PEDIATRIC PHARMACOTHERAPY A Monthly Newsletter for Health Care Professionals from the University of Virginia Children’s Hospital

Volume 1 2 Number 3 March 2006

Serotoni n Syndrome: Pediatric and Neonatal Considerations Marcia L. Buck, Pharm.D., FCCP

oxicity resulting from excessive serotonin is typically rapid . In a recent r eview of 41 cases T activity, referred to as serotonin syndrome, documented since 1995, 61.5% of patients was first described by Oates and Sjoerdsma in present ed within 6 hours of drug initiation, 1960. Since that time, over 100 cases have been dosage change, or overdose. 1 reported .1 Over the past decade, the diagnosis of serotonin syndrome has become more Mild cases may present with mydriasis, frequent, as the use of drugs which raise serum diaphoresis, tachycardia, shivering, clonus, serotonin concentrations has increased .1,2 The hyperreflexia, and tremor . A fever may or may syndrome may result from normal therapeutic use not be present. Clonus, hyperreflexia , and of d rugs which increase serotonin concentrations, tremor are typically more prominent in the lower but is more commonly associated with drug extremities. Moderate cases may present with overdose or interactions between two drug the symptoms previously described, as well as therapies. This issue of Pediatric hypertension, hyperthermia (a core temperature Pharmacotherapy will provide a brief review of up to 40 º C) , horizontal ocular clonus, nausea, serotonin syndrome, as well as some example s vomiting, hyperactive bowel sounds , and from the pediatric literature. diarrhea . Patients often have changes in mental status, including agitation, hypervigilance, and Mechanism pressured speech. 1-3 Serotonin (5 -hydroxytryptamine or 5 -HT) is produced in presynaptic neurons from L - Severe cases may present with profound tryptophan. The concentration of serotonin hypertension and ta chycardia, and proceed available at postsynaptic receptors is regulated rapidly to shock. Patients may exhibit severe through feedback loops which govern reuptake agitation or delirium, seizures, muscular rigidity, and metabolism. Serotonin receptors are divided and hypertonicity. Core temperatures may into seven types, 5 -HT 1 through 5 -HT 7, each of exceed 40 º C, and may be accompanied by which contains several subtypes. Sero to nergic metabolic acidosis, rhabdomyolysis, elevated receptors are found throughout the central amin otr ans ferase s and creatinine, renal failure , nervous system where they are involved in and disseminated intravascular coagulation .1-3 regulation of the sleep -wake cycle, behavior, appetite, temperature, and muscle tone. In the At this time, serotonin syndrome remains a periphery, serotonin neurotransmission is clinical diagnosis. There are no confirmatory involved with the regulation of gastrointestinal laboratory tests. A careful medication history, as motility and vascular tone. 1-3 well as the exclusion of other potential causes, such as a nticholinergic poisoning, malignant Serotonin syndrome results from excessive hyperthermia, and neuroleptic malignant stimulation or agonism at postsynaptic serotonin syndrome , is necessary to establish the receptors. While the specific receptor subtypes diagnosis .1-6 The diagnostic criteria suggested by associated with serotonin syndrome have not Sternbac h may be useful in establish ing the been determined, it has been suggested that diagnosis: excessive serotonin binding at 5 -HT 2A receptors may be the predominant cause of sympt oms. 1-3 1. The patient has had recent exposure to or a change in a serotonergic agent. Clinical Presentation 2. At least three symptoms consistent with Serotonin syndrome is characterized by a wide serotonergic excess are present . range of clinical symptoms related to the triad of 3. Other causes have been ruled out .7 autonomic hyperactivity, neuromuscular hyperactivity , and altered mental status. 1-3 Onset A wide array of drugs (Table 1) can increase St. John’s wort serum serotonin concentr ations, through both Venlafaxine * direct and indirect mechanisms, such as Opioids/opiates inhibition of metabolism through monoamine Dextromethorpha n* oxidase or cytochrome P450 (CYP) 3A4. 1-6 Fentanyl Meperidine * Table 1. Drugs Associated with Serotonin Methadone Syndrom e Pentazocine Tramadol * Drugs that increase serotonin synthesis Others L-tryptophan Brompheniramine Chlorpheniramine Do pamine/serotonin receptor agonists Sibutramine Buspirone ______Lithium * definite as sociation between drug and Sumatriptan development of serotonin syndrome as demonstrated by case reports Dopamine agonists Amantadine The potential for serotonin syndrome is increased Bromocriptine when a new drug from the list is introduced, the Bupropion dose is increased (intentionally or inadvertently) , Levodopa or an inter acting or potentiating drug is ad ded. In a review of 469 patients admitted after SSRI Increase seroto nin release overdose, 14% developed serotonin syndrome. 8 Amphetamines Lithium Drug interactions are another frequent underlying Reserpine source of serotonin excess. A retrospective study of patients receiving meperidine in an emergency Drugs that decrease serotonin metabolism department over a 2 month period revealed that Monoamine oxidase (MAO) in hibitors 26 out of 262 patients (10% ) were taking one or Clorgiline more serotonergic drugs at the time , placing them Isocarboxazid at risk for serotonin syndrome .4 The majority Linezolid were receiving antidepressants. Whil e no Moclobemide patients experienced serotonin syndrome in the Phenelzine period evaluated, the authors highlighted the Selegiline importance of a careful medication history and Tran yl cypromine questioned the routine use of meperidine in the Inhibition of CYP3A4 emergency setting. Ritonavir Management Inhibit serotonin reuptake Management of patients with sero tonin synd rome Tricyclic antidepressants is primarily supportive. Muscular rigidity is Amitriptyline often treated with benzodiazepines, although Clomipramine * severe cases may require mechanical ventilation Desipramine and neuromuscular paralysis to control Doxepin hyperthermia and excessive clonus . Duloxetine Nondepolarizing neuromuscu lar blocking agents Imipramine * are recommended . Depolarizing neuromuscular Nortriptyline blockers , such as succinylcholine , may increase Protriptyline the risk of arrhythmia from the hyperkalemia Trazodone associated with rhabdomyolysis. Antipyretics are Selective serotonin reuptake inhibitor s (SSRI) * not useful in the management of hyperthermia Citalopram ass ociated with serotonin syndrome. 1-5 Escitalopram Fluvoxamine Removal of the causative agent is generally Fluoxetine recommended, unless the case is mild and further Paroxetine treatment outweighs potential risks. Sertraline Administration of a 5 -HT 2A antagonist, such as Other antidepressants cyproheptadine, is often recommended for Nefazodone moderate to severe cases. 1-4 In their 2005 review, Mason and colleagues found that 22% of and tachypneic. Her pupils were dilated. serotonin syndrome cases reported since 1995 Symptoms began to resolve ov er the next day, were treated with cyproheptadine. 2 An initial and she was discharged after 48 hours. The next dose of 12 mg (given orally or through a day, however, she began to experience increased nasogastric tube) has been recom mended for irritab ility, agitation, and tachycardia, and she adults, followed by additional doses of 2 mg at 2 was readmitted. A serum sertraline concentration hour intervals until symptom resolution. This obtained at that time (72 hours after ingestion) may be followed by a maintenance dose of 4 to 8 was 99 ng/mL. She was discharged 7 days later mg every 6 hours until the potential cause is with resolution of most of her symptoms, but she believed to have been eliminated. The dosing of did not experience a full recovery until cypro heptadine in children is less well approximately one month after the ingestion. established, but a dose of 0.25 mg/kg/day up to a maximum of 12 mg/day h as been successful in Three additional cases were reported in 1999. reversing symptoms .5,9 The first of these involved an 11 year old boy who was being treated for attention -deficit 12 In addition, antipsychotic agents with 5 -HT 2a disorder . After failing traditional thera pies, he antagonist activity , such as chlorpromazine , may had been placed on fluvoxamine 50 mg once be use d. In adults, doses of 50 to 100 mg may be daily. With in an hour of taking the first dose, the given intramuscularly every 6 to 8 hours as patient ex perienced agitation and tremors. On needed . More recently, olanzapine, an a typical arrival to the Emergency Department, he was antipsychotic , ha s been used in this setting. In hyperthermic, with jaw myoclonus, dilated most cases, symptoms resolve within 24 hours pupils , and markedl y fluctuating heart rate and after initiation of suppo rtive care. Patients blood pressures. He was initially treated with receiving serotonergic drugs with longer half - benzodiazepines, but eventually required lives or active metabolites may exhibit symptoms intubat ion and mechanical ventilation in order to for a longer period of time. 1-3 allow for p harmacologic neuromuscular blockade with rocuronium . He remained paralyzed f or 24 Pediatric Case Examples hours, but then made a rapid recovery. Within Several pediatric cases of serotonin syndrome 48 hours, his examination was normal. have been reported in the medical li terature . The majority have involved the use of SSRIs. In Another case involved a 12 year old boy 1994, Kaminski and colleagues reported receiving sertraline who developed serotonin serotonin syndrome after an accidental sertraline syndrome after being given erythromycin for an overdose by a 9 year old boy. 10 Upon arrival to infection. 13 Within 4 days of s tarting the Emergency Department, he exhibited erythromycin, he developed agitation and tachycardia, hypert ension , hyperthermia, anxiety. Over the next 10 days, he progressed to hallucinations, and tremors. Symptoms persisted paresthesias, tremulousness, and confusion. upon transfer to the intensive care unit, with a Once the diagnosis was made , both sertraline and heart rate over 200 beats/min and a temperature erythromycin were discontinued . The pa tient of 42.2 º C rectally. He was given activated recover ed over the next 72 ho urs. charcoal and treated with physostigmine, lo razepam, acetaminophen, and chloral hydrate. The third report in 1999 described another The serum sertraline concentration accidental ingestion of sertraline. 9 The patient, a approximately 9 hours after ingestion was 68 24 month old girl, ingested ten 50 mg tablets. ng/mL (in adults, normal therapeutic doses of 50 She was taken to the hospital within an hour of to 100 mg/day produce ma ximum concentrations the ingestion, where she was asymptomatic. S he of 30 to 55 ng/mL) The patient’s s ymptoms was given activated charcoal , which produced progressed, and he eventually developed numerous pill fragments, and was discharged rhabdomyolysis with elevated renal and liver when stable . Twelve hours after the ingestion, transaminases. With continued supportive care, she was taken back to the Emergency he returned to baseline status within 4 days, and Department with agitation and tremors. The was discharged with a mild tremor. temperature on arrival was 38.4 º C. She had dilated pupils, was hyperactive, hyperreflexic, Pao and Tipnis reported a similar case of and ataxic. She was treated with 1 mg sertraline -induced serotonin syndrome in a 5 year cyproheptadine (0.08 mg/kg) orally. Within 40 old girl in 1997. 11 The patient ingested at least minutes, symptoms resolved. She was given a eight 50 mg tablets. Shortly after ingestion, she prescription for 1 mg cyproheptadine every 8 complained of feeling “jittery” and having a fast hours (0.23 mg/kg/day) f or 48 hours, and she heartbeat. On admission to the hosp ital , she was remained asymptomatic. afebrile, diaphoretic, tachycardic, hypertensive, In 2004, Thomas and colleagues reported a case 10. Kaminski CA, Robbbins MS, Weibley RE. Sertraline of serotonin syndrome in a 4 year old girl intoxication in a child. An n E merg Med 1994;23:1371 -4. 11. Pao M, Tipnis T. Serotonin syndrome after sertraline receiving fluoxetine who was subsequent ly overdose in a 5 -year -old girl [letter] . Arch Pediatr Adolesc 14 started on linez olid. She had been receiving Med 1997;151:1064 -7. fluoxetine at a dose of 5 mg da ily for a week for 12. Gill M, LoVecchio F, Selden B. Serotonin syndrome in a acute stress disorder following a burn injury . child after a single dose of flu voxamine . Ann Emerg Med 1999;34:457 -9. After 11 days of fluoxetine therapy, linezolid 13. Lee DO, Lee CD. Serotonin syndrome in a child (140 mg orally every 12 hours) was added to her associated with erythromycin and sertraline. treatment for presumed infection . Two days Pharmacotherapy 1999;19:894 -6. later, she was given fentanyl (200 mcg orally) as 14 . Thomas CR, Rosenberg M, Blythe V, et al. Serotonin syndrome and linezolid [letter] , J A m Acad Child Adolesc a pre -medication for wound debridement . She Psychiatry 2004;43:790. was noted to be agitated and have mydriasis, with eye deviation, after the procedure. She also Formulary Update developed myoclonic movement in the arms and The following actions were taken by the legs. The diagnosis of serotonin syndrome was Pharmacy and Therapeutics Committee at their made at that time, but t he role of the potential meeting on 2/24 /0 6: drug interaction was not recognized . F luoxetine was discontinued and diphenhydramine (25 mg) 1. A combination of ipratropium and albuterol was given. Symptoms began to resolve until for nebulization (Duoneb ®) was added to both the another dose of linezolid was administered. The Inpatient and Outpatient Formularies. interaction was identified , and the linezoli d discontinued. Symptoms resolved over the next 2. Liposomal lidocaine 4% topical cream (LMX - 2 days. 4®) was also added to the Inpatient and Outpatient Formularies. It has the advantage of a Summary faster onset of action than EMLA (30 minutes Serotonin synd rome has become more prevalent versus 60 minutes). Th is product is available in as the use of drugs affecting serotonin a kit with five 5 gram tubes and 10 Tegaderm ™ concentrations has increased. As in adults, the dressings. This product will replace EMLA after increased use of SSRIs and other newer a 3 to 6 mo nth conversion period. antidepressants in pediatric patients places them at risk for this adverse drug effect. While most 3. Daptomycin (Cubicin ®) was added to the cases of serotonin syndrome are mild and require Inpatient Formulary with restriction to minimal supportive care, some patients may Antimicrobial Category A. It is a cyclic develop severe cardiovascular compromise. lipopeptide antibacterial agent with activity Prompt recognition of symptoms, alon g with a against gram positive organisms. complete drug history, can aid in a more rapid response and reduce the likelihood of serious 4. The restriction on the use of dexmedetomidine complications. (Precedex ®) was amended to include use in the PICU. Previous restrictions to patients in the References NNICU and patients undergoing awake 1. Gillman PK. Monoamine oxidase inhibitors, opioids craniotomy or complex spinal procedures wer e analgesics and serotonin toxicity. Br J Anaesth 2005;95:434 - 41. retained. 2. Boyer E W, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112 -20. 5. The 2005 annual report on the Adverse Drug 3. Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome: Reaction Reporting System was presented. For presentation of two cases and review of the literature. Medicine 2000;79:201 -9. more information on the results, contact the Drug 4. Weiner AL. Meperidine as a potential cause of s erotonin Information Center at 4 -8084. syndrome in the emergency department. Acad Emerg Med 1999;6:156 -8. 5. Spirko BA, Wiley JF. Serotonin syndrome: a new pediatric intoxication. Ped iatr Emerg Care 1999;15:440 -3. Contributing Editor:Marcia L. Buck, Pharm.D. 6. Arnold DH. The central serotonin syndrome: paradigm for Editorial Board: Kristi N. Hofer, Pharm.D. psychotherape utic misadventure. Ped Rev 2002;23:427 -32. Michelle W. McCarthy, Pharm.D. 7. Sternbach H. The serotonin syndrome. Am J Psychiatry If you have comments or suggestions for f uture 1991;148:705 -13. 8. Isbister GK, Bowe SJ, Dawson A, et al. Relative toxicity issues, please contact us at Box 800674, UVA of selective serotonin reuptake inhibitors (SSRIs) in Health System, Charlottesville, VA 22908 or overdose. J Toxicol Clin T oxicol 2004;42:277 -85. by e -mail to [email protected] . This 9. Horowitz BZ, Mullins ME. Cyproheptadine for serotonin newsletter is also available at syndrome in an accidental pediatric sertraline ingestion. Pediatr Emerg Care 1999;15:325 -7. www.healthsystem.virginia.edu/internet/pediatr ics/pharma -news/home.cfm