The diagnosis of serotonin syndrome is purely clinical. Therefore, clinical suspicions should rise when a patient displays signs and symptoms of the syndrome following administration or dose increase of drugs known to act on the serotonergic system. Clinical manifestations of serotonin syndrome are described in terms of changes in mental status, autonomic function, and neuromuscular status (Table 49.2). The clinician should have high index of suspicion of this diagnosis should a patient who has been exposed to drugs with serotonergic activity develop a fever and altered mental status, autonomic instability, and increased (lower) limb rigidity [14].

Several diagnostic criteria have been proposed for serotonin syndrome. The most recent diagnostic criteria are the Hunter Serotonin Toxicity Criteria (HSTC). When compared to the gold standard of diagnosis by a medical toxicologist, the HSTC are sensitive (84 %) and specific (97 %). The Hunter Criteria include the use of a serotonergic agent plus one out of five of the following: spontaneous clonus, inducible clonus plus agitation or diaphoresis, ocular clonus plus agitation or diaphoresis, tremor and hyperreflexia, hypertonia, and a temperature above 38 °C plus ocular or inducible clonus [3, 10, 11]. The presence of clonus and hyperreflexia is most important for the diagnosis; however, severe muscle rigidity may mask these symptoms. Prominent features of life-threatening cases include hyperthermia (>38.5 °C), peripheral hypertonicity, and truncal rigidity. These symptoms have shown a high risk of progression to respiratory failure [11]. There are some nonspecific laboratory abnormalities that may be seen in serotonin syndrome which include leukocytosis, low bicarbonate, and elevated creatinine and transaminases. Serum serotonin concentrations do not correlate with the severity of this syndrome [3, 15].

The differential diagnoses for serotonin syndrome are extensive. It includes neuroleptic malignant syndrome (NMS), malignant hyperthermia, anticholinergic toxicity, serotonergic discontinuation syndrome, sympathomimetic drug intoxication, meningitis, encephalitis, heat stroke, and central hyperthermia [3]. The main differential diagnosis is NMS which often has a slower onset, is associated with hyperthermia (>38 °C), and has a much higher mortality [16]. Table 49.3 summarizes some of the clinical features and diagnostic aids that differentiate NMS, malignant hyperthermia, and serotonin syndrome.

During the preoperative evaluation, emphasis should be placed on the history of ingested substances including prescription drug use, over-the-counter medication and dietary supplement use, illicit substance use, and any recent changes in dosing or addition of new drugs to a drug regimen. The onset and description of symptoms and the presence of any comorbidity are of utmost importance. Certain comorbidities, such as depression and chronic pain, may clue the clinician into the use of drugs that can precipitate serotonin syndrome [3]. Hypertension, atherosclerosis, and hyperlipidemia are all associated with reduced endothelial MAO activity which affects serotonin metabolism [17]. Also, a higher incidence of serotonin syndrome has been reported in patients with end-stage renal disease who are on selective serotonin reuptake inhibitors (SSRIs) and hemodialysis. These patients are prone to developing serotonin toxicity, suggesting that this increased toxicity could be related to a decrease in renal function [3, 4]. Furthermore, predisposing factors such as inherited or acquired deficits in peripheral serotonin metabolism may contribute to the development of serotonin syndrome. The preexisting conditions illustrated above coupled with the use of serotonergic drugs increase the chances of serotonin syndrome [17].