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3 Serotonin Syndrome 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
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