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Introduction

Diffuse movement disorders, autonomic dysfunction, and cognitive changes can have a wide range of etiologies, particularly in the perioperative setting. Middle-aged and older individuals who are being treated for various comorbidities are at increased risk for evolving symptoms, with causes that may be challenging to diagnose. This is of one such case.

The Case

A 70-year-old man with benign prostatic hyperplasia presents at your outpatient surgery center for scheduled green-light photoselective vaporization of the prostate. He is classified by the anesthesiologist as American Society of Anesthesiology 2, indicating mild systemic disease with no functional limitations. His medical history includes vestibular migraines, for which he takes high-dose venlafaxine, and gastroesophageal reflux disease.

His medical chart notes an allergy to propofol, observed following two prior surgeries at other medical centers when he awakened with tremor. When questioned about these events by the anesthesiologist, the patient agrees with the suggestion that the tremor was mistakenly attributed to an allergic response. They conclude that it was more likely an adverse effect of the propofol, or another medication administered perioperatively, or was not drug-related at all.

The patient is then prepared for his procedure with administration of propofol 200 mg. During the surgery, he is given ketamine 20 mg and fentanyl boluses for a total of 225 mcg over a period of 2 hours. The surgery is performed successfully without any complications.

On regaining consciousness following the surgery, the patient exhibits spontaneous bilateral muscle spasms in his extremities. He is given intravenous meperidine 25 mg for suspected postoperative shivering. Following this treatment, his involuntary muscle spasms and rigidity intensify, and he begins to sweat profusely.

Case Challenge 1

Treatment and Outcome

At this point, the anesthesia team suspects serotonin syndrome, based on treatment with fentanyl during the surgery, combined with patient's long-term use of high-dose venlafaxine. The presence of these medications and the patient's symptoms – both spontaneous clonus and diaphoresis – also meet the often used to diagnose serotonin syndrome.

Based on this diagnosis, the patient is treated with 4 mg intravenous midazolam, which effectively addresses the bilateral myoclonic jerks and his muscle rigidity. The symptoms resolve fairly quickly, presumably because of the short half-life of fentanyl.

In a follow-up discussion, the patient concurs with the anesthesiologist's observation that this episode was similar to the prior occurrences of perioperative symptoms reported as a propofol allergy.

Case Challenge 2

Discussion

Multiple proserotonergic medications have a compounding effect that can result in serotonin syndrome. Increasing use of antidepressants has resulted in more frequent cases of what was previously a relatively rare diagnosis.³ Between 1999 and 2012, prescription of antidepressants almost doubled, from 6.8% to 13%.⁴

Awareness of this potentially life-threatening condition and its clinical diagnosis are of growing importance, especially in the surgical setting. While middle-aged and older people may be at greater risk due to more common use of antidepressants, serotonin syndrome should be considered as a differential diagnosis for any patient with signs of neuroexcitation.²

Furthermore, anesthesiologists and clinicians should be vigilant for this potential risk of polypharmacy in the preoperative screening process. As this case illustrates, patients with a history of movement disorders associated with previous surgeries may be at particular risk.³

A Diagnostic Conundrum

Diagnosis is entirely clinical. Signs and symptoms can vary considerably based on the severity of serotonergic toxicity, which are generally mild but can become severe and life-threatening, especially if not managed in a timely manner.⁵ The hallmark triad of symptoms is not reliably present in all patients: autonomic dysfunction (i.e., tachycardia, nausea and vomiting, and mydriasis) occurs in 40% of patients, neuromuscular excitation in 50%, and altered mental status (i.e., confusion and agitation) in 40%.⁶

As well, symptoms may not all occur at the same time.² Notably, physical signs such as rigidity may be delayed in patients given large doses of benzodiazepines, since symptoms may be masked by these drugs.⁷

There are three sets of diagnostic criteria for serotonin syndrome. Although expert opinions vary, a 2016 of serotonin syndrome diagnoses found that the Hunter criteria -- reputed to be the diagnostic gold standard -- did not perform better than the Sternbach Criteria and the Radomski Criteria.⁵

While symptoms of serotonin toxicity arise within an hour in about one in four patients, and within 6 hours in 61% of patients,⁸ those of malignant neuroleptic syndrome (which is commonly misdiagnosed as serotonin syndrome) generally develop days to weeks after ingestion of the precipitating medication. Also in contrast to neuroleptic malignant syndrome, relatively few cases of serotonin syndrome present with hyperthermia.²

Medications to Consider

Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) are, to a lesser extent, often implicated -- as are serotonin-norepinephrine reuptake inhibitors and serotonin releasers. An inadequate washout period when switching between antidepressants is another common cause of serotonin syndrome.²

Less conclusive evidence suggests a role for linezolid; methylene blue; procarbazine; lithium; lysergic acid diethylamide (LSD); 3,4-methylenedioxy-methamphetamine (MDMA); opioids such as tramadol, meperidine, and dextromethorphan; some antiemetics such as metoclopramide; migraine medications such as triptans; the herbal preparation St. John's wort; and drugs of abuse such as methylenedioxymethamphetamine (ecstasy) and cocaine.^2,5

Management of Serotonin Syndrome

Serotonin syndrome is managed with immediate cessation of the precipitating medication(s) and supportive treatments. Patients with significant toxicity usually respond to cyproheptadine, a potent 5-HT2A antagonist, within 1 to 2 hours of treatment.⁸

Conclusion

The incidence of serotonin syndrome is increasing and is a particular risk among middle-aged and older patients in the perioperative setting. A careful history and thorough physical examination pre-surgery may help identify patients at increased risk for this potentially dangerous and difficult-to-diagnose condition.²

References

1. Davis JJ, et al "Serotonin syndrome manifesting as patient movement during total intravenous anesthesia with propofol and remifentanil" J Clin Anesth 2013; 25: 52-54.

2. Wang RZ, et al "Serotonin syndrome: Preventing, recognizing, and treating it" Cleveland Clinic J Med 2016; 83: 810-817.

3. Smischney NJ, et al "Serotonin Syndrome in the Perioperative Setting" Am J Case Rep 2018; 19: 833-835.

4. Kantor ED, et al "Trends in prescription drug use among adults in the United States from 1999-2012" JAMA 2015; 314: 1818-1831.

5. Werneke U, et al "Conundrums in neurology: Diagnosing serotonin syndrome – a meta-analysis of cases" BMC Neurology 2016; 16: 97-106.

6. Iqbal MM, et al "Overview of serotonin syndrome" Ann Clin Psychiatry 2012; 24: 310-318.

7. Warner ME, et al "Serotonergic medications, herbal supplements, and perioperative serotonin syndrome" Can J Anaesth 2017; 64: 940-946.

8. Mason PJ, et al "Serotonin syndrome. Presentation of 2 cases and review of the literature" Medicine (Baltimore) 2000; 79: 201-209.

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