Resuscitation 85 (2014) 774–777

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Clinical Paper

Serotonin syndrome after therapeutic hypothermia for cardiac arrest: A case series夽 Jennifer E. Fugate a,∗ , Roger D. White b,c , Alejandro A. Rabinstein a a b c

Division of Critical Care Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, USA Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA

a r t i c l e

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Article history: Received 4 February 2014 Received in revised form 27 February 2014 Accepted 28 February 2014 Keywords: Cardiac arrest Serotonin syndrome Therapeutic hypothermia Fever

a b s t r a c t Aim: To describe causes, manifestations, and diagnosis of serotonin syndrome following therapeutic hypothermia (TH) after cardiac arrest. Methods: Retrospective case series from a tertiary academic medical center. Results: Three male patients suffered witnessed out-of-hospital cardiac arrests and were treated with induced TH. Initial cardiac rhythms included asystole in two and ventricular fibrillation in one. Following completion of rewarming, all three developed neurological signs unexpected for their clinical condition. These included rigidity, hyperreflexia, diffuse tremors, ankle clonus, and marked agitated delirium. Patients also were febrile, hypertensive, and tachycardic. A diagnosis of serotonin syndrome was made in all cases and serotonergic medications were discontinued. All three patients recovered consciousness and two made a full neurological recovery. One patient remained dependent on others for activities of daily living at the time of hospital discharge because of short-term memory impairment. Conclusions: Unexpected neurologic findings and prolonged high fever following recovery from TH can be manifestations of serotonin syndrome rather than post-cardiac arrest anoxic brain injury. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Induced therapeutic hypothermia (TH) has been widely implemented in the routine care of select patients who remain comatose after out-of-hospital cardiac arrest. Patients undergoing cooling protocols are generally sedated for at least 24 h and the neurological status of patients after sedation is lightened is eagerly awaited and is essential for the estimation of neurological prognosis. One of the fundamental aspects in making this assessment is ensuring that the neurological examination is not confounded, particularly by lingering effects of sedatives and analgesics.1 Serotonin syndrome is a rare cause of encephalopathy in intensive care units and is often precipitated by the prescription of opioids (fentanyl in particular) and antiemetics in addition to outpatient medications such as antidepressants.2 Characteristic clinical findings of serotonin syndrome include agitated delirium,

夽 A Spanish translated version of the abstract of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2014.02.030. ∗ Corresponding author at: Department of Neurology, Mayo Clinic, 8WB 200 First Street SW, Rochester, MN 55905, USA. E-mail address: [email protected] (J.E. Fugate). http://dx.doi.org/10.1016/j.resuscitation.2014.02.030 0300-9572/© 2014 Elsevier Ireland Ltd. All rights reserved.

hypertension, tachycardia, rigidity, tremors, hyperreflexia, diarrhea, diaphoresis, and clonus. On the surface, postanoxic encephalopathy and serotonin syndrome may appear to be unrelated. Experimental models, however, indicate that global brain ischemia can cause increased extracellular serotonin release.3 We report three patients who developed serotonin syndrome after treatment with TH following out-of-hospital cardiac arrest. 2. Case 1 A 58-year-old man suddenly lost consciousness and was found slumped in a chair. Bystanders started cardiopulmonary resuscitation (CPR) and upon arrival of paramedics, his cardiac rhythm was found to be ventricular fibrillation. He was defibrillated three times and had return of spontaneous circulation (ROSC) after approximately 10–15 min of CPR. Because of persistent coma, he was intubated and TH was initiated with a surface cooling device. Coronary angiography revealed complete occlusion of the right coronary artery, which was successfully recanalized percutaneously. Following the procedure he was sedated with intravenous (IV) infusions of fentanyl (75–150 mcg h−1 ), midazolam (8 mg h−1 ), and paralyzed with atracurium while cooled to a target temperature of 33 ◦ C for 24 h. He was extubated after rewarming but became febrile

J.E. Fugate et al. / Resuscitation 85 (2014) 774–777

(T 38.8 ◦ C) and hypertensive (188/75 mmHg). He was awake but agitated and unable to follow commands. Two days later he had not improved neurologically. He remained awake but was not interactive. He appeared flushed, had diffuse tremors, rigidity of all extremities (more prominent in lower extremities), fasciculations, and bilateral ankle clonus. An electroencephalogram showed diffuse slowing and triphasic waves; there was no evidence of seizures. A clinical diagnosis of serotonin syndrome was made and his medications were carefully reviewed. In addition to fentanyl, he had been continued on his home antidepressant, sertraline 50 mg daily, and was receiving tramadol for analgesia. These medications were discontinued and the following day he was answering questions and following simple commands. The rigidity had improved but was still present, particularly in the lower extremities. He made a full neurological recovery over the ensuing weeks. 3. Case 2 A 36-year-old man collapsed at home. A friend witnessed the event and began CPR. Paramedics arrived and found him to be in asystole, which evolved into fine ventricular fibrillation after epinephrine was administered. He was defibrillated and ROSC was achieved. He remained comatose following CPR and the TH protocol was initiated. The ECG showed anterolateral ST-segment elevation and coronary angiography revealed a chronic occlusion of the left anterior descending (LAD) coronary artery which was not treated acutely. While in the ICU he was sedated with infusions of fentanyl (25 mcg h−1 ), midazolam (8 mg h−1 ), and paralyzed with atracurium while cooled to a target temperature of 33 ◦ C for 24 h. Continuous EEG showed a reactive background consisting of diffuse theta slowing, episodic low amplitude events, and no potentially epileptogenic activity. Two hours after he reached normothermia he became febrile with temperature reaching 38.5 ◦ C. Sedation was switched to a dexmedetomidine infusion, and when this was temporarily held, he opened his eyes to stimulation but was agitated, not following commands, tachycardic, and hypertensive. He had severe rigidity in the lower extremities associated with hyperreflexia and clonus at the ankles. The surface cooling device was restarted to maintain normothermia. Because of the clinical suspicion for serotonin syndrome, fentanyl was discontinued and hydromorphone (the opioid with least serotonergic activity) was administered for analgesia. The patient had been taking the antidepressant paroxetine prior to admission. Over the next several days, when off sedation, he remained agitated with hypertension and tachycardia. Brain magnetic resonance imaging (MRI) 6 days after his cardiac arrest was normal. His agitation slowly improved and he was extubated on day 9. He was awake and alert with mild persisting encephalopathy manifesting predominantly as impaired attention and deficits with short-term memory. He underwent successful percutaneous angioplasty and stenting of the occluded LAD prior to dismissal to a brain rehabilitation facility on day 20. 4. Case 3 A 53-year-old man living in a correctional facility suddenly lost consciousness. CPR was immediately initiated by witnesses and correctional facility staff using an automated external defibrillator (AED) identified asystole as the initial rhythm. Several cycles of CPR were required prior to ROSC. Initial ECG demonstrated sinus tachycardia with no ST-elevation. Because he remained unconscious, TH was initiated and he was admitted to the CCU where he received IV infusions of fentanyl (125 mcg h−1 ), midazolam

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(9 mg h−1 ), and atracurium. An admission urine screen was negative for metabolites of any prescription medications (including opioids and antidepressants). Temperature was maintained at 33 ◦ C for 24 h and he was subsequently rewarmed at 0.25 ◦ C h−1 . Continuous EEG showed diffuse slowing of the background with episodic low amplitude events and no epileptogenic activity or seizures. When taken off sedation, he opened his eyes and followed simple commands with the upper extremities. He had diffuse rigidity which was severe and more prominent in the lower extremities with bilateral ankle clonus, hyperreflexia, and tremors. He was tachycardic and febrile, requiring a water temperature of 9 ◦ C in the cooling device to maintain a core body temperature of 37 ◦ C. He developed rhabdomyolysis as evidenced by urine dark in color and increase of serum creatinine kinase to 2811 U L−1 . Fentanyl was discontinued and he was treated with enteral cyproheptadine 8 mg and IV diazepam 10 mg, both given every 6 h. He continued to require light sedation with dexmedetomidine for agitation and gradually improved over the following days and he was extubated on day 7. He was alert and oriented, able to have a conversation, moved all extremities without focal weakness, and had no rigidity or clonus. Prior to discharge coronary angiography was carried out, which demonstrated 3-vessel coronary artery disease, for which percutaneous angioplasty and stenting were performed.

5. Discussion We describe three patients with clinical signs consistent with serotonin syndrome following emergence from a TH protocol after cardiac arrest. All three patients had classic features of serotonin syndrome including marked lower extremity rigidity, hyperreflexia, clonus, fever, hypertension, tachycardia, and agitated delirium.4 All had been receiving IV infusions of fentanyl – an opioid that promotes serotonergic transmission – and two had also been taking medications with serotonergic effects prescribed for depression prior to admission (Table 1). Clinical resolution occurred in all patients over days and all regained consciousness. To our knowledge, the occurrence of serotonin syndrome in patients after cardiac arrest has not been previously described. Induced TH is a therapy reserved for patients who remain comatose after CPR because it has been thought to be “neuroprotective” against further hypoxic-ischemic and reperfusion brain injury. Thus, the evaluation of brain function is paramount after patients are rewarmed and an accurate and un-confounded neurological examination is essential to estimate prognosis and guide patient care. The development of serotonin syndrome during or after rewarming confounds the neurological examination and could lead to underestimation of the potential for neurological recovery unless the clinical syndrome is recognized and all medications that promote serotonergic activity are discontinued and subsequently avoided. Alternative diagnoses for the constellation of symptoms of delirium, rigidity, and fever include neuroleptic malignant syndrome, malignant hyperthermia, and thyrotoxicosis. We felt these were unlikely in our patients as none were taking antipsychotic medications, none had exposure to volatile anesthetics, and the temporal course of discontinuation of serotonergic-enhancing medications with clinical improvement. All three of our patients were receiving medications that could be implicated in causing serotonin syndrome, but these are commonly prescribed medications that usually do not trigger such severe adverse effects. It is possible that anoxic-ischemic brain injury contributed to the clinical syndrome. In experimental models, global cerebral ischemia induces increased serotonin levels in the hippocampus and dorsolateral striatum.3 The involved neurochemistry is undoubtedly complex as serotonin acts on several different receptor types in the brain. In experimental

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Table 1 Patient characteristics. Age

Gender

Initial cardiac arrhythmia

Medications

Signs

Treatment

Discharge CPC

1

58

M

Ventricular fibrillation

Sertraline Tramadol Fentanyl

Supportive

1

2

36

M

Asystole

Paroxetine Fentanyl

Supportive

3

3

53

M

Asystole

Fentanyl

Fever Hypertension Agitation Rigidity Fasciculations Tremors Clonus Fever Hypertension Agitation Rigidity Hyperreflexia Clonus Fever Hypertension Agitation Rigidity Hyperreflexia Tremors Clonus

Cyproheptadine 8 mg po every 6 h Diazepam 10 mg IV every 6 h

1

M: male; CPC: Cerebral Performance Category 1 – conscious, alert, able to work, might have mild neurological deficit; CPC3: conscious, dependent on others for independent activities of daily living.

models of brain ischemia, treatment with 5-HT1A agonists results in less hippocampal neuronal death and it has been proposed that stimulation of 5-HT1A receptors may be protective against excitotoxicity.5,6 In contrast, stimulation of 5-HT2A receptors facilitates ischemia-induced release of excitatory amino acids in rodents 7 Investigations studying the effects of administering 5-HT 2A receptor antagonists in rodent models of global ischemia have yielded conflicting results–some showing a protective effect against neuronal ischemia,7 but others showing no effect.8 A small study of a gerbil model of global ischemia found that animals treated with cyproheptadine (a serotonin antagonist) had increased neuronal preservation compared to the placebo group.9 Beyond the role of modulation of excitatory amino acid neurotransmission, serotonin is also involved with thermoregulation, predominantly through 5-HT2A receptors. The debate concerning the relationship of body temperature with mortality and neurological outcomes of post-cardiac arrest patients is longstanding and has been recently reignited. In animal models of ischemia, hypothermia attenuates cascades leading to neurological cell death.10,11 Over the past decade, induced mild hypothermia became a widespread practice endorsed by international guidelines for select patients remaining comatose after out-of-hospital cardiac arrest.12,13 A recent large randomized trial showed no difference in survival or poor neurological outcomes between groups assigned to a targeted temperature of 33 ◦ C compared to 36 ◦ C.14 These findings may shift the focus of discussion from the possible beneficial effects of hypothermia to the potentially harmful effects of hyperthermia. Fever in the first 48 h after cardiac arrest is common, occurring in 40–50% of patients.15–17 In one prospective study, patients who developed post-hypothermic fever (without aggressive treatment) had higher rates of mortality and unfavorable outcomes than those without post-hypothermic fever.17 The relationship is not entirely clear though, because retrospective studies have found that fever is not associated with outcomes in patients treated with TH.15,16 The patients in our series all became febrile post-rewarming but were promptly treated with aggressive temperature control, and all regained consciousness. In speculation, perhaps global brain ischemia provokes an excess release of serotonin as an autoprotective response (5-HT1A stimulation) but also stimulates 5HT2A receptors in the hypothalamus producing fever, which causes further neuronal injury. Further studies on the neurochemistry

response to global anoxia in humans and investigations targeting specific serotonin receptors as potential therapeutic targets are warranted. This small case series intends to raise awareness about the possibility of serotonin syndrome as a complication following rewarming after TH for cardiac arrest. Awareness of this treatable complication may prevent its misdiagnosis as severe brain anoxia. Serotonin syndrome should be considered in patients with refractory fever after cardiac arrest. Conflict of interest Drs. Fugate, White, and Rabinstein declare no conflicts of interest. Funding None. References 1. Wijdicks EF, Hijdra A, Young GB, Bassetti CL, Wiebe S. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;67:203–10. 2. Pedavally S, Fugate JE, Rabinstein AA. Serotonin syndrome in the intensive care unit: clinical presentations and precipitating medications. Neurocrit Care 2013 [Epub ahead of print, September 20]. 3. Globus MY, Wester P, Busto R, Dietrich WD. Ischemia-induced extracellular release of serotonin plays a role in CA1 neuronal cell death in rats. Stroke 1992;23:1595–601. 4. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352: 1112–20. 5. Salazar-Colocho P, Del Rio J, Frechilla D. Neuroprotective effects of serotonin 5-HT 1A receptor activation against ischemic cell damage in gerbil hippocampus: involvement of NMDA receptor NR1 subunit and BDNF. Brain Res 2008;1199:159–66. 6. Oosterink BJ, Korte SM, Nyakas C, Korf J, Luiten PG. Neuroprotection against Nmethyl-d-aspartate-induced excitotoxicity in rat magnocellular nucleus basalis by the 5-HT1A receptor agonist 8-OH-DPAT. Eur J Pharmacol 1998;358: 147–52. 7. Fujikura H, Kato H, Nakano S, Kogure K. A serotonin S2 antagonist, naftidrofuryl, exhibited a protective effect on ischemic neuronal damage in the gerbil. Brain Res 1989;494:387–90. 8. Piera MJ, Beaughard M, Michelin MT, Winslow E, Massingham R. Lack of efficacy of 5-HT2A receptor antagonists to reduce brain damage after 3 minutes of transient global cerebral ischaemia in gerbils. Fund Clin Pharmacol 1995;9: 562–8.

J.E. Fugate et al. / Resuscitation 85 (2014) 774–777 9. Caponnetto C, Del Sette M, Furlan M, et al. Protective effect of cyproheptadine in a gerbil model of cerebral ischemia. Ital J Neurol Sci 1991;12:59–61. 10. Illievich UM, Zornow MH, Choi KT, Scheller MS, Strnat MA. Effects of hypothermic metabolic suppression on hippocampal glutamate concentrations after transient global cerebral ischemia. Anesth Analg 1994;78:905–11. 11. Siesjo BK, Bengtsson F, Grampp W, Theander S. Calcium, excitotoxins, and neuronal death in the brain. Ann N Y Acad Sci 1989;568:234–51. 12. Peberdy MA, Callaway CW, Neumar RW, et al. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122:S768–86. 13. Nolan JP, Morley PT, Hoek TL, Hickey RW. Therapeutic hypothermia after cardiac arrest. An advisory statement by the Advancement Life support Task Force of the International Liaison committee on Resuscitation. Resuscitation 2003;57:231–5.

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14. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med 2013;369:2197–206. 15. Gebhardt K, Guyette FX, Doshi AA, Callaway CW, Rittenberger JC. Prevalence and effect of fever on outcome following resuscitation from cardiac arrest. Resuscitation 2013;84:1062–7. 16. Leary M, Grossestreuer AV, Iannacone S, et al. Pyrexia and neurologic outcomes after therapeutic hypothermia for cardiac arrest. Resuscitation 2013;84:1056–61. 17. Bro-Jeppesen J, Hassager C, Wanscher M, et al. Post-hypothermia fever is associated with increased mortality after out-of-hospital cardiac arrest. Resuscitation 2013;84:1734–40.

Serotonin syndrome after therapeutic hypothermia for cardiac arrest: a case series.

To describe causes, manifestations, and diagnosis of serotonin syndrome following therapeutic hypothermia (TH) after cardiac arrest...
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