Introduction

Serotonin syndrome (SS) is a life-threatening medication reaction that poses significant diagnostic challenges in the perioperative setting. In SS, serotonergic compounds directly or indirectly over-activate serotonin receptors, leading to muscle rigidity, acidosis, autonomic derangement, and respiratory compromise (1). Review of the literature reveals case reports of perioperative SS involving the interaction of intraoperative and preoperative medications, such as fluoxetine and opioids (2-4). However, our case is unique as SS was precipitated by remifentanil and propofol alone, in the absence of any other known serotonergic medications. The case is further confounded by a remote history of methamphetamine use with a negative urine drug screen.

Case Description

A 32-year-old man with a medical history significant for right vestibular schwannoma presented with long-standing symptoms of tinnitus and progressive hearing loss. He had a history of alcohol use disorder and methamphetamine abuse. He had been incarcerated for three months at the time of surgery. The patient denied any personal or family history of anesthesia com- plications. He was not prescribed nor taking any medications before surgery. He denied current substance use. General anesthesia was induced with propofol, lidocaine, and rocuronium and maintained with propofol infusion (120 mcg/kg/min), remifentanil infusion (0.08 mcg/kg/min), and less than half a MAC (minimum alveolar concentration) of inhaled sevoflurane. Dexamethasone and mannitol were administered intraoperatively. After placement of Mayfield pins, he was positioned in the left lateral decubitus position and pressure points were meticulously padded and regularly checked. Surgery proceeded without problems and lasted approximately 14 hours. Halfway through the operation, the patient’s temperature, heart rate, and blood pressure gradually increased despite escalating anesthetic and analgesic doses and attempts at cooling. The patient’s temperature rose from 36.3°C (initial reading at 8:30) to 37°C by 13:30, further climbing to 38°C by 15:00, and peaking at 38.3°C by the end of the case around 22:00. We implemented aggressive cooling measures: applying ice packs to groin sites, maintaining the ambient room temperature at 21°C, and administering 1 L cooled saline, which slowed the rate of temperature rise. End-tidal carbon dioxide (CO2) levels remained stable at approximately 30 mmHg throughout the case, with partial pressure of CO2 (PaCO2) at approximately 36 mmHg. The patient received 4 mg ondansetron prior to emergence and was breathing spontaneously.

Postoperative Course

On emergence from anesthesia, the patient exhibited clonus, shivering, and agitation. Elevated blood pressures required the initiation of a nicardipine infusion (up to 5 mg/hr). In the intensive care unit, the patient continued to demonstrate severe shivering, muscle rigidity, and ocular clonus. He developed lactic acidosis measuring 3.0 mmol/L, hyperthermia to 39°C, and sinus tachycardia to 120 bpm (Table 1). These signs strongly suggested serotonin syndrome. The Malignant Hyperthermia Association of the United States (MHAUS) was consulted to rule out malignant hyperthermia, and they determined that MH was unlikely.

The patient was treated with multimodal therapy, including a cooling blanket, dexmedetomidine infusion (0.5–0.8 mcg/kg/h), benzodiazepine boluses (total 2 mg intravenous midazolam and 2 mg intravenous lorazepam), and a 1 L bolus of ice-cold crystalloid solution. He maintained nor- mal urine output. Laboratory values revealed a peak creatinine kinase level of 19,720 U/L and a lactic acid level of 3.29 mmol/L.

The patient improved over the next 24 hours and disclosed a remote history of methamphetamine (three months prior) and alcohol use (one month prior) while incarcerated. His urine drug screen was negative for any substances, making the likelihood of amphetamine-triggered SS very low. We hypothesized that this patient suffered from SS from prolonged remifentanil and propofol infusions, potentially exacerbated by concurrent illicit drug use.

Table 1. Vital sign trend, OR- operating room, POD- postoperative day, ICU- Intensive Care Unit

	On emergence in OR (POD #0)	2 hours postop in ICU (POD# 0)	12 hours postop in ICU (POD #1)	24 hours postop in ICU (POD #2)
Temperature (Celsius)	38.3	39	38.4	36.4
Heart Rate (beats per minute)	140	120	108	98
Blood Pressure (mmHg)	165/80	130/70	127/64	123/72
Neurological exam	AAOx3, rigors, beats of clonus in lower extremity	AAOx3, following commands; rigors, clonus	Agitated, AAOx3	AAOx4

Discussion Questions:

1. What are the differential diagnoses for this patient?
2. How is serotonin syndrome diagnosed?
3. What is the treatment of SS?
4. What was the inciting cause of the SS?

Differential Diagnoses

The differential diagnoses for this patient included but were not limited to drug reaction, malignant hyperthermia (MH), sepsis, neuroleptic malignant syndrome (NMS), positioning-related crush injury, rhabdomyolysis, alcohol withdrawal, inadequate analgesia or anesthetic depth. MH was deemed less likely given normal EtCO2. Due to the similarities in symptomatology, SS may be confused for NMS, MH, or anticholinergic toxicity. NMS, a life-threatening condition characterized by excess dopaminergic activity, has different inciting agents, a prolonged prodromal period (lasting days to weeks), diminished reflexes, and absence of clonus. Anticholinergic poisoning typically lacks abnormal muscle tone or reflexes. Alcohol withdrawal has a duration of multiple days and requires prerequisite dependence on alcohol.

Serotonin Syndrome Description and Diagnosis

SS, or serotonin toxicity, is a life-threatening condition caused by an excess of serotonergic activity due to impaired metabolism of serotonergic drugs, excess serotonin agonism of a single drug, or combined effect of multiple serotonergic drugs (Table 2) (5,6). The central triad of SS consists of altered mental status, autonomic derangement, and neuromuscular abnormalities (Table 3), as diagnosed by the Hunter Criteria (sensitivity and specificity 84% and 97%, respectively) (Table 4). Our patient’s symptoms of a body temperature >38.5°C and marked hypertonia and rigidity indicated severe serotonin toxicity with a high likelihood for progression to respiratory compromise (7), requiring urgent intervention. Case reports describe the progression of severe SS to rhabdomyolysis, multiorgan failure, and disseminated intravascular coagulopathy (1).

Table 2. Drug mechanisms associated with serotonin toxicity (2).

Effect on Serotonin	Drugs
Decreased breakdown	monoamine oxidase inhibitors (MAOIs), linezolid, methylene blue, procarbazine, and Syrian rue
Decreased reuptake	SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants opioids (meperidine, buprenorphine, tramadol, tapentadol, dextromethorphan), antiepileptics (carbamazepine, valproate), and antiemetics (ondansetron, granisetron, metoclopramide), and the herbal preparation St. John’s wort
Increased production or agonism	tryptophan, lithium, fentanyl, and lysergic acid diethylamide (LSD)
Increased release	fenfluramine, amphetamines, and methylenedioxymethamphetamine (MDMA)
Decreased metabolism of serotonergic drugs	CYP2D6 and CYP3A4 inhibitors: erythromycin, ciprofloxacin, fluconazole, ritonavir, and grapefruit juice

 

Table 3. Spectrum of symptoms in serotonin syndrome (2).

Severity	Neuromuscular excitation	Altered mental status	Autonomic dysfunction
Mild	Hyperreflexia   Tremor   Myoclonus	Anxiety   Restlessness   Insomnia	Diaphoresis   Mydriasis   Tachycardia
Moderate	Opsoclonus   Spontaneous or inducible clonus	Agitation	Hypertension   Hyperthermia (< 40 C)   Hyperactive bowel sounds   GI symptoms
Severe	Rigidity   Respiratory failure   Tonic-clonic seizure	Coma   Delirium   Confusion	Severe hyperthermia (>= 40 C)   Dynamic blood pressure

 

Table 4. Hunter serotonin toxicity criteria decision rules³ 

Current or recent serotonergic agent use AND any of the following:
Spontaneous clonus
Inducible clonus	AND	Agitation or diaphoresis
Ocular clonus	AND	Agitation or diaphoresis
Inducible or ocular clonus	AND	Hypertonia and hyperthermia
Tremor	AND	Hyperreflexia

 

Treatment of SS

Treatment of SS depends on severity, but in all cases involves discontinuation of serotonergic medications. Firstline treatment consists of supportive measures to improve hyperthermia and hypoventilation (5,6). Antipyretics have minimal impact as hyperthermia is not due to hypothalamic derangement, but rather muscle rigidity (6). Effective pharmacological treatments for symptoms of SS include paralytics and benzodiazepines due to their dual action in promoting muscle relaxation and managing agitation. While case reports document the prevention of severe SS with 5HT-1A and 5HT-2A receptor antagonists such as cyproheptadine, larger-scale trials establishing their efficacy remain scarce, particularly in severe cases (8). Cyproheptadine is only available in an oral form but can be crushed and given through a feeding tube. Notably, it can cause sedation and transient hypotension, typically mild and responsive to volume resuscitation. This patient did not receive serotonin antagonists due to the short half-life of the medications (remifentanil and propofol) presumed to have caused this patient’s SS and rapid clinical improvement over the course of a few hours.

Cause of SS

Opioids are known causative agents of serotonin toxicity (9-11). Remifentanil has been shown to worsen muscle rigidity in patients with acute SS (9) and is described as the precipitating agent of SS in patients taking tramadol (2) and fluoxetine (3).

Propofol increases serotonin and dopamine metabolites in the somatosensory cortex of rats (12). While case reports exist that describe propofol-induced SS in humans, these cases involved concurrent administration of other serotonergic medications and concomitant use of serotonin reuptake-inhibiting antidepressants (3,4). While it is theoretically plausible that propofol may contribute to SS when coupled with other risk factors, a definitive causal relationship in humans has not been established.

Methamphetamines also play a role in triggering SS (13). Methamphetamine is an indirect monoamine (specifically dopamine, norepinephrine, and serotonin) agonist and a monoamine oxidase inhibitor, increasing the risk for SS. The terminal half-life of methamphetamine in urine spans approximately 25 hours, yet with repeated dosing persists in the urine for up to 7 days (14). Given that the stimulant effects of the drug wear off after 8 hours and the patient’s negative drug screen results, the likelihood of the drug contributing to this patient’s SS appears low. Methamphetamine accumulates in kidney tissue at a higher rate than brain tissue; the concentration of methamphetamine at any given time after administration should be lower in the brain than in the urine, further decreasing the possibility of it contributing to this patient’s SS (15). However, a negative screen does not rule out a contributing effect from drugs not screened, such as research chemicals, analogs, or cutting agents.

Conclusion

We observed a rare occurrence of SS from prolonged remifentanil and propofol infusion in a patient with a remote history of methamphetamine use. Limited data exist on these medications contributing to SS. Perioperative SS can lead to increased hospital length of stay, unplanned intensive care admission, and severe SS can be fatal (1). In long cases exposing patients to remifentanil and propofol, providers should consider monitoring for symptoms consistent with SS, even in the absence of obvious serotonergic drug interactions, and promptly initiating appropriate management.

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