Dexmedetomidine in the Treatment of Serotonin Syndrome

Background

Serotonin (5-hydroxytryptamine or 5HT) syndrome is classically defined as the triad of acute altered mental status, autonomic instability, and neuromuscular abnormalities following either initiation or increase of dosage of a serotonergic agent. Minor cases may manifest only with subtle signs such as tremor and tachycardia, whereas more severe toxicity presents with altered mental status, sustained myoclonus, hypertension, hyperthermia, and seizures. ¹ Although multiple serotonergic receptors have been implicated, serotonin syndrome is generally thought to be mediated by excessive stimulation of the 5HT-1a and 5HT-2a receptors. ¹ Diagnosis is challenging because there is no confirmatory laboratory testing. Two sets of criteria have been proposed: Sternbach and the Hunter Area Toxicology Service, commonly known as the Hunter Criteria. Hunter criteria, which are more specific and sensitive than Sternbach’s, generally define the syndrome as the presence of a serotonergic agent plus either inducible, ocular, or spontaneous clonus. ²

Treatment of serotonin syndrome can be complex; the primary therapy is removal of the offending agent and avoidance of other drugs with serotonergic activity. Use of γ-aminobutyric acid (GABA) chloride channel agonists such as benzodiazepines, barbiturates, and propofol are often required for control of agitation, seizures, and autonomic instability. ¹

As the number of reported exposures to serotonergic medications to US poison centers increases each year, the incidence of serotonin syndrome is also expected to grow.^1,3 Although most cases do not result in serious morbidity, serotonin syndrome can be life threatening, with several deaths reported annually from serotonergic agents. ³ Thus, investigation of additional treatments for serotonin syndrome remains crucial. The purpose of this case series is to present 3 cases of serotonin syndrome refractory to supportive treatment with GABA receptor enhancers that showed clinical improvement following initiation of dexmedetomidine therapy. Per our institution’s guidelines, this case series was exempt from the institutional review board.

Case 1

A 15-year-old male with no past medical history presented to the emergency department (ED) with altered mental status and hallucinations after abusing an unknown amount of an over-the-counter cold preparation that contained ibuprofen, diphenhydramine, and extended-release dextromethorphan. In the ED, he was agitated, tachycardic to 128 beats/min, had a respiratory rate of 20 breaths/min, a blood pressure of 146/90 mm Hg, and was afebrile. Despite 4 mg of intravenous (IV) lorazepam, the patient remained agitated and was subsequently intubated with rocuronium and etomidate. Following intubation, he was started on a continuous propofol infusion and was admitted to the pediatric intensive care unit (PICU). He was noted to have sustained myoclonus with bilateral achilles reflexes and was hyperreflexic at the patellar tendons.

On day 1 of admission, despite the propofol infusion, the patient remained tachycardic and developed worsening myoclonus; he was transitioned to a continuous midazolam infusion at 0.3 mg/kg/h and a morphine infusion at 0.15 mg/kg/h. To further control his symptoms, he was subsequently bolused with phenobarbital 20 mg/kg IV with mild improvement in myoclonus. On day 2 of admission, the patient became hyperthermic to 38.4°C. Over the next 72 hours, he was observed to have spontaneous full-body myoclonus despite being regularly bolused with phenobarbital; he developed rhabdomyolysis (creatinine kinase peaked at 2133 U/L) and remained persistently hyperthermic. Because of concern for seizure activity, the patient was placed on continuous electroencephalography monitoring; however, there was no epileptiform activity seen.

On hospital day 4, a dexmedetomidine infusion was instituted at 0.05 µg/kg/h and titrated up to 0.8 µg/kg/h. The patient’s heart rate subsequently improved, and his myoclonus and hyperthermia resolved. He was able to be weaned off of all sedation within the next 48 hours and was extubated.

Case 2

A 16-year-old male who was otherwise healthy was admitted to the PICU after intentionally overdosing on methadone, dextromethorphan, and chlorpheniramine in a suicide attempt earlier in the day. The patient was initially found to be minimally responsive but had mild improvement in mental status following 2 mg of IV naloxone. His ED vital signs demonstrated a blood pressure of 87/52 mm Hg, a heart rate of 124 beats/min, and a temperature of 36.7°C. An hour after the naloxone bolus, the patient resedated, was intubated with etomidate and succinylcholine, and was started on a midazolam infusion. A urine drug screen was positive for tetrahydrocannabinol, methylenedioxy-N-methylamphetamine (MDMA), and methadone. On arrival to the PICU 2 hours later, the patient was noted to be hyperthermic to 38.6°C, diaphoretic, and had sustained myoclonus with bilateral achilles reflexes along with hyperreflexia at the patellar tendons. Despite a midazolam infusion at 0.3 mg/kg/h and intermittent midazolam boluses, he continued to have sustained lower-extremity myoclonus, was tachycardic to 124 beats/min, and remained hyperthermic to 38.4°C. His course was further complicated by the development of rhabdomyolysis, with creatinine kinase peaking at 2188 U/L. On hospital day 4, the tachycardia, hyperthermia, and clonus persisted; a dexmedetomidine infusion was started at 0.1 µg/kg/h. Myoclonus was noted to be improved but still present. The following day, dexmedetomidine was increased to 0.2 µg/kg/h with improvement of heart rate and myoclonus and resolution of hyperthermia. Then, 6 days after admission, all sedation was discontinued, and the patient was extubated and subsequently transferred to psychiatry.

Case 3

A 14-year-old female with no significant past medical history presented to the ED following a seizure witnessed by her family. On arrival, she was noted to be unresponsive, diaphoretic, and tachycardic; she was subsequently intubated. Further history revealed that the patient had been recreationally abusing combination products of dextromethorphan and antihistamines for several years. She was subsequently transferred to the PICU at a tertiary care center, where she was persistently agitated despite administration of a propofol infusion and intermittent propofol boluses over the preceding several hours. Her blood pressure was 127/66 mm Hg, temperature was 39.1°C, and heart rate was 126 beats/min. Also, 6 beats of inducible myoclonus were present with achilles reflexes along with hyperreflexia in the patellar tendons. She was subsequently started on a midazolam infusion at 0.08 mg/kg/h, and the propofol infusion was discontinued.

Because of persistent tachycardia, myoclonus, and hyperthermia, dexmedetomidine was infused at 0.5 µg/kg/h on arrival to the PICU. A lumbar puncture returned normal cerebral spinal fluid and pressure. Over the next 36 hours, the patient’s myoclonus, tachycardia, and hyperthermia resolved. She was extubated the day after her admission and made a full recovery.

Discussion

In each of the above cases, the diagnosis of serotonin syndrome was made per Hunter criteria based on the ingestion of a serotonergic agent and inducible myoclonus. All 3 patients had symptoms persist despite high doses of midazolam and/or propofol infusions. Each also demonstrated a temporal relationship in the initiation of dexmedetomidine infusion and improvement in clinical symptoms. These findings are not unique to our experience; recently, other authors have reported a case of a 6-year-old girl with serotonin syndrome refractory to benzodiazepines that was successfully treated with dexmedetomidine. ⁴

Dexmedetomidine is an α-2 adrenergic agonist that has 8 times the affinity for the receptor as clonidine. ⁵ In the central nervous system, activity at α-2 receptors produces sedation and analgesia. ⁶ Dexmedetomidine has advantages over other sedating agents because of minimal suppression of respiratory function. ⁷ Although generally well tolerated, the most common side effects are hypotension, bradycardia, and nausea. ⁵ Encouragingly, a recent review investigating the use of dexmedetomidine in the overdose patient demonstrated a relatively low incidence of serious side effects, of which bradycardia was the most common. ⁸ This is in concordance with our case series, where no serious adverse events were observed secondary to the dexmedetomidine infusion. Furthermore, dexmedetomidine has been reported to be safe and effective in treating ethanol withdrawal and delirium.^9,10

Dexmedetomidine’s modulation of serotonin neurotoxicity has been the subject of several recent animal models. Rats that were pretreated with dexmedetomidine had lower serotoninergic activity on histological examination of the locus coeruleus, nucleus tractus solitarii, and raphe dorsalis compared with rats that received normal saline. ¹¹ These findings are supported by other mouse and rat models that demonstrate reduced serotonergic activity when treated with an α-2 receptor agonist.^12-15

One suggested mechanism for α-2 modulation of serotonin neurotoxicity is a reduction, through negative feedback, in central noradrenergic stimulation of serotonergic neurons. In one study, the ability of clonidine, a selective α-2 agonist, to reduce serotonin function in rat central nervous tissue was aborted by the presence of 6-hydroxydopamine, a potent neurotoxin that destroys noradrenergic neurons. ¹³ Furthermore, amphetamine coadministration, with subsequent norepinephrine release, antagonized clonidine’s inhibition of serotonin activity. ¹³ Consequently, the inhibitory effect of clonidine was hypothesized to be modulated through a decreased release of norepinephrine in nerves innervating 5HT neurons. ¹³ This conclusion was strengthened by a subsequent study that reported that the induction of serotonin syndrome in rats was inhibited by metamine, a drug that lowers noradrenergic activity. ¹⁶ Other authors have also postulated that inhibitory α-2 adrenoceptors may also be found directly on serotonergic neurons. ¹⁷

There are several limitations to this case series. Other than a standard urine drug screen performed in one patient, analytic testing was not performed; other unidentified substances may have confounded the presentation and clinical course. Furthermore, although a temporal association in clinical improvement was noted following initiation of dexmedetomidine, the patients also received other standard therapies, including high-dose GABA agonists. Consequently, the patients’ clinical improvements may have occurred regardless of dexmedetomidine initiation.

Conclusion

This case series highlights 3 cases of refractory serotonin syndrome, where initiation of dexmedetomidine temporally preceded stabilization of the autonomic nervous system, as reflected by improvement in tachycardia, myoclonus, and hyperthermia. In each case, dexmedetomidine was associated with weaning of other sedatives and successful extubation. Although no human studies exist, several animal models suggest that α-2 stimulation can stabilize serotonin neurotoxicity. Even though data are limited, dexmedetomidine may be considered as adjunctive therapy in the treatment of refractory serotonin syndrome and warrants further research.