL, and she was treated with 3 U of regular insulin. By the end of the operative day, she had received a total intake of 3,750 mL and had a urinary output of 2,885 mL. She received her usual bedtime dose of lorazepam (1 mg) orally. Laboratory data and neurologic findings for the recovery period through postoperative day 3 are summarized in Table 1. On the morning of postoperative day 1, the patient remained sleepy but arousable to painful stimuli (sternal rub). Her speech was difficult to understand. According to the anesthesiologist on call, she was “barely able to answer simple questions.” There were no apparent focal neurologic deficits. She had received no pain medication since surgery. At times, the patient would arouse and attempt to weakly climb out of bed or pull out invasive lines and the urinary catheter. To improve her mental status, all sedating medications were held. When agitation and disorientation became hazardous to her safety, 2 mg of lorazepam was incrementally administered. Her routine medications had been resumed. On postoperative day 2, restraints were required to maintain patient safety. By postoperative day 3, her condition deteriorated. She produced copious amounts of green urine, and serum sodium levels continued to climb. Her lithium level (1.6 mEq/L) was within the normal range. As the day progressed, her level of consciousness continued to decline, necessitating intubation for airway

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protection. She was transferred to the intensive care unit (ICU). A consulting psychiatrist believed that the cause of her altered sensorium was multifactorial and recommended that administration of all sedative medications be stopped. Consultation with a nephrologist described 2 possible causes of her altered mental status: (1) hypernatremia secondary to lithium-induced diabetes insipidus and (2) methylene blue toxicity. Electrolyte abnormalities developed on postoperative day 2 and peaked on day 3. These electrolyte abnormalities coincided with a high urinary output, indicative of diabetes insipidus. Changes in the patient’s sensorium before postoperative day 2 were likely caused by methylene blue toxicity. Lithium treatment was discontinued at the recommendation of the nephrology service. The patient was aggressively hydrated and given desmopressin to treat diabetes insipidus. A neurology consultation at this time recommended slow correction of hypernatremia and supportive care. Further neurologic testing was suggested if the patient’s condition remained unchanged after several days off sedatives and with sodium correction. For 10 days postoperatively, she continued to have green-tinged urine, suggesting that methylene blue may have been contributing to her altered sensorium. During the remainder of her hospitalization, she experienced multiple setbacks, including prolonged altered mental status while off sedating drugs, extubation followed by cardiopulmonary arrest, and tracheostomy for long-term respiratory support. Long-term physical therapy was needed to restore her strength and ability to function independently. She was eventually discharged from an extended care facility to home 110 days after surgery.

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Discussion • Pharmacology of Methylene Blue. Methylene blue is a heterocyclic aromatic compound that turns intensely blue in solution. At physiologic pH, it is a highly ionized drug.2 The chemical structure of methylene blue resembles the tricyclic scaffold of phenothiazines, the basis for first-generation antipsychotic medications.3,4 The pharmacokinetics of intravenous methylene blue indicates that it is extensively distributed into deeper compartments. The apparent volume of distribution after an intravenous dose is reported to be 21.0 L/kg, unusual for a highly ionized drug. A multicompartmental mode of distribution suggests that factors outside of plasma protein binding account for its high volume of distribution and slow rate of disappearance.2 Animal studies conducted show a 10-fold higher concentration of methylene blue distribution after intravenous administration in the brain and bile compared with concentrations reached in the blood.5 Questions regarding the distribution profile of methylene blue still exist when discussing the plasma space, nonblood space, and lipid space, warranting further research. Vutskits et al6 studied the CNS effects of methylene blue on isoflurane-anesthetized rats. In addition to a decrease in the minimal alveolar concentration seen with methylene blue infusion, they noted apoptotic neurons in all brain regions after a single bolus injection of 5 mg/kg. Mature neurons in vitro exposed to nonlethal doses of methylene blue underwent morphologic changes, including dendritic retraction, indicating persistent remodeling. A typical dose of methylene blue administered for parathyroidectomy staining is 7.5 mg/kg, with some institutions dosing as low as 5 mg/kg.3,7 The UK National Poison Information Service recommends that doses of greater than 4 mg/kg not be given because they correlate more often with neurologic side effects.8 The US Food and Drug Administration recently issued a drug safety communication on potential interactions between methylene blue and serotonergic psychiatric drugs.9 Reports of serotonin syndrome have resulted in the recommendation that methylene blue should generally not be given to patients taking serotonergic drugs. • Literature Case Review. Including the case report presented, there have been 31 cases of methylene blue– associated encephalopathy following parathyroidectomy (Table 2). Most cases (84%) involved women. The incidence of primary parathyroid adenoma favors women over men (3:1 to 4:1); therefore, it is likely that sex differences in methylene blue encephalopathy mimic the prevalence of parathyroidectomy in the general population. The age of patients with methylene blue toxicity ranged from 34 to 80 years. Methylene blue was administered intravenously either preoperatively or intraoperatively. Dosages ranged from 1.75 mg/kg to 7.5 mg/kg. Patient weight and BMI were

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not consistently reported. In the 7 cases (23%) in which BMI was reported, it ranged from 23 to 49 kg/m2. It is not known if methylene blue was dosed by actual or ideal body weight. The dosage of methylene blue administered was compared with the severity of CNS symptoms. Cases were classified as severe if reintubation with mechanical ventilation was required for more than 24 hours, or if patient recovery took longer than 96 hours. There was no correlation between the dose of methylene blue and the severity of encephalopathy. One death was reported, at the time presumed by the authors to be a result of the patient’s comorbidities.10 The medical history of the reported cases often revealed a psychiatric history, treated with 1 or more medications (Table 3). The medications reported often interacted with serotonin. In one case report, there was neither a history of psychiatric disorders nor treatment with any psychotropic medication.11 There is no mention in most of the case reports when the patient received the last dose before surgery, or what dosages were taken. An attempt was made to identify signs and symptoms present with the development of the encephalopathy. These signs and symptoms were further classified as early vs late in the course of the pathology. Early symptoms were those identified at the time of the infusion to the end of time in the PACU. Usually, methylene blue was administered during surgery after induction of general anesthesia. In 2 instances, the infusion was begun in the preoperative area, with the patients experiencing nausea and vomiting. Nausea and vomiting is one potential autonomic disturbance seen in serotonin syndrome12 and may be an early signal of CNS toxicity. Since doses in the other cases were administered with the patient under anesthesia, there were insufficient data to confirm this. All patients received a general anesthetic for parathyroidectomy. Although not reported in detail in each case, most patients received similar medications and dosages: midazolam, fentanyl, propofol, a neuromuscular blocker, and isoflurane or sevoflurane. Some patients received an antiemetic. Some patients had residual neuromuscular blockade reversed before extubation. Common signs and symptoms observed following methylene blue administration are identified in Figure 1. Fever, sweating, or shivering were reported in some instances. In our case, the patient’s temperature began to rise shortly after the start of the methylene blue infusion. Fever, shivering, and diaphoresis are findings consistent with serotonin syndrome.12 These findings may be early signs of toxicity. It was not possible to determine from the other case studies whether febrile reactions occurred or if temperature was monitored. In approximately 30% of the cases, a delay in recovery from anesthesia was described by terms such as “slow to awaken,” “lethargic,” “depressed level of consciousness,”

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Reference Methylene Case and Age Associated blue dosage No. year (y) Sex medications (mg/kg) Presentation

Symptom duration (days)

1 Stanford,22 1999 49 F Paroxetine NR

Agitation, confusion, uncontrolled limb movements, enlarged pupils, brisk reflexes, hypertension, febrile

2

F Fluoxetine 7.5 2 Martindale,8 2003 60

Rotational nystagmus; dilated, non- reactive pupils; rigid, jerky movements; agitation; diaphoresis; speech problems

2

3 Bach,23 2004

Aphasic, disoriented, clonus

2

65 M Citalopram 7.5 4 Mathew,14 2006

59

Nausea during infusion, slowness to awaken, agitation, disorientation, shivering, diaphoresis

14

42-80 2 M, SRI 7.5 5-16 Kartha,10 2006 10 F

Confusion, difficult to arouse, delirium, NR; agitation, sluggish pupils, nonverbal, 1 death vision loss, blurred vision, tremors, jerky movements, inappropriate speech

52 F Venlafaxine 7.5 17 Majithia,7 2006

Delayed recovery from anesthesia, nystagmus, aphasia, confusion

2

48 M NR 4 18 Patel,11 2006

Vomiting during infusion, generalized tonic-clonic seizure

4

66 F Clomipramine 5 19 Khan,3 2007

Slowness to waken, confusion, agitation, jerky movements

2

65 F Paroxetine, carbimazole 1.75 20 Mihai,27 2007

Agitation, aphasia, not following commands

2

21 Sweet,15 2007

Vertigo, confusion, lethargy, aphasia

3

73 F Escitalopram 5

Lethargy, aphasia, depressed level of consciousness

2

23 Sweet,15 2007

60

F

Venlafaxine

3

Agitation, confusion, aphasia

3

24 Sweet,15 2007

48

F

Fluoxetine, bupropion

3

Confusion, lethargy, vertigo

2

3

Confusion, disorientation

2

44 F Citalopram NR 26 Khavandi,24 2008

Agitation, incomprehensible sounds, vague staring, dilated pupils with sluggish response, myoclonus, brisk reflexes

3

58 F Paroxetine 5 27 Ng,4 2008

Sedated in PACU; agitation; disorienta- tion; nonpurposeful movements; increased muscle tone; rapid, fluid eye movements

2

67 F Duloxetine 7.5 28 Rowley,13 2009

Slowness to waken; agitation; disorienta- tion; not following commands; nystagmus; diaphoresis; slow, roving gaze

2

55 F Citalopram, bupropion 7.5 29 Pollack,25 2009

Agitation, confusion, diaphoresis, hypertension, tachycardia, aphasia, dilated pupils, cortical blindness, choreiform movements

3

77 F Clomipramine 5 30 Héritier Barras,26 2010

Confusion, agitation, mydriasis, rigidity, shivering, hyperreflexia, fever, hypertension, tachycardia, clonus

7

31 Shopes, 2013 50 F Lithium, lamotrigine, 7.5 (present case) carbamazepin, gabapentin

Fever; lethargy; agitation; slow, slurred speech; confusion; unfocused, wandering gaze

110

60

M

Paroxetine

F

Fluoxetine

6

5

22 Sweet 15 2007

25 Sweet,15 2007

34 F Mirtazapine, quetiapine, venlafaxine

Table 2. Summary of Methylene Blue Cases Abbreviation: NR, not recorded; PACU, postanesthesia care unit; SRI, serotonin reuptake inhibitor.

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Inhibits No. of serotonin Category Name cases uptake SSRI Citalopram 3

Escitalopram

1

X X



Fluoxetine

3

X



Paroxetine

4

X

SNRI Duloxetine 1

Venlafaxine

3

X X

Figure 1. Incidence (%) of Symptoms Following Methylene Blue Administration (n = 31)a

TCA

Clomipramine 1

X

a Ocular and speech abnormalities are described in the text (see

Antipsychotic, bipolar

Quetiapine

1

X

Literature Case Review).



Lamotrigine

1

X



Lithium

1

X

Others Bupropion 2

Carbamazepine

1



Gabapentin

1



Lorazepam

1



Mirtazapine

1

X

Table 3. Drugs Associated With Methylene Blue Encephalopathy Abbreviations: SSRI, selective serotonin reuptake inhibitor; SNRI, selective norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; X, yes.

or “difficult to arouse.” Confusion and agitation were common. Delirium and hallucinations were reported in 13% of the cases. Speech abnormalities ranged from aphasia to inappropriate sounds (singing) to slow speech. Incomprehensible sounds were reported in one case. Ocular signs included vision loss; dilated pupils; nystagmus; unfocused gaze; slow, roving conjugate gaze; rapid, fluid eye movements; and blurred vision. Abnormal movements were sometimes noted. These included inappropriate or jerky movements, increased tone/rigidity, and hyperreflexia/clonus. One patient experienced seizures.11 A variety of neurologic tests were performed. In 12 (39%) of the cases, a computed tomographic (CT) scan was obtained. In 2 cases, magnetic resonance imaging (MRI) was performed. Neither CT nor MRI revealed any pathologic findings. In one case, a cerebral angiogram was normal.13 In one case, an electroencephalogram (EEG) showed bilateral slowing of the background rhythm.13 Recovery from the encephalopathy was usually within 48 hours (Figure 2). Three patients had prolonged recovery (> 96 hours). In one case of prolonged encephalopathy, the patient had long-standing renal failure and required dialysis to facilitate recovery.14 In our case, the patient’s course was complicated by lithium-induced diabetes insipidus. One patient died.10 All patients who recovered experienced no residual neurologic abnormalities.

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Figure 2. Time to Complete Recovery (n = 19)a a The y-axis represents number of cases.

• Etiology. The true incidence of postoperative acute mental status changes as a direct result of methylene blue infusion is difficult to estimate. There have been no prospective studies looking for neurologic abnormalities in patient receiving methylene blue during parathyroidectomy. It is possible that patients with delayed recovery from anesthesia or mild disorientation could have their symptoms attributed to a number of causes: hypoxia, hypercapnia, excessive sedative administration, or metabolic derangements. Sweet and Standiford15 retrospectively reviewed 132 consecutive cases of parathyroidectomy involving methylene blue infusion. They found that 17 patients were receiving treatment with serotonin reuptake inhibitors. Five (3.7%) of the 132 patients were taking serotonin reuptake inhibitors and experienced altered postoperative mental status. Encephalopathy did not develop in all patients receiving serotonin reuptake inhibitors; rather, the incidence of postoperative encephalopathy among these patients in their review was 29.4%.15 Although selective serotonin reuptake inhibitors (SSRI) have frequently been associated with methylene blue encephalopathy, there is one case report in which the patient was not reported to be receiving any medications.11 As seen from the listing of reported medications among the cases presented, a variety of psychotropic drugs have some serotonergic effects. Our case study is, to our knowledge, the first in which lithium is implicated in the development of methylene blue encephalopathy. One theory for altered mental status in those receiv-

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ing SSRIs proposes that a toxicity similar to serotonin syndrome develops as a result of the serotonin-enhancing properties of methylene blue. The nature of the neurotoxicity may be more complex than simple serotonin syndrome and may involve a variety of mechanisms, including some degree of neuronal cell death.16 Serotonin syndrome is a potential complication associated with medications that increase cerebral serotonin neurotransmission. It is a diagnosis of exclusion suggested by a triad of autonomic instability, mental status changes, and neuromuscular abnormalities. The mental status changes include confusion, hypomania, and agitation. Autonomic hyperactivity and neuromuscular abnormalities can be seen as ataxia, myoclonus, hyperreflexia, tremor, nausea, vomiting, diarrhea, fever, and labile blood pressure.12 Treatment of serotonin syndrome is supportive. One recent report describes the use of lipid therapy (2.5 mL/ kg of 20% lipid emulsion) to treat a patient with an intentional overdose of venlafaxine, lamotrigine, and diazepam. The rigidity and hyperreflexia experienced by the patient disappeared after administration of the emulsion.17 Because not all patients on SSRI regimens who receive methylene blue experience encephalopathy, there could be additional factors that increase susceptibility to serotonin syndrome. Factors that could increase vulnerability to serotonin toxicity include polymorphisms of genes encoding the serotonin transporter18 or those that compromise clearance of serotonin.19 Polymorphism of 5-hydroxytryptamine (5-HT) receptor genes could affect serotonergic transmission; it is possible that there could be interactions between medications such as an SSRI, methylene blue, and ondansetron that contribute to serotonin syndrome.20 Patients receiving psychotropic drugs are at risk of encephalopathy with methylene blue administration; therefore, the risks associated with discontinuation of these drugs preoperatively should be carefully considered. The psychiatry department should be consulted to evaluate suicide risk and/or the switch to alternative therapy. Many of these drugs have prolonged half-lives. Serotonin syndrome has been described 5 weeks after a patient stopped fluoxetine therapy.21

Conclusion Methylene blue toxicity is nearly always associated with its administration to patients treated with psychotropic medications, particularly those affecting CNS serotonin levels. Methylene blue should be administered with caution to these patients. No safe dosage regimen has been established. No recommendations can currently be made regarding the safety of methylene blue administration if or when antidepressant medications are discontinued. Methylene blue toxicity has occurred at a wide range of doses.

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Methylene blue may be administered in the awake patient preoperatively to aid in early recognition of toxicity (nausea, vomiting, febrile reactions). Continuous temperature monitoring may be helpful to detect hyperpyrexia during infusion of methylene blue. Anesthesia providers should suspect methylene blue toxicity in any patient who experiences a delayed recovery from general anesthesia. The signs and symptoms often mimic those of serotonin syndrome. Methylene blue toxicity is a diagnosis of exclusion; there are no focal neurologic deficits. Other possible causes of altered mental status (cerebrovascular accident), seizure, electrolyte abnormality, hypoxia, hypercapnia, malignant hyperthermia, neuroleptic malignant syndrome) should be excluded. Neurologic tests, including CT, MRI, and EEG studies, have failed to show abnormalities in cases of methylene blue toxicity. In patients at risk of methylene blue toxicity, the need for inpatient monitoring should be anticipated. While patients are hemodynamically stable, they may require repeated intubation and support of ventilation during the initial stages of toxicity. Full recovery most often occurs in 2 or 3 days. REFERENCES 1. Ng BKW, Cameron AJD. The role of methylene blue in serotonin syndrome: a systematic review. Psychosomatics. 2010;51(3):194-200. 2. Kozaki A, Watanabe J. Dose dependency of apparent volumes of distribution for methylene blue in rabbits. J Pharmacobiodynamics. 1981;4(1):49-57. doi:10.1248/bpb1978.4.49. 3. Khan MAS, North AP, Chadwick DR. Prolonged postoperative altered mental status after methylene blue infusion during parathyroidectomy: a case report and review of the literature. Ann R Coll Surg Engl. 2007;89(2):W9-W11. doi:10.1308/147870807X160434. 4. Ng BKW, Cameron AJ, Liang R, Rahman H. Serotonin syndrome following methylene blue infusion during parathyroidectomy: a case report and literature review [French]. Can J Anaesth. 2008;55(1):3641. doi:10.1007/BF03017595. 5. Peter C, Hongwan D, Küpfer A, Lauterburg BH. Pharmacokinetics and organ distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol. 2000;56(3):247-250. doi:10.1007/s002280000124. 6. Vutskits L, Briner A, Klauser P, et al. Adverse effects of methylene blue on the central nervous system. Anesthesiology. 2008;108(4):684-692. 7. Majithia A, Stearns MP. Methylene blue toxicity following infusion to localize parathyroid adenoma. J Laryngol Otol. 2006;120(2):138-140. doi:10.1017/S0022215105005098. 8. Martindale SJ, Stedeford JC. Neurological sequelae following methylene blue injection for parathyroidectomy. Anaesthesia. 2003;58(10):10411042. doi:10.1046/j.1365-2044.2003.03415_23.x. 9. Drug Safety Communication: Serious CNS reactions possible when given to patients taking certain psychiatric medications. Rockville, MD: Food and Drug Administration; July 26, 2011. Updated October 20, 2011. http://www.fda.gov/Drugs/DrugSafety/ucm263190.htm. Accessed March 7, 2013. 10. Kartha SS, Chacko CE, Bumpous JM, Fleming M, Lentsch EJ, Flynn MB. Toxic metabolic encephalopathy after parathyroidectomy with methylene blue localization. Otolaryngol Head Neck Surg. 2006;135(5):765-768. doi:10.1016/j.otohns.2006.05.026. 11. Patel AS, Singh-Ranger D, Lowery KA, Crinnion JN. Letter to the editor: adverse neurologic effect of methylene blue used during parathyroidectomy. Head Neck. 2006;28(6):567-568. doi:10.1002/hed.20416. 12. Aminoff M, ed. Neurology and General Medicine. Philadelphia, PA:

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Churchill Livingstone/ Elsevier; 2008:1106. 13. Rowley M, Riutort K, Shapiro D, Casler J, Festic E, Freeman WD. Methylene blue-associated serotonin syndrome: a ‘green’ encephalopathy after parathyroidectomy. Neurocrit Care. 2009;11(1):88-93. doi:10.1007/s12028-009-9206-z. 14. Mathew S, Linhartova L, Raghuraman G. Hyperpyrexia and prolonged postoperative disorientation following methylene blue infusion during parathyroidectomy. Anaesthesia. 2006;61(6):580-583. doi:10.1111/j.1365-2044.2006.04619.x. 15. Sweet G, Standiford SB. Methylene-blue–associated encephalopathy. J Am Coll Surg. 2007;204(3):454-458. doi:10.1016/j.jamcollsurg.2006.12.030. 16. Oz M, Lorke DE, Hasan M, Petroianu GA. Cellular and molecular actions of methylene blue in the nervous system. Med Res Rev. 2011; 31(1):93-117. doi:10.1002/med.20177. 17. Dagtekin O, Marcus H, Müller C, Böttiger BW, Spöhr F. Lipid therapy for serotonin syndrome after intoxication with venlafaxine, lamotrigine and diazepam. Minerva Anestesiol. 2011;77(1):93-95. 18. Murphy GM, Hollander SB, Rodrigues HE, Kremer C, Schatzberg AF. Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. Arch Gen Psychiatry. 2004;61(11):1163-1169. doi:10.1001/archpsyc.61.11.1163. 19. Stanford SC, Stanford BJ. Reply to JL Palmer. Postoperative delirium indicating an adverse drug reaction involving selective serotonin reuptake inhibitor, paroxetine? J Psychopharmacol. 2000;14(2):186187. doi:10.1177/026988110001400210. 20. Stanford SC, Stanford BJ, Gillman PK. Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of postoperative delirium. J Psychopharmacol. 2010;24(10):1433-1438. doi:10.1177/0269881109105450. 21. Dvir Y, Smallwood P. Serotonin syndrome: a complex but easily avoidable condition. Gen Hosp Psychiatry. 2008;30(3):284-287. doi:10.1016/j.genhosppsych.2007.09.007. 22. Stanford BJ, Stanford SC. Postoperative delirium indicating an

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adverse drug interaction involving the selective serotonin reuptake inhibitor, paroxetine? J Psychopharmacol. 1999;13(3):313-317. doi:10.1177/026988119901300322. 23. Bach KK, Lindsay FW, Berg LS, Howard RS. Prolonged postoperative disorientation after methylene blue infusion during parathyroidectomy. Anesth Analg. 2004;99(5):1573-1574. 24. Khavandi A, Whitaker J, Gonna H. Serotonin toxicity precipitated by concomitant use of citalopram and methylene blue. Med J Aust. 2008;189(9):534-535. 25. Pollack G, Pollack A, Delfiner J, Fernandez J. Parathyroid surgery and methylene blue: a review with guidelines for safe intraoperative use. Laryngoscope. 2009;119(10):1941-1946. doi:10.1002/lary.20581. 26. Héritier Barras A, Walder B, Seeck M. Serotonin syndrome following methylene blue infusion: a rare complication of antidepressant therapy. J Neurol Neurosurg Psychiatry. 2010;81(12):1421-1422. doi: 10.1136/jnnp.2009.172221. 27. Mihai R, Mitchell EW, Warwick J. Dose-response and postoperative confusion following methylene blue infusion during parathyroidectomy. Can J Anaesth. 2007;54(1):79-81. doi:10.1007/BF03021907.

AUTHORS Ellen Shopes, CRNA, MHS, MSN, CCRN, is a staff nurse anesthetist at the Tucson Veterans Affairs (VA) Health Care System, Tucson, Arizona. Email: [email protected]. Wayne Gerard, MD, was a staff anesthesiologist at the Tucson VA Health Care System at the time of this case report. Jessica Baughman, CRNA, was a student at the Midwestern University Nurse Anesthesia Program, Glendale, Arizona, at the time of this case report.

ACKNOWLEDGMENT The authors thank Shari Burns, CRNA, EdD, Midwestern University Nurse Anesthesia Program; and Lillibeth Fermin, MD, Tucson VA Health Care System, for their guidance and support in the preparation of this manuscript.

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