Secondary Logo

Journal Logo

Serotonin Syndrome

The Potential for a Severe Reaction Between Common Perioperative Medications and Selective Serotonin Reuptake Inhibitors

Adler, Alexandra R. MD; Charnin, Jonathan A. , MD; Quraishi, Sadeq A. MD, MHA, MMSc

doi: 10.1213/XAA.0000000000000217
Case Reports: Clinical Care

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed to patients of all ages. Although generally considered safe, therapy with SSRIs can be complicated by serotonin syndrome (SS), a life-threatening condition. We present a case of SS that developed in a young man who was receiving a stable dose of fluoxetine and then received several commonly used medications during an emergent appendectomy. Because polypharmacy in the perioperative setting may trigger SS, it is important for anesthesiologists to be cognizant of the interactions between SSRIs and common perioperative medications to formulate anesthetic plans that optimize patient safety.

From the *Department of Medicine, Cambridge Health Alliance, Cambridge, Massachusetts; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts; and Department of Anesthesia, Harvard Medical School, Boston, Massachusetts.

Accepted for publication May 25, 2015.

Funding: None.

The authors declare no conflicts of interest.

Address correspondence to Alexandra R. Adler, MD, Department of Medicine, Cambridge Health Alliance, 1493 Cambridge St., Cambridge, MA 02139. Address e-mail to

Serotonin syndrome (SS) is a rare but potentially fatal clinical event.1 Diagnosis follows the Hunter Criteria Decision Rules.2 To satisfy these criteria, a patient must have received a serotonergic drug and must demonstrate characteristic symptoms, which may include hyperthermia, clonus, diaphroesis, ocular clonus, agitation, and/or hyperreflexia.2 Several anesthetic drugs and routine perioperative drugs have been implicated in cases of serotonin toxicity, especially in patients already taking serotonergic medications.3–9 Given the widespread use of serotonergic psychiatric medications in the general population, it is important for anesthesiologists to identify patients at increased risk for serotonin toxicity and to recognize and effectively manage perioperative cases of SS.10–12 We present the case of a patient on fluoxetine who developed SS after receiving low doses of several routinely used perioperative medications.

Back to Top | Article Outline


Because the case report could be written in a manner that deidentified the patient and not compromise the scientific value of the article, the IRB at Cambridge Health Alliance and Massachusetts General Hospital deemed this work to be exempt from written patient consent.

Back to Top | Article Outline


A Caucasian man, in his 20s weighing approximately 80 kg, was scheduled for emergent laparoscopic appendectomy because of a perforated appendix. In the preoperative holding area, his vital signs were (1) temperature 37.1°C; (2) heart rate 130 beats/min; (3) arterial blood pressure 177/90 mm Hg; and (4) oxygen saturation 98%. Laboratory values were all within normal limits, except for a white blood cell count of 16.9 × 109/L. His medical history was significant only for a diagnosis of depression, for which he had been taking a stable dose of 40 mg fluoxetine daily (last taken on the day of surgery). He had no family history of anesthesia complications and had never undergone surgery.

The patient received fentanyl (100 μg in divided doses) in the emergency department for pain. Preoperatively, he received midazolam (2 mg IV) and metoclopramide (10 mg IV). General anesthesia was induced with fentanyl (100 μg IV), propofol (100 mg IV), and etomidate (20 mg IV), and succinylcholine (100 mg IV) was used to facilitate tracheal intubation. Ertapenem was given as the preincisional prophylactic antibiotic. Anesthesia was maintained with sevoflurane (2.4%–2.9% inspired; oxygen:air = 1 L:1 L) and hydromorphone (5 mg IV in divided doses), and cisatracurium (2–8 mg IV in divided doses) maintained neuromuscular relaxation. Once the surgeon identified purulence in the abdomen, the procedure was converted to an open approach to improve surgical exposure and adequately washout the peritoneal cavity. To expand antimicrobial coverage, the patient received cefazolin (2 g IV) and metronidazole (500 mg IV). Methylene blue (MB, 100 mg IV) was administered twice to confirm ureteral integrity after the intraabdominal surgical manipulation. Reversal of the neuromuscular blocking drugs with glycopyrrolate (0.6 mg IV) and neostigmine (5 mg IV) was given after confirming 2 strong twitches with a train-of-four count using a peripheral nerve stimulator (Life-tech Inc., Stafford, TX). Ondansetron (4 mg IV) was also administered at the end of the case. During emergence, the patient was noted to be hypertensive (136/84–158/105 mm Hg) and tachycardic (126–134 beats/min). His end-tidal carbon dioxide remained consistently between 37 and 40 mm Hg throughout the case until tracheal extubation.

In the postanesthesia recovery unit, the patient was found to be restless and confused. He was febrile (38.8°C), hypertensive (128/68–167/106 mm Hg), and persistently tachycardic (160 s). He was transferred to the intensive care unit (ICU), where he was agitated and writhing in his bed. He initially received another dose of fentanyl (50 μg IV) and then haloperidol (1 mg IV), but continued to have worsening confusion and agitation. Given the hyperpyrexia and recent surgery, an initial diagnosis of malignant hyperthermia (MH) was assumed and dantrolene (110 mg IV in 2 divided doses) was promptly initiated. A medical toxicologist was consulted when it was noted that in addition to mild trismus, the patient also had hyperreflexia without clonus, rigidity, and horizontal nystagmus. Given the patient’s use of a selective serotonin reuptake inhibitor (SSRI) and exposure to multiple serotonergic medications perioperatively, the more likely diagnosis of SS was established. The patient was subsequently reintubated for airway protection facilitated by the administration of sedative hypnotic doses of midazolam (4 mg IV) and etomidate (40 mg IV). Supportive therapy was initiated and sedation and analgesia were achieved with the use of continuous midazolam and morphine infusions. When the patient’s fever curve reached a peak of 40.3°C in the first 7 hours after ICU admission and did not respond to round-the-clock doses of acetaminophen (650 mg per nasogastric tube [PNGT]) and a continuous cooling blanket, therapy with cyproheptadine (12 mg PNGT initial dose followed by 8 mg every 6 hours PNGT) was initiated. His fever curve trended down to 36.8°C over the next 36 hours, although he continued to spike intermittent fevers over the next 5 days (38.1°C–39.5°C).

Initial laboratory testing in the ICU revealed a significant increase in the serum creatinine level (1.8 mg/dL; baseline 0.7 mg/dL), an anion gap of 17 mEq/L, 5690 U/L creatinine kinase, 10.1 mg/dL systemic lactic acid, 0.4 mg/dL direct bilirubin, and 345 IU/L lactate dehydrogenase. Arterial blood gas analysis just before reintubation was consistent with a predominantly metabolic acidosis (pH 7.26, 242 mm Hg PO2, 40 mm Hg PCO2, 22 mm Hg HCO3). The patient was initially maintained on volume control ventilation (600 tidal volume/16 respiratory rate/5 positive end-expiratory pressure/0.3% FIO2), and with daily spontaneous breathing trials, he was weaned to pressure support ventilation by postoperative day (POD) 3. Rhabdomyolysis was managed with aggressive fluid support, and the patient was able to maintain a urine output >100 mL/h. Serum creatinine levels recovered to baseline levels by POD 5. The patient’s ICU course was also notable for Gram-negative sepsis with pan-sensitive Pseudomonas (which was treated with imipenem). The patient was successfully tracheally extubated on POD 6, transferred to the general ward on POD 8, restarted on 10 mg fluoxetine on POD 11 based on the recommendations from the inpatient psychiatry team, and discharged from the hospital on POD 12. Urine and serum drug screens obtained in the emergency department before surgery were negative.

Back to Top | Article Outline


SS is a potentially lethal toxidrome characterized by agitation, clonus, hyperreflexia, and hyperthermia. Our patient demonstrated postoperative hyperthermia and ocular clonus and, therefore, satisfied the Hunter Criteria Decision Rules.2 He received several drugs in addition to fluoxetine, which may have precipitated SS, including: (1) ondansetron9; (2) fentanyl4,6,9; (3) MB1,13–19; (4) metoclopramide20; and (5) metronidazole.21

Between 1988 and 2008, the use of antidepressants among adults in the United States increased by almost 400%12,22 and so too has the number of cases of SS (Fig. 1).a Conservative estimates suggest that between 1995 and 2012, the number of hospital discharges for SS have increased approximately 400% as well (Fig. 1). Moreover, the costs associated with the care of these patients have increased since 1995 (Fig. 2).a Among adults aged 18 years and older in the United States, approximately twice as many women use prescription antidepressants compared with men, a trend that has been seen since 1988.12 The incidence of SS is also higher in women; between 1995 and 2012, 58% to 71% of discharges with a principal diagnosis of SS occurred in women.a

Figure 1

Figure 1

Figure 2

Figure 2

Despite this growing trend, SS is an underrecognized phenomenon among healthcare providers and can have many serious clinical consequences including metabolic acidosis, rhabdomyolysis, seizures, renal failure, and disseminated intravascular coagulopathy.22 The onset of SS may be confused with that of MH or neuroleptic malignant syndrome (NMS), all of which can present with hyperthermia. Both MH and SS have a rapid onset, but MH typically occurs after exposure to inhaled anesthetics (and succinylcholine) and presents with increasing concentrations of end-tidal carbon dioxide. Some patients with MH develop skeletal muscle rigidity.23 Although both NMS and SS can present with altered mental status, autonomic instability, and rigidity, NMS is generally characterized by bradykinesia, a history of dopamine antagonist use, and a slower onset than SS.8,22

Our patient’s crisis likely resulted from an interaction between fluoxetine and a combination of perioperative drugs, leading to serotonin toxicity. SS is caused by an increase in intrasynaptic serotonin to toxic levels.8 The 2 major mechanisms implicated in this are inhibition of reuptake and inhibition of metabolism (specifically, inhibition of the first step, which is performed by monoamine oxidase [MAO]). Not surprisingly, the most common scenario for the development of SS is when a patient receives a combination of a SSRI and a MAO inhibitor.18,22,24 Evidence also suggests that polymorphisms of the CPY2D6 gene may increase the risk of SS.9

Some common perioperative medications including meperidine, fentanyl, ondansetron, and metoclopramide are weak SSRIs and have been associated with SS in patients receiving SSRIs or serotonin–norepinephrine reuptake inhibitors (SNRIs).3–5,7–9,22 Tramadol may also contribute to serotonin toxicity by acting as a SSRI.8,25 Conversely, MB acts as an MAO inhibitor and is used in the operating room to verify the integrity of structures or surgical anastomoses and also in the ICU setting in patients with drug-induced methemoglobinemia or vasodilatory hypotension.18 After IV administration, MB partially inhibits MAO subtype B and completely inhibits MAO subtype A.13,26 It is interesting to consider the role that MB may have played in this case. This patient received a total of 2.4 mg/kg MB. There are several reports of the development of SS after administration of MB (>5 mg/kg) in patients who were taking an SSRI or SNRI, 1 of which was fatal.1,14,18,19 Three case reports have suggested that even lower doses of MB (1–2 mg/kg) could precipitate SS.15–17 Although there are no accounts of SS after an interaction between an SSRI and just metronidazole, there are published cases of SS where the antibiotic, a potent MAO inhibitor, was used in conjunction with other serotonergic medications.21

In summary, we present the case of a healthy young man who underwent an emergent appendectomy and developed perioperative SS. Given the frequent prevalence of SSRI use in the general population and the serotonergic effects of several commonly used perioperative medications, it is crucial that anesthesiologists recognize patients at risk for serotonin toxicity (SSRI or SNRI use and female sex) to develop safe and individualized anesthetic plans. Furthermore, greater familiarity with the signs and symptoms of SS2 and its potential complications (seizures, rhabdomyolysis, and disseminated intravascular coagulation) will likely improve patient safety. Timely and aggressive management of patients with SS may include (1) controlled airway and mechanical ventilation; (2) sedation with benzodiazepines (given their potent antiseizure profile and the potential undesirable effects of alternative sedatives, e.g., metabolic acidosis with prolonged, high-dose propofol infusions); (3) analgesia with opioids that likely have the lowest serotonergic activity (morphine and hydromorphone)8; (4) hemodynamic stabilization with IV vasopressors or antihypertensive drugs; (5) treatment of fever with active cooling, acetaminophen, and cyproheptadine (a first-generation histamine-1 blocker that also acts as a serotonin receptor antagonist at the 5HT-1a and 5HT-2 receptors and has been used in the treatment of mild to moderate cases of SS)27; and (6) aggressive hydration for acute renal insufficiency or continuous renal replacement therapy for acute renal failure. Although SS is a rare condition, it is an increasingly important consideration in the differential diagnosis of a patient with neurological symptoms in the postoperative setting.

Back to Top | Article Outline


a Accessed January 25, 2015.
Cited Here...

Back to Top | Article Outline


1. Top WM, Gillman PK, de Langen CJ, Kooy A. Fatal methylene blue associated serotonin toxicity. Neth J Med. 2014;72:179–81
2. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96:635–42
3. Rang ST, Field J, Irving C. Serotonin toxicity caused by an interaction between fentanyl and paroxetine. Can J Anaesth. 2008;55:521–5
4. Altman CS, Jahangiri MF. Serotonin syndrome in the perioperative period. Anesth Analg. 2010;110:526–8
5. Davis JJ, Buck NS, Swenson JD, Johnson KB, Greis PE. Serotonin syndrome manifesting as patient movement during total intravenous anesthesia with propofol and remifentanil. J Clin Anesth. 2013;25:52–4
6. Wilson L, Rooney T, Baugh RF, Millington B Recognition and management of perioperative serotonin syndrome. 2012;33:319–21
7. Song HK. Serotonin syndrome with perioperative oxycodone and pregabalin. Pain Physician. 2013;16:E632–3
8. Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth. 2005;95:434–41
9. Beatty NC, Nicholson WT, Langman LJ, Curry TB, Eisenach JH. Pharmacogenetic workup of perioperative serotonin syndrome. J Clin Anesth. 2013;25:662–5
10. . National Center for Health Statistics. National ambulatory medical care survey: 2006 summary. 2008:1–40 Available at
11. . National Center for Health Statistics. National ambulatory medical care survey: 2010 summary tables. 2013:1–33
12. Pratt LA, Brody DJ, Gu Q. National Center for Health Statistics data brief: antidepressant use in persons aged 12 and over: United States, 2005–2008. NCHS Data Brief. 2011:1–8
13. Peter C, Hongwan D, Küpfer A, Lauterburg BH. Pharmacokinetics and organ distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol. 2000;56:247–50
14. Martindale SJ, Stedeford JC. Neurological sequelae following methylene blue injection for parathyroidectomy. Anaesthesia. 2003;58:1041–2
15. Mihai R, Mitchell EW, Warwick J. Dose-response and postoperative confusion following methylene blue infusion during parathyroidectomy. Can J Anaesth. 2007;54:79–81
16. Shanmugam G, Kent B, Alsaiwadi T, Baskett R. Serotonin syndrome following cardiac surgery. Interact Cardiovasc Thorac Surg. 2008;7:656–7
17. Schwiebert C, Irving C, Gillman PK. Small doses of methylene blue, previously considered safe, can precipitate serotonin toxicity. Anaesthesia. 2009;64:924
18. Ng BK, Cameron AJ. The role of methylene blue in serotonin syndrome: a systematic review. Psychosomatics. 2010;51:194–200
19. Grubb KJ, Kennedy JL, Bergin JD, Groves DS, Kern JA. The role of methylene blue in serotonin syndrome following cardiac transplantation: a case report and review of the literature. J Thorac Cardiovasc Surg. 2012;144:e113–6
20. Fisher AA, Davis MW. Serotonin syndrome caused by selective serotonin reuptake-inhibitors-metoclopramide interaction. Ann Pharmacother. 2002;36:67–71
21. Karamanakos PN. The possibility of serotonin syndrome brought about by the use of metronidazole. Minerva Anestesiol. 2008;74:679
22. Boyer Edward W, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352:1112–20
23. Ali SZ, Taguchi A, Rosenberg H. Malignant hyperthermia. Best Pract Res Clin Anaesthesiol. 2003;17:519–33
24. Spritz N. Oversight of physicians’ conduct by state licensing agencies. Lessons from New York’s Libby Zion case. Ann Intern Med. 1991;115:219–22
25. Gombar S, Bhatia N. Serotonin syndrome in the perioperative period: role of tramadol. Anesth Analg. 2010;111:1077
26. Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. Br J Pharmacol. 2007;152:946–51
27. Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med. 1998;16:615–9
© 2015 International Anesthesia Research Society