- Email: [email protected]
Serotonin Syndrome After Methylene Blue Administration During Cardiac Surgery: A Case Report and Review
Serotonin Syndrome After Methylene Blue Administration During Cardiac Surgery: A Case Report and Review Timothy Wolvetang, Rineke Janse, MD, and Maarten ter Horst, MD, PhD
EROTONIN SYNDROME, described for the first time by Rapport et al in 1948, is a syndrome that is caused by toxic levels of serotonin.1 Selective serotonin reuptake inhibitors (SSRIs) and many other drugs can cause serotonin syndrome (SS), a rare but potentially lethal complication of these drugs.2,3 The syndrome is well-described in psychiatric literature because SS occurs in approximately 14% to 16% of persons with an SSRI overdose, often intentional. Excess serotonin manifests itself through a spectrum of clinical features, ranging from tremor and diarrhea in mild cases to delirium, neuromuscular rigidity, and hyperthermia in severe cases. Later signs and symptoms include metabolic acidosis, rhabdomyolysis, seizures, renal failure, and disseminated intravascular coagulation. Because there is no test available to confirm SS, criteria to diagnose the syndrome were derived by Sternbach in 1991.3 Dunkley et al revised Sternbach’s criteria, creating the Hunter criteria, which improved the sensitivity and specificity to 84% and 97%, respectively.4 Many cases of SS occur in patients who use a combination of serotonergic agents.4 This multi-drug scenario is very common during general anesthesia for cardiac surgery. Nearly 1 in 5 patients with ischemic heart disease are diagnosed with depression and treated with antidepressants such as SSRIs.5 Vasoplegic syndrome is a common reaction to cardiopulmonary bypass, occurring in 5% to 25% of patients.6 Cardiopulmonary bypass initiates a proinflammatory state in which cytokines and endotoxins increase the expression of nitric oxide synthase, which ultimately leads to vasodilatation via an increase in cyclic guanosine monophosphate that blocks calcium from entering the smooth muscle cells.7 Methylene blue blocks accumulation of cyclic guanosine monophosphate, leading to higher intracellular calcium concentrations, which increases vascular responsiveness.6 Treating vasoplegia with methylene blue has become common because it improves outcome in vasoplegic patients.8,9 Methylene blue and its metabolite azure B are noteworthy reversible inhibitors of monoamine oxidase A which, particularly in combination with SSRIs, have been linked to increased serotonin levels in the brain and serotonin toxicity.10,11 SS is one of the drug-induced hyperthermic syndromes, which also include malignant hyperthermia (MH), neuroleptic malignant syndrome (NMS), anticholinergic syndrome, and sympathomimetic syndrome. Management of SS includes benzodiazepines and supportive care. To the authors’ knowledge, only 3 cases of SS after cardiac surgery have been reported.12-14
S
CASE PRESENTATION
A 64-year-old female was treated for severe mitral valve regurgitation with a mitral valve repair. Her prehospital medication included paroxetine (SSRI), quetiapine (atypical antipsychotic drug), and clonazepam. In addition to depression,
this patient had a history of autoimmune hepatitis, stable multiple sclerosis, and a wedge excision of the upper lobe of the left lung as treatment for an adenocarcinoma 1 year before the mitral valve repair. Her history also included an estimated 50 pack-years of cigarette smoking, but no other substance abuse. The surgical phase was unremarkable except for persistent low blood pressure unresponsive to norepinephrine infusion and intermittent boluses on institution of cardiopulmonary bypass. This suspected vasoplegia was treated with vasopressin and methylene blue, 2 mg/kg. Before the end of the procedure the patient was rewarmed gradually by cardiopulmonary bypass to 371C, using central and nasal temperatures as control. To facilitate quick recovery, desflurane, granisetron, 1 mg, and sketamine, 25 mg, were administered. The patient’s airway was extubated in the operating room. On admission to the intensive care unit postoperatively, the patient was somnolent but responsive to verbal stimuli, and mydriasis was noted. However, over the next 8 hours her neurologic state deteriorated. Her temperature gradually rose to 40.51C, her extremities became hypertonic without myoclonus, and nystagmus was observed. Blood tests revealed hyperkalemia of 6.5 mmol/L and creatinine of 1.69 mg/dL. The creatine kinase rose from 631 IU/L (normal range 0-144 IU/L) to 1,735 IU/L on the first postoperative day and gradually decreased to values less than 1,000 IU/L on the second postoperative day. High-sensitivity troponin T and creatine kinase MB remained relatively stable. On the third and fourth postoperative days the creatine kinase decreased to 618 IU/L and 463 IU/L, respectively. Liver function tests showed a mild elevation of aspartate amino transferase (72 U/L), with normal alanine amino transferase (24 U/L). Kidney function decreased with glomerular filtration rates dropping from 63 mL/min preoperatively to 31 mL/min. Because of her neurologic deterioration, computerized tomography of the brain was performed, which ruled out intracranial hemorrhage and ischemic stroke. Because the patient had used 2 agents recognized as potentially causative of SS and NMS, paroxetine and quetiapine, both causative agents were stopped. The clinical signs
From the Department of Anesthesiology, Erasmus Medical Center, Rotterdam, The Netherlands. T.W. and R.J. contributed equally to this article. Address reprint requests to T. Wolvetang, MPA in training, Erasmus Medical Center, Department of Anesthesiology, H-1276, s-Gravendijkwal 230, 3000 CA Rotterdam, The Netherlands. E-mail: T.Wolvetang@ aerasmusmc.nl © 2015 Elsevier Inc. All rights reserved. 1053-0770/2602-0033$36.00/0 http://dx.doi.org/10.1053/j.jvca.2015.11.019 Key words: cardiac surgery, serotonin syndrome, methylene blue, postoperative hyperthermia
Journal of Cardiothoracic and Vascular Anesthesia, Vol ], No ] (Month), 2015: pp ]]]–]]]
1
2
developed very gradually, so malignant hyperthermia was clinically unlikely. The patient was sedated with midazolam and her airway was reintubated. With supportive care, including intravenous fluids, passive cooling, and sedation, her temperature dropped to normothermia within 6 hours. Infection parameters remained within the normal postoperative range, and blood cultures were negative for bacterial growth. Kidney function improved within 3 days and liver enzymes and creatine kinase values dropped to normal in 4 days. The patient was weaned successfully from sedation and ventilation on the third postoperative day and transferred to the ward on the seventh day. The patient developed postoperative delirium for which, as standard care, haloperidol was started on the ward, without a relapse of symptoms. On the 12th postoperative day, the patient had recovered completely, and she was discharged to another hospital.
WOLVETANG ET AL
DISCUSSION
The Hunter criteria suggest serotonin toxicity in the presence of a serotonergic agent—paroxetine and quetiapine in this patient—and 1 of the 5 following clusters of symptoms: (1) spontaneous clonus, (2) inducible clonus and agitation or diaphoresis, (3) ocular clonus and agitation or diaphoresis, (4) tremor and hyperreflexia, and (5) hypertonia, hyperthermia (4381C), and ocular or inducible clonus.4 Fig 1 depicts a flowchart of the Hunter criteria. The symptoms of this patient correlated with the fifth cluster, circled in Fig 1. In addition to the preoperative serotonergic medication, several other agents that affect serotonin activity (Table 1) were administered during the surgical phase. Methylene blue was administered to treat vasoplegia, a common complication of cardiopulmonary bypass, with an incidence of 5% to 25%.6
Fig 1. Flowchart of the Hunter criteria. The symptoms of the patient correlate with the fifth cluster, circled in the figure. Adapted from Dunkley EJ, Isbister GK, Sibbritt D, et al: The Hunter Serotonin Toxicity Criteria: Simple and accurate diagnostic decision rules for serotonin toxicity. QJM 96:635-642, 2003.
SEROTONIN SYNDROME AFTER METHYLENE BLUE ADMINISTRATION
Table 1. An Overview of Medication Recognized as Causative for Serotonin Syndrome Serotonin Syndrome
Impaired reuptake Cocaine MDMA Meperidine Tramadol Pentazocine SSRI SNRI Serotonin modulator TCA St John’s wort 5-HT3 antagonist Metoclopramide Valproate Carbamazepine Sibutramine Dextromethorphan Cyclobenzaprine Dopamine reuptake inhibitors Trazodone
Increase formation Tryptophan Impaired reuptake Cocaine MDMA Meperidine Tramadol Inhibit metabolism MAOs Direct agonist Buspirone Quetiapine Increase sensitivity Lithium Interactions Methylene blue
NOTE. Drugs recognized as causative for serotonin syndrome by Boyer et al,2 with quetiapine, trazodone,10 and methylene blue added.16 Abbreviations: MDMA, 3,4-methylenedioxymethamphetamine; SSRI, serotonin reuptake inhibitors; SNRI, serotonin norepinephrine reuptake inhibitors; TCA, tricyclic antidepressants; MOA, monoamine oxidase.
Methylene blue is a preferred therapeutic option to treat vasoplegia because it reverses the refractory hypotension through nitric oxide-mediated pathways, reducing catecholamine infusion and thus preventing possible malperfusion.15 Methylene blue, however, has been reported to play a role in causing serotonin toxicity. Grubb et al reported a case of SS after methylene blue administration to treat vasoplegic syndrome during heart transplantation.13 In 2011, the US Food and Drug Administration published a drug safety communications warning of serious reactions when methylene blue is administered in patients taking psychiatric medications, namely SSRIs, serotonin norepinephrine reuptake inhibitors, clomipramine, and tricyclic antidepressants.10,16 Vasoplegia after cardiac surgery is associated with higher morbidity and mortality. Treatment of vasoplegia with methylene blue has been associated with better outcome.8,9 In the presence of SSRIs, however, treatment of vasoplegia with methylene blue should be considered carefully because SS is a serious complication with, in this particular case, reintubation and prolonged intensive care unit stay. With regard to the patient’s hyperthermia, her temperature was not excessively rewarmed during surgery and on the ward her temperature was passively cooled. Granisetron also has been described as a causative agent,2 because it blocks 5-HT3 receptors, increasing the amount of serotonin available postsynaptically. Stimulation of the
3
postsynaptic 5-HT1A and 5-HT2A receptors has been implicated in SS,17 but no single receptor is solely responsible.2 Research has shown that ketamine inhibits neuronal serotonin reuptake in rat brains. Later research pointed out that both ketamine isomers mitigate serotonin uptake. In addition, high concentrations of ketamine also increase serotonin efflux.18 Even though ketamine has not been linked to SS, it is an interesting theory that warrants further investigation. The effect of cardiopulmonary bypass on serotonin levels still is unclear. It has been demonstrated that serotonin levels decrease during cardiopulmonary bypass due to hemodilution and adsorption of serotonin by cardiopulmonary bypass tubing.12 Cardiopulmonary bypass might therefore play a protective role concerning SS. Nonetheless, the combined effect of the administered causative agents increasing serotonin levels, with the corresponding decline in both kidney and liver function, decreasing metabolization and excretion of those causative agents could be an explanation for the development of SS. As mentioned before, there is no diagnostic test for SS, therefore other diagnoses had to be excluded in this particular case. A relapse of multiple sclerosis was unlikely because it was diagnosed in 1979 without any complaints since and with nonspecific signs on magnetic resonance imaging. Because of the patient’s lung cancer adenocarcinoma, her blood autoantibodies were tested for a possible paraneoplastic syndrome, but the results were negative. Because there is a small correlation between autoimmune hepatitis and Hashimoto’s disease,19 antithyroglobulin antibodies were examined and the results were negative also. Thyroid storm was unlikely because there were no signs of cardiovascular dysfunction other than those related to the surgical procedure, no jaundice, no precipitant history, and no nausea or vomiting. Concerning the other drug-induced hypermetabolic syndromes, MH was ruled out due to the slow progress of the symptoms, and moreover, the symptoms diminished after sedation. Other grounds to exclude MH were the absence of acidosis and profuse sweating. Furthermore, the patient’s extremities were hypertonic rather than characterized by generalized muscle rigidity. The guidelines of the Malignant Hyperthermia Association of the United States20 and the European Malignant Hyperthermia Group21 do not describe mental status changes, mydriasis, and nystagmus for symptoms of hyperthermia. The relatively quick onset made NMS less likely because NMS typically develops in up to 72 hours. Furthermore, quetiapine, a dopamine-receptor antagonist, was not withdrawn, and signs of NMS should not diminish after administration of benzodiazepines.22 The diagnosis of NMS was also made less likely by administration of haloperidol without reappearance of any of the clinical symptoms on the ward. The diversity in the presentation of SS and similarities with other drug-related hypermetabolic syndromes make it difficult to diagnose SS. Every clinician should be aware of the possible and potentially lethal side effects of SSRIs. In the event that vasoplegia is treated with methylene blue, physicians must be aware of possible SS. There is some evidence that ketamine also can contribute to SS. Treatment of SS encompasses sedation, supportive care, and cessation of causative agents.
4
WOLVETANG ET AL
REFERENCES 1. Rapport MM, Green AA, Page IH: : Serum vasoconstrictor, serotonin; isolation and characterization. J Biol Chem 176:1243-1251, 1948 2. Boyer EW, Shannon M: The serotonin syndrome. N Engl J Med 352:1112-1120, 2005 3. Sternbach H: The serotonin syndrome. Am J Psychiatry 148: 705-713, 1991 4. Dunkley EJ, Isbister GK, Sibbritt D, et al: The Hunter Serotonin Toxicity Criteria: Simple and accurate diagnostic decision rules for serotonin toxicity. QJM 96:635-642, 2003 5. Jiang W: Impacts of depression and emotional distress on cardiac disease. Cleve Clin J Med 75 (Suppl 2):S20-25, 2008 6. Fischer GW, Levin MA: Vasoplegia during cardiac surgery: Current concepts and management. Semin Thorac Cardiovasc Surg 22: 140-144, 2010 7. Lenglet S, Mach F, Montecucco F: Methylene blue: Potential use of an antique molecule in vasoplegic syndrome during cardiac surgery. Expert Rev Cardiovasc Ther 9:1519-1525, 2011 8. Levin RL, Degrange MA, Bruno GF, et al: Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg 77:496-499, 2004 9. Leyh RG, Kofidis T, Strüber M, et al: Methylene blue: The drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass? J Thorac Cardiovasc Surg 125:1426-1431, 2003 10. Gillman PK: A review of serotonin toxicity data: Implications for the mechanisms of antidepressant drug action. Biol Psychiatry 59: 1046-1051, 2006 11. Petzer A, Harvey BH, Wegener G, Azure B, et al: A metabolite of methylene blue, is a high-potency, reversible inhibitor of monoamine oxidase. Toxicol Appl Pharmacol 258:403-409, 2012 12. Shanmugam G, Kent B, Alsaiwadi T, et al: Serotonin syndrome following cardiac surgery. Interact Cardiovasc Thorac Surg 7:656-657, 2008
13. Grubb KJ, Kennedy JL, Bergin JD, et al: The role of methylene blue in serotonin syndrome following cardiac transplantation: A case report and review of the literature. J Thorac Cardiovasc Surg 144: e113-116, 2012 14. Smith CJ, Wang D, Sgambelluri A, et al: Serotonin syndrome following methylene blue administration during cardiothoracic surgery. J Pharm Pract 28:207-211, 2015 15. Kofidis T, Strüber M, Wihelmi M, et al: Reversal of severe vasoplegia with single-dose methylene blue after heart transplantation. J Thorac Cardiovasc Surg 122:823-824, 2001 16. FDA Drug Safety Communication: Updated information about the drug interaction between methylene blue (methylthioninium chloride) and serotonergic psychiatric medications. Available at: http://www. fda.gov/Drugs/DrugSafety/ucm276119.htm. Accessed June 30th, 2015. 17. Mills KC: Serotonin syndrome. A clinical update. Crit Care Clin 13:763-783, 1997 18. Tso MM, Blatchford KL, Callado LF, et al: Stereoselective effects of ketamine on dopamine, serotonin and noradrenaline release and uptake in rat brain slices. Neurochem Int 44:1-7, 2004 19. Bernard C, Frih H, Pasquet F, et al: Thymoma associated with autoimmune diseases: 85 cases and literature review. Autoimmun Rev 15(1):82-92, 2016 20. Malignant Hyperthermia Association of the United States web page. Available at: MHAUS.org http://www.mhaus.org/healthcareprofessionals. Accessed November 13th 2015. 21. Glahn KP, Ellis FR, Halsall PJ, et al: Recognizing and managing a malignant hyperthermia crisis: Guidelines from the European Malignant Hyperthermia Group. Br J Anaesth 105:417-420, 2010 22. Gurrera RJ, Caroff SN, Cohen A, et al: An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. J Clin Psychiatry 72:1222-1228, 2011
EROTONIN SYNDROME, described for the first time by Rapport et al in 1948, is a syndrome that is caused by toxic levels of serotonin.1 Selective serotonin reuptake inhibitors (SSRIs) and many other drugs can cause serotonin syndrome (SS), a rare but potentially lethal complication of these drugs.2,3 The syndrome is well-described in psychiatric literature because SS occurs in approximately 14% to 16% of persons with an SSRI overdose, often intentional. Excess serotonin manifests itself through a spectrum of clinical features, ranging from tremor and diarrhea in mild cases to delirium, neuromuscular rigidity, and hyperthermia in severe cases. Later signs and symptoms include metabolic acidosis, rhabdomyolysis, seizures, renal failure, and disseminated intravascular coagulation. Because there is no test available to confirm SS, criteria to diagnose the syndrome were derived by Sternbach in 1991.3 Dunkley et al revised Sternbach’s criteria, creating the Hunter criteria, which improved the sensitivity and specificity to 84% and 97%, respectively.4 Many cases of SS occur in patients who use a combination of serotonergic agents.4 This multi-drug scenario is very common during general anesthesia for cardiac surgery. Nearly 1 in 5 patients with ischemic heart disease are diagnosed with depression and treated with antidepressants such as SSRIs.5 Vasoplegic syndrome is a common reaction to cardiopulmonary bypass, occurring in 5% to 25% of patients.6 Cardiopulmonary bypass initiates a proinflammatory state in which cytokines and endotoxins increase the expression of nitric oxide synthase, which ultimately leads to vasodilatation via an increase in cyclic guanosine monophosphate that blocks calcium from entering the smooth muscle cells.7 Methylene blue blocks accumulation of cyclic guanosine monophosphate, leading to higher intracellular calcium concentrations, which increases vascular responsiveness.6 Treating vasoplegia with methylene blue has become common because it improves outcome in vasoplegic patients.8,9 Methylene blue and its metabolite azure B are noteworthy reversible inhibitors of monoamine oxidase A which, particularly in combination with SSRIs, have been linked to increased serotonin levels in the brain and serotonin toxicity.10,11 SS is one of the drug-induced hyperthermic syndromes, which also include malignant hyperthermia (MH), neuroleptic malignant syndrome (NMS), anticholinergic syndrome, and sympathomimetic syndrome. Management of SS includes benzodiazepines and supportive care. To the authors’ knowledge, only 3 cases of SS after cardiac surgery have been reported.12-14
S
CASE PRESENTATION
A 64-year-old female was treated for severe mitral valve regurgitation with a mitral valve repair. Her prehospital medication included paroxetine (SSRI), quetiapine (atypical antipsychotic drug), and clonazepam. In addition to depression,
this patient had a history of autoimmune hepatitis, stable multiple sclerosis, and a wedge excision of the upper lobe of the left lung as treatment for an adenocarcinoma 1 year before the mitral valve repair. Her history also included an estimated 50 pack-years of cigarette smoking, but no other substance abuse. The surgical phase was unremarkable except for persistent low blood pressure unresponsive to norepinephrine infusion and intermittent boluses on institution of cardiopulmonary bypass. This suspected vasoplegia was treated with vasopressin and methylene blue, 2 mg/kg. Before the end of the procedure the patient was rewarmed gradually by cardiopulmonary bypass to 371C, using central and nasal temperatures as control. To facilitate quick recovery, desflurane, granisetron, 1 mg, and sketamine, 25 mg, were administered. The patient’s airway was extubated in the operating room. On admission to the intensive care unit postoperatively, the patient was somnolent but responsive to verbal stimuli, and mydriasis was noted. However, over the next 8 hours her neurologic state deteriorated. Her temperature gradually rose to 40.51C, her extremities became hypertonic without myoclonus, and nystagmus was observed. Blood tests revealed hyperkalemia of 6.5 mmol/L and creatinine of 1.69 mg/dL. The creatine kinase rose from 631 IU/L (normal range 0-144 IU/L) to 1,735 IU/L on the first postoperative day and gradually decreased to values less than 1,000 IU/L on the second postoperative day. High-sensitivity troponin T and creatine kinase MB remained relatively stable. On the third and fourth postoperative days the creatine kinase decreased to 618 IU/L and 463 IU/L, respectively. Liver function tests showed a mild elevation of aspartate amino transferase (72 U/L), with normal alanine amino transferase (24 U/L). Kidney function decreased with glomerular filtration rates dropping from 63 mL/min preoperatively to 31 mL/min. Because of her neurologic deterioration, computerized tomography of the brain was performed, which ruled out intracranial hemorrhage and ischemic stroke. Because the patient had used 2 agents recognized as potentially causative of SS and NMS, paroxetine and quetiapine, both causative agents were stopped. The clinical signs
From the Department of Anesthesiology, Erasmus Medical Center, Rotterdam, The Netherlands. T.W. and R.J. contributed equally to this article. Address reprint requests to T. Wolvetang, MPA in training, Erasmus Medical Center, Department of Anesthesiology, H-1276, s-Gravendijkwal 230, 3000 CA Rotterdam, The Netherlands. E-mail: T.Wolvetang@ aerasmusmc.nl © 2015 Elsevier Inc. All rights reserved. 1053-0770/2602-0033$36.00/0 http://dx.doi.org/10.1053/j.jvca.2015.11.019 Key words: cardiac surgery, serotonin syndrome, methylene blue, postoperative hyperthermia
Journal of Cardiothoracic and Vascular Anesthesia, Vol ], No ] (Month), 2015: pp ]]]–]]]
1
2
developed very gradually, so malignant hyperthermia was clinically unlikely. The patient was sedated with midazolam and her airway was reintubated. With supportive care, including intravenous fluids, passive cooling, and sedation, her temperature dropped to normothermia within 6 hours. Infection parameters remained within the normal postoperative range, and blood cultures were negative for bacterial growth. Kidney function improved within 3 days and liver enzymes and creatine kinase values dropped to normal in 4 days. The patient was weaned successfully from sedation and ventilation on the third postoperative day and transferred to the ward on the seventh day. The patient developed postoperative delirium for which, as standard care, haloperidol was started on the ward, without a relapse of symptoms. On the 12th postoperative day, the patient had recovered completely, and she was discharged to another hospital.
WOLVETANG ET AL
DISCUSSION
The Hunter criteria suggest serotonin toxicity in the presence of a serotonergic agent—paroxetine and quetiapine in this patient—and 1 of the 5 following clusters of symptoms: (1) spontaneous clonus, (2) inducible clonus and agitation or diaphoresis, (3) ocular clonus and agitation or diaphoresis, (4) tremor and hyperreflexia, and (5) hypertonia, hyperthermia (4381C), and ocular or inducible clonus.4 Fig 1 depicts a flowchart of the Hunter criteria. The symptoms of this patient correlated with the fifth cluster, circled in Fig 1. In addition to the preoperative serotonergic medication, several other agents that affect serotonin activity (Table 1) were administered during the surgical phase. Methylene blue was administered to treat vasoplegia, a common complication of cardiopulmonary bypass, with an incidence of 5% to 25%.6
Fig 1. Flowchart of the Hunter criteria. The symptoms of the patient correlate with the fifth cluster, circled in the figure. Adapted from Dunkley EJ, Isbister GK, Sibbritt D, et al: The Hunter Serotonin Toxicity Criteria: Simple and accurate diagnostic decision rules for serotonin toxicity. QJM 96:635-642, 2003.
SEROTONIN SYNDROME AFTER METHYLENE BLUE ADMINISTRATION
Table 1. An Overview of Medication Recognized as Causative for Serotonin Syndrome Serotonin Syndrome
Impaired reuptake Cocaine MDMA Meperidine Tramadol Pentazocine SSRI SNRI Serotonin modulator TCA St John’s wort 5-HT3 antagonist Metoclopramide Valproate Carbamazepine Sibutramine Dextromethorphan Cyclobenzaprine Dopamine reuptake inhibitors Trazodone
Increase formation Tryptophan Impaired reuptake Cocaine MDMA Meperidine Tramadol Inhibit metabolism MAOs Direct agonist Buspirone Quetiapine Increase sensitivity Lithium Interactions Methylene blue
NOTE. Drugs recognized as causative for serotonin syndrome by Boyer et al,2 with quetiapine, trazodone,10 and methylene blue added.16 Abbreviations: MDMA, 3,4-methylenedioxymethamphetamine; SSRI, serotonin reuptake inhibitors; SNRI, serotonin norepinephrine reuptake inhibitors; TCA, tricyclic antidepressants; MOA, monoamine oxidase.
Methylene blue is a preferred therapeutic option to treat vasoplegia because it reverses the refractory hypotension through nitric oxide-mediated pathways, reducing catecholamine infusion and thus preventing possible malperfusion.15 Methylene blue, however, has been reported to play a role in causing serotonin toxicity. Grubb et al reported a case of SS after methylene blue administration to treat vasoplegic syndrome during heart transplantation.13 In 2011, the US Food and Drug Administration published a drug safety communications warning of serious reactions when methylene blue is administered in patients taking psychiatric medications, namely SSRIs, serotonin norepinephrine reuptake inhibitors, clomipramine, and tricyclic antidepressants.10,16 Vasoplegia after cardiac surgery is associated with higher morbidity and mortality. Treatment of vasoplegia with methylene blue has been associated with better outcome.8,9 In the presence of SSRIs, however, treatment of vasoplegia with methylene blue should be considered carefully because SS is a serious complication with, in this particular case, reintubation and prolonged intensive care unit stay. With regard to the patient’s hyperthermia, her temperature was not excessively rewarmed during surgery and on the ward her temperature was passively cooled. Granisetron also has been described as a causative agent,2 because it blocks 5-HT3 receptors, increasing the amount of serotonin available postsynaptically. Stimulation of the
3
postsynaptic 5-HT1A and 5-HT2A receptors has been implicated in SS,17 but no single receptor is solely responsible.2 Research has shown that ketamine inhibits neuronal serotonin reuptake in rat brains. Later research pointed out that both ketamine isomers mitigate serotonin uptake. In addition, high concentrations of ketamine also increase serotonin efflux.18 Even though ketamine has not been linked to SS, it is an interesting theory that warrants further investigation. The effect of cardiopulmonary bypass on serotonin levels still is unclear. It has been demonstrated that serotonin levels decrease during cardiopulmonary bypass due to hemodilution and adsorption of serotonin by cardiopulmonary bypass tubing.12 Cardiopulmonary bypass might therefore play a protective role concerning SS. Nonetheless, the combined effect of the administered causative agents increasing serotonin levels, with the corresponding decline in both kidney and liver function, decreasing metabolization and excretion of those causative agents could be an explanation for the development of SS. As mentioned before, there is no diagnostic test for SS, therefore other diagnoses had to be excluded in this particular case. A relapse of multiple sclerosis was unlikely because it was diagnosed in 1979 without any complaints since and with nonspecific signs on magnetic resonance imaging. Because of the patient’s lung cancer adenocarcinoma, her blood autoantibodies were tested for a possible paraneoplastic syndrome, but the results were negative. Because there is a small correlation between autoimmune hepatitis and Hashimoto’s disease,19 antithyroglobulin antibodies were examined and the results were negative also. Thyroid storm was unlikely because there were no signs of cardiovascular dysfunction other than those related to the surgical procedure, no jaundice, no precipitant history, and no nausea or vomiting. Concerning the other drug-induced hypermetabolic syndromes, MH was ruled out due to the slow progress of the symptoms, and moreover, the symptoms diminished after sedation. Other grounds to exclude MH were the absence of acidosis and profuse sweating. Furthermore, the patient’s extremities were hypertonic rather than characterized by generalized muscle rigidity. The guidelines of the Malignant Hyperthermia Association of the United States20 and the European Malignant Hyperthermia Group21 do not describe mental status changes, mydriasis, and nystagmus for symptoms of hyperthermia. The relatively quick onset made NMS less likely because NMS typically develops in up to 72 hours. Furthermore, quetiapine, a dopamine-receptor antagonist, was not withdrawn, and signs of NMS should not diminish after administration of benzodiazepines.22 The diagnosis of NMS was also made less likely by administration of haloperidol without reappearance of any of the clinical symptoms on the ward. The diversity in the presentation of SS and similarities with other drug-related hypermetabolic syndromes make it difficult to diagnose SS. Every clinician should be aware of the possible and potentially lethal side effects of SSRIs. In the event that vasoplegia is treated with methylene blue, physicians must be aware of possible SS. There is some evidence that ketamine also can contribute to SS. Treatment of SS encompasses sedation, supportive care, and cessation of causative agents.
4
WOLVETANG ET AL
REFERENCES 1. Rapport MM, Green AA, Page IH: : Serum vasoconstrictor, serotonin; isolation and characterization. J Biol Chem 176:1243-1251, 1948 2. Boyer EW, Shannon M: The serotonin syndrome. N Engl J Med 352:1112-1120, 2005 3. Sternbach H: The serotonin syndrome. Am J Psychiatry 148: 705-713, 1991 4. Dunkley EJ, Isbister GK, Sibbritt D, et al: The Hunter Serotonin Toxicity Criteria: Simple and accurate diagnostic decision rules for serotonin toxicity. QJM 96:635-642, 2003 5. Jiang W: Impacts of depression and emotional distress on cardiac disease. Cleve Clin J Med 75 (Suppl 2):S20-25, 2008 6. Fischer GW, Levin MA: Vasoplegia during cardiac surgery: Current concepts and management. Semin Thorac Cardiovasc Surg 22: 140-144, 2010 7. Lenglet S, Mach F, Montecucco F: Methylene blue: Potential use of an antique molecule in vasoplegic syndrome during cardiac surgery. Expert Rev Cardiovasc Ther 9:1519-1525, 2011 8. Levin RL, Degrange MA, Bruno GF, et al: Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg 77:496-499, 2004 9. Leyh RG, Kofidis T, Strüber M, et al: Methylene blue: The drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass? J Thorac Cardiovasc Surg 125:1426-1431, 2003 10. Gillman PK: A review of serotonin toxicity data: Implications for the mechanisms of antidepressant drug action. Biol Psychiatry 59: 1046-1051, 2006 11. Petzer A, Harvey BH, Wegener G, Azure B, et al: A metabolite of methylene blue, is a high-potency, reversible inhibitor of monoamine oxidase. Toxicol Appl Pharmacol 258:403-409, 2012 12. Shanmugam G, Kent B, Alsaiwadi T, et al: Serotonin syndrome following cardiac surgery. Interact Cardiovasc Thorac Surg 7:656-657, 2008
13. Grubb KJ, Kennedy JL, Bergin JD, et al: The role of methylene blue in serotonin syndrome following cardiac transplantation: A case report and review of the literature. J Thorac Cardiovasc Surg 144: e113-116, 2012 14. Smith CJ, Wang D, Sgambelluri A, et al: Serotonin syndrome following methylene blue administration during cardiothoracic surgery. J Pharm Pract 28:207-211, 2015 15. Kofidis T, Strüber M, Wihelmi M, et al: Reversal of severe vasoplegia with single-dose methylene blue after heart transplantation. J Thorac Cardiovasc Surg 122:823-824, 2001 16. FDA Drug Safety Communication: Updated information about the drug interaction between methylene blue (methylthioninium chloride) and serotonergic psychiatric medications. Available at: http://www. fda.gov/Drugs/DrugSafety/ucm276119.htm. Accessed June 30th, 2015. 17. Mills KC: Serotonin syndrome. A clinical update. Crit Care Clin 13:763-783, 1997 18. Tso MM, Blatchford KL, Callado LF, et al: Stereoselective effects of ketamine on dopamine, serotonin and noradrenaline release and uptake in rat brain slices. Neurochem Int 44:1-7, 2004 19. Bernard C, Frih H, Pasquet F, et al: Thymoma associated with autoimmune diseases: 85 cases and literature review. Autoimmun Rev 15(1):82-92, 2016 20. Malignant Hyperthermia Association of the United States web page. Available at: MHAUS.org http://www.mhaus.org/healthcareprofessionals. Accessed November 13th 2015. 21. Glahn KP, Ellis FR, Halsall PJ, et al: Recognizing and managing a malignant hyperthermia crisis: Guidelines from the European Malignant Hyperthermia Group. Br J Anaesth 105:417-420, 2010 22. Gurrera RJ, Caroff SN, Cohen A, et al: An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. J Clin Psychiatry 72:1222-1228, 2011