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Serotonin Syndrome


Serotonin syndrome is a preventable, drug-related complication that results from increased brain-stem serotonin activity, usually precipitated by the use of one or more serotonergic drugs. Its clinical presentation consists of autonomic dysfunction, alteration in mental status, and neuromuscular disorder. Early recognition and treatment is important, because this condition is potentially fatal. Management includes withdrawal of causative agents and supportive measures such as hemodynamic stabilization, sedation, temperature control, hydration, and monitoring for complications. Serotonin antagonists, specifically cyproheptadine, have been used, but the documented benefits are purely anecdotal.

Introduction
Bettina C. Prator

J Neurosci Nurs. 2006;38(2):102-105. ©2006 American Association of Neuroscience Nurses
Posted 11/29/2006
Abstract and Introduction
Serotonin syndrome, also known as serotonin toxicity, is an iatrogenic disorder that was first reported in the 1950s and is associated with the use of monoamine-oxidase-inhibitor (MAOI) antidepressants and tryptophan (Martin, 1996). Not until 1982 was the first case report published that referred to the condition as serotonin syndrome (Mills, 1997). According to Sternbach (1991), age and gender are not related to the incidence of or predisposition to the syndrome. With the advent of selective serotonin-reuptake inhibitors (SSRIs), the number of noted cases of serotonin syndrome has increased. A 2002 Toxic Exposure Surveillance System report revealed that of 26,733 patients on SSRIs, 27% developed significant morbidity and 93 died (Boyer & Shannon, 2005). With the increased incidence of serotonin syndrome and its potentially life-threatening effects, nurses need to know how to recognize and manage this condition. This article presents a case study and then reviews the pathophysiology, clinical presentation, and current treatment strategies for serotonin syndrome, emphasizing the role of nursing.
Case Study

A 55-year-old man was transferred from a community hospital emergency department to a major teaching hospital emergency department with chief complaints of altered mental status and fever. Immediately before transfer, the patient was treated with intravenous vancomycin and ceftriaxone for possible meningitis. On arrival at the emergency department, the patient was noted to be confused, restless, and diaphoretic, with a body temperature of 102.7º F and a heart rate of 130 beats per minute. Further examination revealed tremors at rest, inducible and spontaneous bilateral myoclonus of the feet, and hyperreflexia, specifically in both lower extremities. The patient’s past medical history included depression and anxiety, for which he had been taking phenelzine sulfate and clonazepam for the last few years. His spouse reported that he had been taking tramadol for the last 2 months, as needed, for headaches. A head CT scan revealed no acute process. A urine drug screen was negative, and a complete blood count was unremarkable. Blood chemistry revealed sodium 151mmol/L, potassium 4.4 meq/L, chloride 115 meq/L, bicarbonate 21 meq/L, BUN 34 mg/dl, creatinine 2.0 mg/dl, and glucose 112 mg/dl. An arterial blood gas revealed metabolic acidosis with pH 7.32; pCO2 and pO2 were otherwise unremarkable. Due to severe restlessness that did not improve with lorazepam, the patient was intubated and chemically paralyzed with rocuronium. Diagnostic lumbar puncture was then done with an opening pressure of 8 mm Hg. Cerebrospinal fluid chemistries, bacterial antigen, and gram stain were negative. A serum creatine kinase of 24,421 IU/L with serum myoglobin of 4,944 mg/ml was noted; urine myoglobin was 239 mg/ml. Aggressive fluid resuscitation using intravenous saline at 250 cc/hr was initiated. The patient was then admitted to the neurotrauma intensive care unit (NTICU) with a diagnosis of serotonin syndrome and rhabdomyolysis.

Supportive measures including sedation, mechanical ventilation, and fluid resuscitation were provided at the NTICU. Phenelzine sulfate and tramadol were withheld. On his second day on the NTICU, the patient’s confusion and agitation improved, no further tachycardia and fever were noted, and a reduction in tremors and hyperreflexia was observed. Serum creatinine and CK were within normal limits. The patient was extubated and transferred out of the NTICU after 24 hours.
Pathophysiology

Serotonin is a neurotransmitter synthesized both peripherally and centrally from dietary amino acid L-tryptophan. Serotonin is produced peripherally by the intestinal chromaffin cells and centrally by nuclei found in the lower pons and upper brain stem (Mills, 1997). It regulates emotional, personality, sleep, appetite, temperature, pain, sexual, and cardiopulmonary functions in the central nervous system. It also regulates smooth muscle tone, specifically of the blood vessels and gastrointestinal tract in the periphery (Boyer & Shannon, 2005).

Serotonin syndrome is a state of excess serotonin activity caused by therapeutic use, overdosage, withdrawal, or drug interaction of one or more serotonergic drugs (Mills, 1995). The mechanisms that result in such a depressants (MAOIs, SSRIs, and tricyclics), analgesics, hyperserotonergic state include an increase in serotonin production or decrease in serotonin metabolism. Boyer and Shannon (2005) identified medications such as antidepressants (MAOIs, SSRIs, and tricyclics), analgesics, weight-loss medications, antibiotics, over-the-counter drugs, street drugs, and dietary supplements as common serotonergic agents that could precipitate serotonin syndrome ( Table 1 ). Specifically, dextromethorphan, meperidine, tramadol, fluoxetine, citalopram, imipramine, and MAOIs have been commonly associated with severe cases of serotonin syndrome (Gillman, 1998).
Differential Diagnosis

Diagnosis of serotonin syndrome is based on clinical presentation and history of serotonergic-agent use. No laboratory or radiological test is available to confirm the diagnosis. Sternbach (1991) developed diagnostic criteria to define serotonin syndrome based on a triad of cognitive-behavioral, neuromuscular, and autonomic derangements. Physical presentation includes confusion, agitation, reduced level of consciousness, seizures, myoclonus/clonus, hyperreflexia, tremors, muscle rigidity, ataxia, akathisia, hyperthermia, hypertension, tachycardia, diaphoresis, lacrimation, mydriasis, shivering, and diarrhea. Dunkley, Isbister, Sibbritt, Dawson, and Whyte (2003) conducted a retrospective study and developed another diagnostic approach known as the Hunter Serotonin Toxicity Criteria, which was reported to be simpler than Sternbach’s criteria, with higher specificity (97% versus 96%) and sensitivity (84% versus 75%). The Hunter Serotonin Toxicity Criteria are based on a study of 2,222 patients admitted with overdose of one or more serotonergic agents; data on each patient’s clinical presentation were collected and analyzed. Based on the results of this analysis, serotonin syndrome was described as a spectrum of signs and symptoms including clonus, hyperreflexia, tremors, agitation, diaphoresis, hypertonicity, and hyperthermia with a history of use of one or more serotonergic agents. Using both sets of criteria as frameworks, Fig 1 illustrates the diagnosis of serotonin syndrome.

Figure 1.

Diagnosis of serotonin syndrome

Because serotonin syndrome is a diagnosis of exclusion, it is imperative to consider other diagnoses. Metabolic, toxic, and infectious causes should be ruled out based on the patient’s history and presentation. Common differential diagnoses include, but are not limited to, encephalitis, meningitis, delirium tremens, malignant hyperthermia, and intoxications (specifically with adrenergic or anticholinergic agents).

Neuroleptic malignant syndrome (NMS) should always be considered, as it commonly presents with muscle rigidity and autonomic abnormalities that could be mistaken for serotonin syndrome (Mills, 1997). As emphasized by Birmes, Coppin, Schmitt, and Lauque (2003), it is important to make the distinction between NMS and serotonin syndrome to provide the appropriate intervention, specifically with pharmacological treatment (see Table 2 ). Dopamine agonists, such as bromocriptine, are commonly used to treat NMS but may exacerbate the symptoms of serotonin syndrome.
Treatment

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Early diagnosis and prompt initiation of treatment are important in the treatment of serotonin syndrome. Management strategies include elimination of the precipitating agents and supportive measures to control agitation, hyperthermia, and autonomic dysfunction, which are commonly manifested as fluctuations in blood pressure and heart rate (Boyer & Shannon, 2005). Fatal complications such as seizures, coma, hypotension, ventricular arrhythmias, disseminated intravascular coagulation, rhabdomyolysis, metabolic acidosis, and renal failure may occur. The nurse should be vigilant about recognizing such potential problems and prepared to intervene promptly and appropriately. In severe cases, cardiopulmonary support is necessary with endotracheal intubation and mechanical ventilation, sedation, neuromuscular paralysis, and use of intravenous fluids and vasoactive drugs.

As Sternbach (2003) emphasized, no prospective studies have been done to evaluate pharmacological treatment. Current strategies are based on anecdotal reports of human cases and literature on animal models. Benzodiazepines are commonly used to achieve sedation and reduce muscle rigidity, although the addition of nondepolarizing paralyzing agents may be necessary as second-line therapy. The use of agents known to have nonspecific antiserotonergic actions, such as cyproheptadine, chlorpromazine, methysergide, and propanolol, has been advocated, although their efficacy in humans has not been established (Graudins, Stearman, & Chan, 1998). Specifically, cyproheptadine, a histamine-1 receptor antagonist approved by the Food and Drug Administration as an antihistamine to treat allergic conditions, was noted to reduce experimentally induced hyperserotonergic signs in animals and has been commonly used in the treatment of serotonin syndrome. McDaniel (2001) reported three cases of serotonin syndrome and reiterated that cyproheptadine reduced the severity of signs and symptoms but did not alter the time required for resolution. In addition, Chan et al. (1998) wrote that cyproheptadine does not have any dopamine antagonist properties and thus can be safely administered in cases in which NMS cannot be differentiated from serotonin syndrome.
Nursing Implications

Because of the increasing use of psychopharmacologic drugs known to increase serotonin neurotransmission, such as SSRIs, and the increasing incidence of polypharmacy, some predict that more cases of serotonin syndrome will be reported. Nurses are expected to have adequate knowledge about the syndrome so they can provide effective and efficient nursing care to these patients.

Supportive nursing measures address hemodynamic stability, safety, hydration, fever control, and monitoring for complications as the mainstay of serotonin-syndrome management. Alteration in hemodynamic status secondary to autonomic dysfunction, as manifested by fluctuations in heart rate and blood pressure, is common. Vital signs should be frequently monitored and recorded, and should be addressed if abnormal. Muscle rigidity and agitation are common, so patients risk hurting themselves or others. Patient usually require adequate sedation, appropriate physical restraints, and fall-prevention measures. Ensuring adequate sedation for patients who are chemically paralyzed is also important. Boyer and Shannon (2005) emphasized the lack of benefit from the use of antipyretics such as acetaminophen in serotonin syndrome, because the hyperthermia is due to increased muscular activity rather than an alteration in hypothalamic temperature regulation. Traditional nursing measures such as cold baths, cooling blankets, and the use of bedside fans are important. Hydration needs should be addressed by providing adequate intravenous fluid and monitoring intake and output. In cases of rhabdomyolysis and renal failure, urine alkalinazation and high-volume fluid resuscitation are necessary. Nurses should closely monitor patients for possible complications such as seizures, coma, hypotension, arrhythmias, metabolic acidosis, rhabdomyolysis, renal failure, and disseminated intravascular coagulation, which can occur in severe cases of serotonin syndrome.
Summary

The incidence of serotonin syndrome is increasing with the use of serotonergic drugs and specifically with polypharmacy (Fennel & Hussain, 2005). Pharmacological treatment of this syndrome is still not established. Removal of the offending agent and supportive care directed toward symptom management remain the primary treatment strategies. Nurses in particular play a crucial role in managing patients with serotonin syndrome. Nurses need to be knowledgeable about the pathophysiology, signs, and symptoms of serotonin syndrome, with the goal of reducing morbidity and mortality, to be able to meet the needs of these patients.

Table 1. Drugs with Serotonergic Activity that May Cause Serotonin Syndrome

Table 2. Comparison of Serotonin Syndrome and Neuroleptic Malignant Syndrome

References

1. Birmes, P., Coppin, D., Schmitt, L., & Lauque, D. (2003). Serotonin syndrome: A brief review. Canadian Medical Association Journal, 16, 1439–1442.
2. Boyer, E.W., & Shannon, M. (2005).The serotonin syndrome. New England Journal of Medicine, 352, 1112–1120.
3. Chan, B. S. H., Graudins, A., Whyte, I. M., Dawson, A. H., Braitberg, G., & Duggin, G. G. (1998). Serotonin syndrome resulting from drug interactions. Medical Journal of Australia, 169, 523–525.
4. Dunkley, E. J. C., Isbister, G. K., Sibbritt, D., Dawson,A. H., & Whyte, I. M. (2003).The Hunter Serotonin Toxicity Criteria: Simple and accurate diagnostic decision rules for serotonin toxicity. QJM: Monthly Journal of the Association of Physicians, 96, 635–642.
5. Fennel, S. & Hussain, M. (2005). Serotonin syndrome: Case report and. current concepts. Irish Medical Journal, 98, 143–144.
6. Gillman, P. K. (2005). The serotonin syndrome. New England Journal of Medicine, 352 (23), 2454–2456.
7. Graudins,A., Stearman,A., & Chan, B. (1998).Treatment of the serotonin syndrome with cyproheptadine. The Journal of Emergency Medicine, 16, 615–619.
8. Martin, T. G. (1996). Serotonin syndrome. Annals of Emergency Medicine, 28, 520–526.
9. McDaniel, W. W. (2001). Serotonin syndrome: Early management with cyproheptadine. The Annals of Pharmacotherapy, 35, 870–873.
10. Mills, K. C. (1995). Serotonin syndrome. American Family Physician, 52, 1475–1482.
11. Mills, K. C. (1997). Serotonin syndrome:A clinical update. Critical Care Clinic, 13, 763–783.
12. Sternbach, H. (2003). Serotonin syndrome: How to avoid, identify, and treat dangerous drug interactions. Current Psychiatry, 5, 15–24.

Acknowledgements

To David Powner, MD, University of Texas Health Science Center at Houston Medical School, Department of Neurosurgery: Thank you for your encouragement and suggestions. To my husband, Paul: Thanks for the love and support.
Reprint Address

Questions or comments about this article may be directed to Bettina C. Prator, MSN RN ANP ACNP, at 813/844-8522 or [email protected] .

Bettina C. Prator is a nurse practitioner at Tampa General Hospital, Surgery Department, in Tampa, FL

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