Serotonin Syndrome

Practice Essentials

Serotonin syndrome is classically described as involving a combination of autonomic hyperactivity, hemodynamic changes, neuromuscular derangements, and changes in mental status. This article is aimed at providing a general understanding of this condition, describing its presentation in the perioperative setting, outlining how to manage it, and illustrating some different scenarios in which it may arise.

Serotonin syndrome can be precipitated by pharmaceuticals, botanicals, and recreational drugs. The diagnosis is based on clinical symptoms rather than on any particular laboratory studies; the Hunter criteria are most often used for this purpose. The utility of these criteria notwithstanding, diagnosis of serotonin syndrome can be challenging, particularly in the perioperative setting.

It is important to obtain an accurate and thorough history of medications and recent ingestions so that the symptoms of this syndrome can be distinguished from those of other disease processes that present similarly. Serotonin syndrome can have a variety of clinical presentations, but the majority of cases manifest within 24 hours of a change of dose or initiation of a drug.

Treatment of serotonin syndrome involves the following measures:

Discontinuance of all serotoninergic agentsSupportive care with the goal of normalizing vital signsSedation with benzodiazepinesAdministration of serotonin antagonists (eg, cyproheptadine)

The prognosis is generally good.

NMS is the condition most commonly cited in the differential diagnosis when serotonin syndrome is a concern. NMS involves exposure to or withdrawal from a dopamine antagonist; it is related to an inherited genetic mutation in skeletal muscle and is provoked in the presence of certain neuroleptics (eg, haloperidol). [4]

Compared with serotonin syndrome, which presents within 24 hours of exposure, NMS usually has a more gradual onset, generally presenting in days to weeks. The altered mental status in serotonin syndrome often manifests in the form of global symptoms such as agitation and delirium, whereas in NMS, symptoms are more localized (eg, dysphagia, incontinence, and increased secretions).

In addition, NMS often has extrapyramidal side effects, including muscle rigidity and rhabdomyolysis, which can lead to leukocytosis, increased creatinine kinase and hepatic transaminase levels, and metabolic acidosis. Finally, unlike serotonin syndrome, NMS is rarely associated with hyperreflexia and myoclonus. It must be noted, however, that in cases involving both serotonergic and dopaminergic drugs, differentiation between serotonin syndrome and NMS can be very difficult.

Serotonin syndrome is diagnosed on the basis of clinical manifestations, as well as a comprehensive medication review. Perioperative diagnosis of serotonin syndrome can be facilitated by the use of the Hunter serotonin toxicity criteria, which are based on a specific set of clinical features in specific combinations and which have a sensitivity of 84% and a specificity of 97%.

According to the Hunter criteria, the patient must have taken a serotoninergic agent within the preceding 5 weeks and must also have one of the following [1] :

Muscle rigidity plus temperature higher than 38ºC plus ocular clonus/inducible clonusOcular clonus plus agitation/diaphoresisInducible clonus plus agitation/diaphoresisSpontaneous clonusTremor plus hyperreflexiaHypertonia

As mentioned earlier, serotonin syndrome typically manifests within 24 hours of exposure to the offending agent. Early manifestations and symptoms of mild serotonin syndrome include the following:

TachycardiaDiaphoresisDilated pupilsMyoclonusIncreased deep tendon reflexesRestlessnessAnxietyGait abnormalitiesDifficulty concentratingSleep disturbancesShiveringMuscle twitching

Late manifestations and symptoms of moderate-to-severe serotonin syndrome include the following:

Hyperactive bowel soundsDiarrheaHypertensionSevere hyperthermiaMuscle rigidityDisseminated intravascular coagulation (DIC)Multiple organ failureShock

Rhabdomyolysis is the most common and serious complication, occurring in 25% of cases. Generalized seizures occur in approximately 10% of cases. Early diagnosis of serotonin toxicity is vital because the condition can progress and become fatal.

There is no laboratory test that specifically confirms the diagnosis of serotonin syndrome; however, there are some nonspecific laboratory findings associated with the syndrome, including the following:

Increased white blood cell (WBC) countIncreased creatine phosphokinase (CPK) levelDecreased bicarbonate level

Additionally, case reports have found several electroencephalographic (EEG) abnormalities to be associated with serotonin syndrome, [5] including the following:

Delta range activitySlow wavesSpike and wavesPolyspike and wavesTriphasic waves

Management

When serotonin toxicity is suspected, the most important initial step is to remove the offending agent. The best-known serotoninergic agents are antidepressants, [6, 7, 8] as follows:

Monoamine oxidase inhibitors (MAOIs; eg, MAO-A [isocarboxazid, phenelzine, tranylcypromine] or MAO-B [rasagiline, safinamide, selegiline])Tricyclic antidepressants (TCAs; eg, amitriptyline, amoxapine, clomipramine, cyclobenzaprine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine)Selective serotonin reuptake inhibitors (SSRIs; eg, citalopram, escitalopram, fluoxetine, paroxetine, fluvoxamine, sertraline, vortioxetine)Serotonin-norepinephrine reuptake inhibitors (SNRIs) (eg, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, venlafaxine)Bupropion

However, there are many other pharmaceuticals of which practitioners should also be aware as potential offending agents, including various common perioperative and labor medications, as follows:

Opioids (eg, fentanyl, meperidine, oxycodone, hydrocodone, tramadol)5-hydroxytryptamine (5-HT; ie, serotonin) antagonists (eg, ondansetron, granisetron, dolasetron, palonosetron)Triptans (eg, sumatriptan, eletriptan, frovatriptan, rizatriptan)Stimulants (eg, amphetamine, dexmethylphenidate, dextroamphetamine, diethylpropion, lisdexamfetamine, methylphenidate)MetoclopramideTrazodoneMirtazapineMethylene blueLinezolid

For the intensivist, it is important to know that antipsychotics (eg, olanzapine, risperidone, and quetiapine) and antibiotics (eg, linezolid) are also often implicated. Additionally, recreational drugs and over-the-counter (OTC) drugs (eg, 3,4-methylenedioxy-methamphetamine [MDMA; ecstasy], bath salts, and St John's wort) have been associated with serotonin syndrome. Patients taking high doses of a serotoninergic drug are particularly vulnerable

Once serotonin syndrome has been diagnosed, and after the offending agent has been removed, supportive care is the mainstay of treatment. The syndrome often resolves within 24 hours after discontinuance of the serotoninergic agent and initiation of supportive care. More often than not, these patients will need intensive care unit (ICU) monitoring, including the following:

Oxygen administrationIntravenous (IV) fluidsContinuous cardiac monitoring (including QTc and QRS duration monitoring)Airway support/intubation

In the setting of recent ingestion, the use of activated charcoal to assist with gastrointestinal (GI) decontamination may be considered.

One of the most important components of treatment is administration of benzodiazepines, which can alleviate numerous symptoms, especially agitation.

If the patient is hyperthermic (especially > 40ºC), it is important to begin active external cooling. Because the rise in temperature is of muscular origin, antipyretics are of no use, and paralytics are indicated when fever is high.

For both hemodynamic instability and agitation, there is some evidence to suggest that dexmedetomidine may be useful to treat these symptoms of serotonin toxicity. [10]

For severe hypertension, easily titratable medications (eg, clevidipine or esmolol), should be employed. In cases of refractory hypotension, vasopressors should be used.

Finally, the serotonin antagonist cyproheptadine has been recommended for the treatment of serotonin syndrome. [11] Mirtazapine, a 5-HT3 and 5-HT2 antagonist, has also been used in a small number of cases; however, multiple studies have suggested that this agent does not change outcomes.

Although many different agents have been used in the care of patients with serotonin syndrome, there are a number that are not recommended, including olanzapine, chlorpromazine, propanolol, bromocriptine, and dantrolene.

Typically, serotonin syndrome starts usually within hours after initiation of a medication regimen, increase of the dosage, or overdose. It will continue as long as the serotoninergic agents remain in the system. The prognosis for patients with serotonin syndrome is generally favorable, provided that the syndrome is promptly recognized and that its associated complications are treated appropriately.

REFERENCES

1 Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005 Mar 17. 352 (11):1112-20. [Medline].

2 Birmes P, Coppin D, Schmitt L, Lauque D. Serotonin syndrome: a brief review. CMAJ. 2003 May 27. 168 (11):1439-42. [Medline]. [Full Text].

3 Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med. 2009. 60:355-66. [Medline]. [Full Text].

4 Keck PE Jr, Caroff SN, McElroy SL. Neuroleptic malignant syndrome and malignant hyperthermia: end of a controversy?. J Neuropsychiatry Clin Neurosci. 1995 Spring. 7 (2):135-44. [Medline].

5 Krishnamoorthy T, Knighton J, Merton L. The role of electroencephalography in the diagnosis of serotonin syndrome. J Intensive Care Soc. 2016 Aug. 17 (3):258-261. [Medline]. [Full Text].

6 LoVecchio F, Mattison E. Atypical and serotonergic antidepressants. Tintinalli JE. Stapczynski JS, Ma OJ, Yealy DM, Meckler GD, Cline DM, eds. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. 8th ed. New York: McGraw-Hill; 2016. 1219-24.

Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin syndrome. Ochsner J. 2013 Winter. 13 (4):533-40. [Medline]. [Full Text].

7 Warner ME, Naranjo J, Pollard EM, Weingarten TN, Warner MA, Sprung J. Serotonergic medications, herbal supplements, and perioperative serotonin syndrome. Can J Anaesth. 2017 Sep. 64 (9):940-946. [Medline].

8 Smischney NJ, Pollard EM, Nookala AU, Olatoye OO. Serotonin Syndrome in the Perioperative Setting. Am J Case Rep. 2018 Jul 16. 19:833-835. [Medline]. [Full Text].

Rushton WF, Charlton NP. Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacother. 2014 Dec. 48 (12):1651-4. [Medline].

9 McDaniel WW. Serotonin syndrome: early management with cyproheptadine. Ann Pharmacother. 2001 Jul-Aug. 35 (7-8):870-3. [Medline].

10 van Ewijk CE, Jacobs GE, Girbes ARJ. Unsuspected serotonin toxicity in the ICU. Ann Intensive Care. 2016 Dec. 6 (1):85. [Medline]. [Full Text].

Martino EA, Winterton D, Nardelli P, Pasin L, Calabrò MG, Bove T, et al. The Blue Coma: 11 The Role of Methylene Blue in Unexplained Coma After Cardiac Surgery. J Cardiothorac Vasc Anesth. 2016 Apr. 30 (2):423-7. [Medline].

12 Pedavally S, Fugate JE, Rabinstein AA. Serotonin syndrome in the intensive care unit: clinical presentations and precipitating medications. Neurocrit Care. 2014 Aug. 21 (1):108-13. [Medline].

13 Hencken L, To L, Ly N, Morgan JA. Serotonin Syndrome Following Methylene Blue Administration for Vasoplegic Syndrome. J Card Surg. 2016 Apr. 31 (4):208-10. [Medline].

Wen SW, Yang Q, Garner P, Fraser W, Olatunbosun O, Nimrod C, et al. Selective serotonin reuptake inhibitors and adverse pregnancy outcomes. Am J Obstet Gynecol. 2006 Apr. 194 (4):961-6. [Medline].

14 Fleschler R, Peskin MF. Selective serotonin reuptake inhibitors (SSRIs) in pregnancy: a review. MCN Am J Matern Child Nurs. 2008 Nov-Dec. 33 (6):355-61; quiz 362-3. [Medline].

Roth CK, Hering SL, Campos S. Serotonin Syndrome in Pregnancy. Nurs Womens Health. 2015 Aug-Sep. 19 (4):345-9. [Medline].