Evaluation and Management of Children with Acute Mental Health Or Behavioral Problems

CLINICAL REPORT Guidance for the Clinician in Rendering Pediatric Care

Evaluation and Management of Children With Acute Mental Health or Behavioral Problems. Part II: Recognition of Clinically Challenging Mental Health Related Conditions Presenting With Medical or Uncertain Symptoms Thomas H. Chun, MD, MPH, FAAP, Sharon E. Mace, MD, FAAP, FACEP, Emily R. Katz, MD, FAAP, AMERICAN ACADEMY OF PEDIATRICS Committee on Pediatric Emergency Medicine, AMERICAN COLLEGE OF EMERGENCY PHYSICIANS Pediatric Emergency Medicine Committee

INTRODUCTION This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have Part I of this clinical report (http:// www. pediatrics. org/ cgi/doi/ 10. fi led confl ict of interest statements with the American Academy 1542/ peds. 2016- 1570) discusses the common clinical issues that may of Pediatrics. Any confl icts have been resolved through a process approved by the Board of Directors. The American Academy of be encountered in caring for children and adolescents presenting to the Pediatrics has neither solicited nor accepted any commercial emergency department (ED) or primary care setting with a mental health involvement in the development of the content of this publication. condition or emergency and includes the following: Clinical reports from the American Academy of Pediatrics benefi t from expertise and resources of liaisons and internal (AAP) and external • Medical clearance of pediatric psychiatric patients reviewers. However, clinical reports from the American Academy of Pediatrics may not refl ect the views of the liaisons or the organizations • Suicidal ideation and suicide attempts or government agencies that they represent. • Involuntary hospitalization The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking • Restraint of the agitated patient into account individual circumstances, may be appropriate. ⚬ All clinical reports from the American Academy of Pediatrics Verbal restraint automatically expire 5 years after publication unless reaffi rmed, ⚬ Chemical restraint revised, or retired at or before that time. DOI: 10.1542/peds.2016-1573 ⚬ Physical restraint PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). • Coordination with the medical home

Part II discusses the challenges a pediatric clinician may face when To cite: Chun TH, Mace SE, Katz ER, AAP AMERICAN ACADEMY evaluating patients with a mental health condition, which may be OF PEDIATRICS Committee on Pediatric Emergency Medicine. contributing to or a complicating factor for a medical or indeterminate Evaluation and Management of Children With Acute Mental clinical presentation. Topics covered include the following: Health or Behavioral Problems. Part II: Recognition of Clinically Challenging Mental Health Related Conditions • Somatic symptom and related disorders Presenting With Medical or Uncertain Symptoms. Pediatrics. 2016;138(3):e20161573 • Adverse effects of psychiatric medications

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 138 , number 3 , September 2016 :e 20161573 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 1 Common Symptoms of Somatic Symptom and Related Disorders14 headaches, chest pain, nausea, 5 Pseudoneurologic Gastrointestinal symptoms and fatigue. Patients with somatic Amnesia Abdominal pain symptom and related disorders use all Difﬁ culty with swallowing or voice Nausea types of medical services (eg, primary, Vision or hearing impairment Vomiting specialty, ED, and mental health care) Syncope Bloating 4,6– 8 Seizure Diarrhea more frequently, are more likely 4 Paralysis or paresis Multiple food intolerances to “doctor shop,” and in 2005, were Pain symptoms Cardiopulmonary symptoms estimated to have incrementally Headache Chest pain added $265 billion to the cost of Back pain Dyspnea health care in the United States. 9 Extremity pain Palpitations Dysuria Dizziness Clinical Features and Studies of ⚬ Antipsychotic adverse effects refer to an individual’s subjective Pediatric Somatic Symptom and Related Disorders ⚬ Neuroleptic malignant syndrome experience of physical symptoms. These diagnoses can also be applied The clinical presentations of somatic ⚬ Serotonin syndrome to situations in which the level of symptom and related disorders • Children with special needs distress or disability is thought to be are myriad, most often involving (autism spectrum disorders [ASDs] disproportionate to what is typically neurologic, pain, autonomic, or and developmental disorders associated with the physical findings. gastrointestinal tract symptoms [DDs]) For example, when a medical (Table 1). Children and adolescents • Mental health screening condition is present, if the physical often report such symptoms 10, 11 problems do not fully explain the and often have multiple visits for The report is written primarily from reported symptoms or severity, these symptoms in primary care and the perspective of ED clinicians, but it a somatic symptom and related other settings. 3,5, 12, 13 Vague, poorly is intended for all clinicians who care disorder may apply. 2 described complaints, recent or for children and adolescents with current stressful events, symptoms acute mental health and behavioral Additional criteria for somatic that fluctuate with activity or problems. An executive summary of symptom disorders include the stress, and lack of physical findings this clinical report can be found at requirement that the complaints and laboratory abnormalities are http:// www. pediatrics. org/ cgi/ doi/ or fixations are not associated common. 3 10. 1542/ peds. 2016- 1574. with material gain, nor are they intentionally produced. 3 Symptoms Symptoms of pediatric somatic that are intentionally created are symptom and related disorders often SOMATIC SYMPTOM AND RELATED classified as factitious disorders; do not meet strict Diagnostic and DISORDERS those that result in material gain are Statistical Manual of Mental Disorders, Overview categorized as malingering. Lastly, Fifth Edition diagnostic criteria the symptoms result in significant and defy categorization. Other The Diagnostic and Statistical impairment in psychosocial difficulties in caring for patients with Manual of Mental Disorders, Fifth functioning (eg, relationships with these disorders in the ED are that Edition recognizes 7 distinct somatic family or friends, academic or few patients will have received a symptom and related disorders, occupational difficulties). 1 formal diagnosis, and ED clinicians including somatic symptom rarely have access to sufficient disorder, illness anxiety disorder, Epidemiologic studies have found clinical information to confirm conversion disorder (functional that somatic symptom and related the diagnosis. 15 – 17 In addition, the neurologic symptom disorder), disorders are both common and a diagnosis of a “psychosomatic” illness psychological factors affecting significant contributor to health care can be stigmatizing to patients and other medical conditions, factitious usage and costs. In adult primary families, resulting in them feeling disorder, other specified somatic care populations, between 10% and unheard, disrespected, and defensive symptom and related disorder, and 15% of patients have a diagnosis of 1 about their symptoms. 5 For these unspecified somatic symptom and of these disorders.4 Among children and other reasons, some prefer related disorder.1 Each disorder and adolescents, recurrent abdominal the term “medically unexplained has specific diagnostic criteria, pain and headaches account for symptoms”.2, 6, 18, 19 which apply to both adults and 5% and between 20% and 55% of children and which are not adjusted pediatric office visits, respectively; Several studies, including 1 for children. All these disorders 10% of adolescents report frequent performed jointly in the Pediatric

Downloaded from www.aappublications.org/news by guest on September 26, 2021 e2 FROM THE AMERICAN ACADEMY OF PEDIATRICS Research in Office Settings and Other studies in other settings of identified PNES patients (the Ambulatory Sentinel Practice echo these findings. In a pediatric authors recognize that PNES is often Network collaboratives, have cardiology clinic study, Tunaoglu unrecognized and underdiagnosed identified demographic and risk et al 26 reported a prevalence of 74% in the ED), Selbst and Clancy 29 found factors associated with pediatric for psychiatric disorders, primarily that all had multiple previous ED somatic symptom and related depression, anxiety, and somatic visits, 8 of 10 patients had been disorders.2, 8, 20, 21 Patients who are symptom and related disorders, prescribed anticonvulsants in the adolescents, female, from minority in patients referred for chest pain past, 6 received anticonvulsants ethnicities, from nonintact families, with normal medical workups. either in the ED or before arrival in or from urban dwellings; who have Campo et al 27 recruited patients the ED by prehospital personnel, all past histories of psychological from a pediatric primary care office. but 1 had invasive procedures and trauma; whose parents have lower Using standardized psychiatric testing, and 8 were admitted to the education levels; and who have interviews, they found that patients hospital. Other studies have found other family members with somatic with recurrent abdominal pain similar rates of extensive medical symptom and related disorders were significantly more likely to be testing in children with PNES. 30 are more likely to present with diagnosed with anxiety (79%) and Accurate diagnosis and appropriate unexplained medical symptoms. depressive disorders (43%) than referrals for these patients may be Such patients are also at much controls. In a study from a pediatric important, as Wyllie et al 31 found higher risk of comorbid psychiatric rheumatology clinic, Kashikar-Zuck that on follow-up, 72% of patients’ problems.8 et al 28 also conducted standardized PNES had resolved after psychiatric psychiatric interviews among treatment. A particularly challenging Other studies have approached this patients with juvenile fibromyalgia. problem when treating potential topic by investigating the prevalence A high prevalence of current and PNES in the ED is that some of these of and relationships between lifetime anxiety and mood disorders patients will have both a true seizure psychiatric conditions in patients was detected in this population. disorder and PNES, making airway with unexplained medical symptoms. management and the decision to give Emiroğlu et al 22 studied 31 patients Somatic Symptom and Related anticonvulsants for apparent seizure referred to a pediatric neurology Disorders and the ED activity difficult and complex for ED clinic for headache, vertigo, and physicians. Somatic symptom and related syncope. When comprehensive disorders are a particularly vexing testing did not reveal an identifiable Several studies have investigated problem in the ED because of the medical cause for their symptoms, the impact of somatic symptom and potential harm to patients that may the patients were interviewed by a related disorders on emergency result from diagnostic uncertainty. child psychiatrist. A large majority department patients. Knockaert It is understandable that a patient (93.5%) were found to have a et al 32 prospectively enrolled with 1 of these disorders might diagnosable disorder according to 578 adult patients presenting undergo extensive, invasive testing Diagnostic and Statistical Manual to a Belgian ED with chest pain. such as a lumbar puncture, be of Mental Disorders, Fourth Edition Although the majority of these exposed to radiographic studies criteria, the most common being patients were found to have a with ionizing radiation, or be given mood and somatic symptom and cardiac or pulmonary disease as potent medications to treat their related disorders. Other pediatric the etiology of their chest pain, the symptoms, which in turn could result headache studies have found similar authors classified “somatization in significant respiratory, cardiac, results. 23, 24 Guidetti et al 25 followed disorder” as the third leading cause central nervous system (CNS), patients for 8 years after referral (9.2%) of these ED visits. Another or hematologic adverse effects, to a pediatric neurology headache interesting finding from this study potentially necessitating additional clinic. At follow-up, persistence or was that somatization disorder medications or procedures such worsening of headaches was highly was more common among patients as endotracheal intubation and associated with the presence of who were self-referred to the ED mechanical ventilation to treat these comorbid psychiatric conditions, and those brought by ambulance. adverse effects. and resolution of headaches strongly Although formal psychiatric correlated with the absence of mental Psychogenic nonepileptic evaluation was not performed on health conditions. In this study, seizures (PNES, previously called all patients, and classification as the most common mental health “pseudoseizures”) in pediatric ED somatization disorder was based conditions were anxiety disorders patients are an illustrative example on the available clinical information and depression. of this conundrum. In their review and the final discharge diagnoses,

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 138 , number 3 , September 2016 e3 the authors believe that their The mental health evaluation and cases. 2, 5, 10, 18 This may include various methods underestimated the true treatment typically took place a psychotherapies (eg, cognitive– prevalence. Other studies have found few weeks after the ED visit, with behavioral, rehabilitative, operant a higher prevalence of mental health patients receiving a mean of 3.8 interventions, self-management disorders among adult ED patients psychotherapy sessions (range: 1–25 strategies, and family or group with chest pain. 17 sessions). After the psychotherapy therapy), consistent communication intervention, at 1-year follow-up, between all treating providers, Lipsitz et al 33 studied 32 pediatric ED they found a mean reduction of 3.2 and comprehensive treatment of patients who presented with chest ED (69%) visits per patient (SD, 6.4; comorbid psychiatric conditions.2 pain and for whom no medical cause 95% CI, 1.3–5.0; P < .001), compared was found. Using a semistructured Although these treatment modalities with the year before the index Diagnostic and Statistical Manual are not practical or possible for ED visit. In addition, at follow-up of Mental Disorders, Fourth Edition the ED setting, there are some patients reported significant interview to detect anxiety disorders, strategies that are applicable and improvement in their somatic they found that 81% met diagnostic may be helpful. Experts suggest the symptoms and high satisfaction with criteria for an anxiety disorder, with following 2, 5, 18: the psychotherapeutic referral and 28% meeting full criteria for panic • intervention. Although this was not a Provide reassurance: First and disorder. Other pain symptoms such randomized controlled trial, patients foremost, it is important to convey as headaches, abdominal pain, and who were referred to psychotherapy to the patient and family that the back pain were common in these but did not attend treatment did not patient’s symptoms are being children, as were impaired quality show any changes in their ED use at 1 heard and taken seriously. Taking of life and multiple domains of daily year follow-up. time to obtain a detailed history functioning. In a secondary analysis and comprehensive physical of a larger study on maternal and Treatment Strategies examination can help accomplish pediatric mental health problems, this goal. Some children and Dang et al 34 explored the relationship Medically unexplained symptoms families may be reassured by the between mothers’ somatic symptoms are extremely frustrating for knowledge that their symptoms and subsequent pediatric ED use patients, families, and medical are not life or limb threatening. In for their child. Maternal somatic providers. Parents and children addition, eliciting and addressing symptoms were assessed with the often think that they are not being the child’s and family’s anxiety and Patient Health Questionnaire 15, listened to and that physicians fears about the patient’s symptoms a validated measure for inquiring have misdiagnosed the problem, or may be both clinically illuminating about common somatic problems in potential causes of the symptoms for the ED provider and comforting outpatient settings. After covariates have not been adequately evaluated. 2, 10 to the patient and family. It may were adjusted for, mothers with high These feelings can be intense also be important to reaffirm that somatic symptom scores reported and may be rooted in a fear that their ED and outpatient providers higher rates of depression symptoms, a medical illness is being missed, are working and will continue to difficulty caring for themselves and frustration over the lack of success work with them to continue to their child, and a greater use of the in resolving the symptoms, the evaluate and treat their symptoms. ED for their child (odds ratio, 1.8; stigma of being labeled or perceived • Communicate: Strategies to 95% confidence interval [CI], 0.99– as “psychosomatic,” or difficulty in improve communication include 3.38; P = .055). acknowledging that psychological emphasizing collaboration and physical symptoms may be Although there are no known studies between the patient, family, related. 18 of interventions for pediatric ED and all caregivers; identifying patients, Abbass et al 35 performed Prognosis often is unpredictable. common goals and outcomes; and an intriguing prospective study of In some cases, the episode can be introducing the idea of working adult ED patients with suspected brief and resolve. In other cases, on improving functioning in somatic symptom and related the course is chronic and difficult to addition to working toward disorders. If the treating ED physician treat. The chronicity of the symptoms symptom resolution. In addition, made a provisional diagnosis of and previous response to treatment educating the patient and family somatization after completing the may be informative about the likely about the limitations of the ED medical evaluation of the patient, a treatment course. Most experts setting, as well as the benefits of referral was made for an outpatient agree that an empathetic, consistent, other settings for evaluation and mental health evaluation and multidisciplinary, long-term treatment, may be helpful. Lastly, intensive, short-term psychotherapy. treatment plan is helpful for chronic exploring the patient and family’s

Downloaded from www.aappublications.org/news by guest on September 26, 2021 e4 FROM THE AMERICAN ACADEMY OF PEDIATRICS openness to the possibility that the TABLE 2 Antipsychotic Adverse Symptoms symptoms may be psychologically Neurotransmitter Symptoms Antipsychotics Commonly related may be an important first Associated With Symptom step. Determining and using terms Dopamine such as stress, temperament, Nigrostriatal tract Extrapyramidal symptoms (eg, dystonia, High-potency “typical” anxiety, “nerves,” and other terms dyskinesia, akathisia, Parkinsonism) antipsychotics (haloperidol) that are acceptable to the patient Tuberoinfundibular Hyperprolactinemia All “typical” antipsychotics, tract risperidone and family may assist in this goal. Preoptic tract Hypothermia Rare, possibly more common with • Coordinate care: Contacting atypical antipsychotics and communicating with all Acetylcholine Sinus tachycardia, dry mucous Low-potency “typical” antipsychotics (muscarinic) membranes, mydriasis, urinary (chlorpromazine) involved care providers may be retention time consuming but is important α-Adrenergic Orthostatic hypotension, reﬂ ex Atypical antipsychotics in implementing a cohesive, tachycardia comprehensive evaluation and Histamine Sedation “Typical” antipsychotics treatment plan and may have Mechanism unknown Potential etiology: Wt gain, obesity, hyperlipidemia, Atypical antipsychotics the added benefit of providing Pancreatic versus metabolic syndrome, impaired glucose Highest risk: clozapine, olanzapine reassurance to the patient and CNS adrenergic tolerance, hyperglycemia, type 2 Lower risk: quetiapine, risperidone α α family as well as decreasing 1, 2, dopamine diabetes Lowest risk: ziprasidone, frustration and improving D2, muscarinic, aripiprazole histamine H , satisfaction. 1 serotonin1, serotonin2, or serotonin ADVERSE EFFECTS OF PSYCHIATRIC 6 MEDICATIONS The use of all psychotropic migraines (ie, prochlorperazine, also been used as antiemetics and medications in pediatric populations metoclopramide, promethazine, antipruritics and to treat headaches, over the last 2 decades has markedly and trimethobenzamide) are hiccups, and various neurologic increased.36, 37 Antipsychotic use, phenothiazines, the same type of disorders such as Parkinson disease, in particular, has shown large medications as first-generation, hemiballismus, ballismus, Tourette increases.38 Especially notable is “typical” antipsychotics. Droperidol, syndrome, and Huntington chorea.50, 51 39–41 their burgeoning off-label use, which has been used as an antiemetic The common adverse effects of including in preschool-aged and for agitation, is a butyrophenone, antipsychotics can be conceptualized 42–44 children. Given the frequency the same class as the antipsychotic and organized around the CNS and multiple medication regimens haloperidol. 45 The number neurotransmitters on which they with which psychotropic agents are and scope of medications with act. 45, 50 – 54 Table 2 lists the common 36 being prescribed, ED clinicians serotonergic effects are surprising adverse effects of antipsychotics and are likely to encounter children and and are detailed in this section. the medications with which they are adolescents taking 1 or many of these Either alone or in combination most commonly associated. medications. This section focuses on with psychotropic serotonergic the clinical problems and diagnostic It is important to note that drugs, these medications can result and treatment dilemmas one may antipsychotics have other clinically in serotonin toxicity. Given how encounter in the ED when caring for significant effects, including “black frequently these medications are pediatric patients on antipsychotics box” warnings from the US Food used in clinical practice, familiarizing and antidepressants. and Drug Administration (FDA) oneself with them and their potential for thioridazine and droperidol An additional important adverse effects may be beneficial to because of their potential to consideration for ED clinicians ED clinicians. cause dysrhythmias. Almost all is that many commonly used antipsychotics cause some degree medications not typically Antipsychotic Adverse Effects of QTc prolongation because of a thought of as psychotropic Antipsychotics are prescribed quinidinelike effect. For most of the agents have dopaminergic and for various childhood disorders, medications, however, the degree of serotonergic properties similar including oppositional–defiant QTc prolongation is small, which has to those of antipsychotics and disorder, conduct disorder, attention- given rise to a debate about the actual antidepressants. For example, deficit/hyperactivity disorder, and risk of dysrhythmias and torsades drugs used as antiemetics and for ASDs. 46 – 49 These medications have de pointes with antipsychotics

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 138 , number 3 , September 2016 e5 administered in their usual doses and TABLE 3 Risk Factors for QTc Prolongation or TABLE 4 QTc Prolongation Associated With routes of administration. 45, 47, 48, 55 – 60 Dysrhythmias With Antipsychotic Use Antipsychotics

Of note, intravenous (IV) haloperidol Coadministration with other QTc-prolonging Medication Mean QTc Prolongation, ms 61 medications has been studied but carries an Thioridazine 25–30 IV administration or high doses FDA non–black box warning because Ziprasidone 5–22 Medically ill patients of deaths associated with high doses Pimozide 13 Electrolyte abnormalities 62 Clozapine 8–10 and IV administration. Therefore, Hepatic, renal, or cardiac impairment Haloperidol 7 experts suggest that intramuscular Congenital long QT syndromes Quetiapine 6 dosing of antipsychotics in the ED Risperidone 0–5 is the parental preferred route of Olanzapine 2 administration. Table 3 details the tics or spasms usually involving Aripiprazole 0 factors that are thought to increase the face, the extraocular muscles the risk of QT prolongation and (oculogyric crisis), and the neck, back, c generally occur weeks to months 48,51, 63,64 and limb muscles and tends to occur sudden death. Table 4 lists after the patient starts antipsychotic the degree of QT prolongation for after the first few doses of medication c therapy. 51 Drug-induced 65 or after an increase in dosage. common antipsychotics. Parkinsonism syndrome is often Laryngeal dystonia is a rare, potentially treated by adding an anticholinergic Cardiac: Black Box Warning life-threatening adverse event that agent, adding a dopaminergic presents as a choking sensation, Both thioridazine and droperidol agonist (eg, amantadine), or difficulty breathing, or stridor. 45, 48 have been issued FDA black box decreasing the dosage of a typical warnings for a potential association Akathisia is a subjective feeling antipsychotic or switching to an with prolonged QT interval, torsades atypical antipsychotic. Considering de pointes, and sudden death. Since of restlessness, which generally occurs within the first few days the diagnosis of drug-induced then, several studies have disputed Parkinsonism may be important, 55–60 of antipsychotic medication this risk with droperidol. because early diagnosis and rapid A large retrospective review of administration. Akathisia is found 51 withdrawal of the antipsychotic 2468 patients given droperidol in in up to 25% of patients and has also been reported in patients drug may improve the possibility the ED found that no cardiovascular 50 receiving a single, standard dose of complete recovery. Tardive event occurred that did not have an dyskinesia is characterized by rapid alternative explanation, and only (10 mg) of prochlorperazine. Both acute dystonia and acute akathisia involuntary facial movements (eg, 6 serious adverse events occurred, blinking, grimacing, chewing, or with 1 cardiac arrest in a patient tend to occur early in the course of treatment (ie, days to weeks after tongue movements) and extremity with a normal QT interval out of or truncal movements. Respiratory 2468 patients (0.2% = 6/2468). 56 beginning an antipsychotic) and are easily reversed. To minimize dyskinesia is often undiagnosed, A pediatric study also suggested can lead to recurrent aspiration the safety and efficacy of droperidol these adverse effects, some advocate coadministering 25 to 50 mg of pneumonia, and includes orofacial when used to treat agitation, nausea dyskinesia, dysphonia, dyspnea, 66 diphenhydramine or 1 to 2 mg and vomiting, headache, and pain. and respiratory alkalosis. 45 Tardive Thus, “although droperidol can be of benztropine when giving an antipsychotic. 69 Others prefer to dyskinesia occurs in 5% of young associated with prolongation of the patients per year and is more QT interval, there is not convincing treat with anticholinergic agents (ie, diphenhydramine or benztropine) common with older, “typical” evidence that the drug causes antipsychotics. 50 severe cardiac events.”60 Despite only if acute symptoms occur, Although antipsychotic medications these and other studies, since the followed by 2 days of oral therapy, have been noted to lower the seizure black box warning was issued, given the prolonged half-life of threshold in a dose-dependent manner, use of droperidol has declined antipsychotics. antipsychotic medication–induced exponentially.67, 68 The delayed-onset neurologic syndromes are Parkinsonism and seizures are rare (usually <1%) when Neurologic tardive dyskinesia. The hallmarks therapeutic doses are used, except for Acute extrapyramidal syndromes of Parkinsonism are shuffling gait, clozapine, which has a 5% incidence of 45,51 associated with antipsychotic cogwheel muscle rigidity, mask seizures at high dosages. medications include acute dystonia, facies, bradykinesia or akinesia, Metabolic akathisia, and a Parkinsonian pill-rolling tremors, and cognitive syndrome. Acute dystonia is impairment. These symptoms are Adverse effects, such as weight characterized by involuntary motor found in up to 13% of patients and gain, hyperglycemia, and

Downloaded from www.aappublications.org/news by guest on September 26, 2021 e6 FROM THE AMERICAN ACADEMY OF PEDIATRICS hyperlipidemia, are common, to determine, with estimates ranging be the case. Both second-generation especially with second-generation, from 0.02% to 3%.45, 71, 75 Fortunately, atypical antipsychotics and the third- “atypical” antipsychotics. 45, 50, 51, 70 mortality from NMS has decreased generation aripiprazole, which has Antipsychotics vary in their from 76% in the 1960s to <10% to partial dopamine agonist activity, metabolic adverse effects, with the 15% more recently. 72, 76 –78 Experts have all been implicated in causing highest risk associated with clozapine suggest considering NMS in the NMS. 76, 79, 83 – 87 and olanzapine, an intermediate risk differential diagnosis of patients Despite its name, NMS can also be with quetiapine, risperidone, and presenting with fever and altered triggered by the administration chlorpromazine, and the lowest risk mental status who are taking or may or withdrawal of other, with haloperidol, ziprasidone, and have taken an antipsychotic. 74 aripiprazole.53 nonantipsychotic medications. NMS affects patients of all ages, with Administration of tricyclic Other an apparent predominance in young antidepressants, selective serotonin reuptake inhibitors (SSRIs), and adults and male patients (2:1). 73, 79 – 81 Agranulocytosis is a potential lithium have been associated with It is unclear whether these are truly adverse effect of the atypical NMS. 75 NMS also has been associated risk factors or reflect the patient antipsychotic drug clozapine. Patients with the abrupt withdrawal of population with the greatest use on clozapine regularly have complete medications (eg, dopaminergic drugs of antipsychotic medications.75 blood cell counts performed, usually used to treat Parkinson disease, such Coadministration of psychotropic weekly or monthly, to monitor as levodopa, as well as baclofen, agents seems to be an especially high for this adverse effect. Other amantadine, some antipsychotics, risk factor for precipitating NMS; adverse effects of various atypical and some antidepressants). 74 Lastly, in 1 study, more than half of people antipsychotics include somnolence, the introduction to this section with reported NMS cases were anxiety, agitation, oral hypoesthesia, enumerates some of the medications taking concomitant psychotropic headache, nausea, vomiting, commonly thought to be antiemetics 51 agents. 77 Other risk factors include insomnia, and tremor. or antimigraine therapies. They dehydration, physical exhaustion, Neuroleptic Malignant Syndrome are, in fact, phenothiazines (ie, the preexisting organic brain disease, same class of medications as first- Neuroleptic malignant syndrome and the use of long-acting depot generation, typical antipsychotics), (NMS) is a potentially lethal antipsychotics. Neither duration but because of the clinical conditions syndrome consisting of the of exposure to the drug nor toxic for which they are used, they may tetrad of mental status changes, overdoses of antipsychotics appear not be suspected for being at risk for fever, hypertonicity or rigidity, to be associated with NMS. In triggering NMS. and autonomic dysfunction. It is addition, reintroducing the original presumed to be attributable to a precipitating drug may not lead to Pathophysiology lack of dopaminergic activity in the a reoccurrence of NMS, although The cause of NMS is postulated to CNS, although hyperactivity of the patients with a history of NMS are at be a lack of dopaminergic activity sympathetic nervous system may increased risk of recurrence.76, 77 The in the CNS, principally affecting also be involved. The deficiency onset of NMS generally occurs within the D receptors. Dopamine D of central dopaminergic activity 7 days of starting or increasing 2 2 receptor antagonism leads to the can be attributable to dopamine antipsychotics and may last for 5 manifestations of the NMS. Blockade antagonists or dopamine receptor to 10 days even after the initiating of D receptors in the hypothalamus blockade, dysfunction of the agent is stopped. With depot forms 2 produces an increased set point and dopamine receptors, or withdrawal of antipsychotics, however, onset loss of heat-dissipating mechanisms. of dopamine agonists. 50, 71, 72 of NMS symptoms may be more Antagonism of the D receptors insidious and may last longer, up to 2 With the increasing use of in the nigrostriatal pathways and 15 to 30 days. 71, 76, 82 antipsychotic medications in the spinal cord via extrapyramidal pediatric population, clinicians caring It was initially thought that newer pathways produces muscle rigidity for children and adolescents may atypical antipsychotics, which have and tremor. In the periphery, the encounter this syndrome. 73 Given both serotonin and dopamine- increased release of calcium from that NMS can be difficult to recognize blocking properties, would not the sarcoplasmic reticulum causes and attenuated or incomplete cause NMS because of their lower increased contractility, leading presentations are possible, NMS is activity at dopamine receptors and to muscle rigidity, increased heat challenging to diagnose. 71, 74 The their greater antiserotoninergic production (with worsening of incidence of NMS has been difficult activity. This has not turned out to hyperthermia), and muscle cell

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 138 , number 3 , September 2016 e7 TABLE 5 Differential Diagnosis of NMS72, 89 results reflect consensus on the Toxicologic Psychiatric relative importance of individual Serotonin syndrome Delirium clinical and diagnostic features for Anticholinergic poisoning Lethal catatonia making a diagnosis of NMS. On a Sympathomimetics Factitious fever 100-point scoring system (ie, the Malignant hyperthermia Munchausen syndrome Monoamine oxidase inhibitor CNS total number of points sum up to Monoamine oxidase inhibitor interaction with drugs Intracranial tumors 100), each clinical feature of NMS or foods was assigned a number of “priority Central anticholinergic syndrome Vasculitis points.” The point system is not Lithium Stroke meant to be used as a method for Phencyclidine Seizure Infectious disease Other making the diagnosis of NMS; that Encephalitis Heatstroke is, there is no threshold number of Meningitis Rheumatologic (eg, systemic lupus points that indicate the presence or erythematosus, lupus cerebritis) absence of NMS. Rather, it is meant Tetanus Malignancies to help clinicians determine which Endocrine HIV/AIDS Pheochromocytoma Porphyria features of NMS are more important Thyroid disease Familial Mediterranean fever in making the diagnosis. The greater Adrenal disease the number of points assigned, the greater the significance of the feature in making the diagnosis of breakdown with elevated creatine Complications include renal NMS. The Delphi panel made the kinase and rhabdomyolysis. In failure from rhabdomyolysis, following assignments: exposure to addition, D receptor antagonism by thromboemboli, dysrhythmias, 2 dopamine antagonist or withdrawal eliminating tonic inhibition of the cardiovascular collapse, and of dopamine agonist within 3 days sympathetic nervous system leads to respiratory failure from aspiration (20 points), hyperthermia (>100.4°F sympathoadrenal hyperactivity and pneumonia or tachypneic oral on ≥2 occasions [18 points]), autonomic instability. 72, 75 hypoventilation caused by rigidity (17 points), mental status diminished chest wall compliance alteration (13 points), creatine kinase Clinical Presentation from muscle rigidity, which may elevation (≥4 times upper limit of The hallmarks of NMS are result in endotracheal intubation and normal [10 points]), sympathetic hyperthermia, altered mental status, ventilatory support. 50, 71 nervous system lability (10 points), muscle rigidity, and autonomic Diagnosis hypermetabolism (5 points), and instability. Manifestations of negative workup for infectious, toxic, autonomic dysfunction, which Because there are no pathognomonic metabolic, or neurologic causes (7 may occur before other symptoms, clinical or laboratory criteria, NMS is points). Sympathetic nervous system include fever up to 41°C or higher, a clinical diagnosis. The differential lability was defined as 2 or more tachycardia, blood pressure diagnosis for NMS is broad and is of the following: elevated (systolic instability, diaphoresis, pallor, outlined in Table 5. An important or diastolic ≥25% of baseline) or cardiac dysrhythmia, diaphoresis, component of the diagnosis is a fluctuations (≥20 mm Hg diastolic sialorrhea, and dysphagia. 71, 88 history of antipsychotic use or or ≥25 mm Hg systolic change withdrawal of a dopaminergic The most common neurologic within 24 hours) in blood pressure, agent. 45, 86 Numerous diagnostic finding is lead pipe rigidity, although diaphoresis, or urinary incontinence. criteria have been proposed, which akinesia, dyskinesia, or waxy Hypermetabolism was defined as have included the classic clinical flexibility may be present. 45, 77 The a heart rate increase ≥25% above symptoms and other supplemental alteration in mental status often takes baseline and respiratory rate ≥50% criteria. 1,79, 81, 88 Additional proposed the form of delirium but varies from above baseline. criteria include elevated creatine alert mutism to agitation to stupor to kinase, 81 leukocytosis, incontinence, coma. 50, 76 Motor abnormalities may Leukocytosis, generally in the dysphagia, mutism, and metabolic include rigidity, akinesia, intermittent range of 15 000 to 30 000 cells per acidosis.1, 79, 81 tremors, and involuntary movements. cubic millimeter, and electrolyte Other less common neurologic Recently, a Delphi panel of findings consistent with dehydration or neuromuscular signs include a international NMS experts convened may be present. The etiology of positive Babinski, chorea, seizures, to discuss NMS diagnostic criteria. 90 elevated alkaline phosphatase, lactic opisthotonos, trismus, and oculogyric Although its purpose was not to dehydrogenase, and transaminases crisis.76, 86 create a new set of criteria, the indicating impaired liver function

Downloaded from www.aappublications.org/news by guest on September 26, 2021 e8 FROM THE AMERICAN ACADEMY OF PEDIATRICS is unknown but may be secondary trials, limiting the strength of the Serotonin Syndrome to acute fatty liver changes from evidence base. The most frequently Serotonin syndrome occurs in all the hyperpyrexia. An elevated administered drugs have been ages, from infants and children serum aldolase and creatine kinase, dantrolene, bromocriptine, and to older adults. It has even been often greater than 16 000 IU/L, amantadine. Dantrolene decreases reported in newborn infants as a may be attributable to severe, muscle rigidity, and thermogenesis result of in utero exposure. 92 The sustained muscle contractions. caused by the tonic contraction of incidence of and mortality from The elevated creatine kinase may muscles. It blocks the release of serotonin syndrome have been lead to rhabdomyolysis, acute calcium from smooth muscle cells’ increasing and may escalate in the myoglobinuria, and renal failure. sarcoplasmic reticulum, uncoupling future 93, 94 because of the growing A nonspecific common finding is actin and myosin chains, resulting number and use of proserotonergic the presence of a low serum iron in muscle relaxation. Commonly medications, such as SSRIs, other concentration in patients with used dosages in NMS are 1 mg/kg classes of psychiatric medications NMS. 77, 86, 91 If a lumbar puncture by IV push followed by 0.25 to 0.75 (eg, other antidepressants is performed, the cerebrospinal mg/kg every 6 hours. The drug and anxiolytics), antibiotics, fluid results may be normal or have may be continued until symptoms opiate analgesics, antiemetics, nonspecific findings. Findings on resolve or a maximum of 10 mg/kg is anticonvulsants, antimigraine drugs, an EEG, if obtained, are variable. reached.72, 77 anti-Parkinsonism drugs, muscle The EEG results may be normal The utility of CNS dopaminergic relaxants, and weight-reduction or or demonstrate findings of a agents is unclear and controversial. bariatric medications ( Table 6). In nonspecific encephalopathy, such Therefore, consultation with a addition to prescription medications, as diffuse slowing. 71, 76 There are toxicologist or poison control center a wide variety of over-the-counter no specific findings on postmortem may be helpful. Bromocriptine is a medications, herbal and dietary histopathology of the brain. 71 centrally acting dopamine agonist. supplements, and drugs of abuse Differentiating NMS from serotonin Experts suggest an initial dosage of have all been associated with syndrome and other toxidromes can 1.25 to 2.5 mg twice a day, which serotonin syndrome.95 be challenging. Clinical features that may be increased to 10 mg 3 times a may help are detailed in Table 7 and day. Muscle rigidity usually responds Serotonin syndrome occurs in the section on serotonin syndrome. quickly to bromocriptine, but approximately 16% to 18% of fever, blood pressure, and creatine patients who overdose with an Treatment kinase levels may take several SSRI. 93 The true incidence of Management of NMS involves days to normalize. Amantadine has serotonin syndrome is difficult to primarily supportive care and dopaminergic and anticholinergic estimate, given that many instances removal of the initiating agent. If effects. A common starting dosage are probably undiagnosed or 96,97 NMS is triggered by the abrupt is 100 mg orally, with a maximum misdiagnosed. Variable clinical withdrawal of an anti-Parkinsonism dosage of 200 mg twice a day. 72, 77, 86 manifestations (eg, lack of the drug, reintroduction of the drug may Benzodiazepines are often classic triad of symptoms), wide be considered.72 Cardiorespiratory used for agitation and rigidity. spectrum of disease from mild to compromise may be managed with Electroconvulsive therapy has been life-threatening, symptoms that are standard, supportive measures. used in some pharmacotherapy- easily misattributed to the patient’s Dehydration or elevated creatine resistant cases. 72, 77 underlying mental condition (eg, anxiety and akathisia), lack of kinase and rhabdomyolysis may ED clinicians may not have seen be treated with IV fluids. If renal awareness of the disorder, and or treated many cases of NMS. the vast number of medications, failure occurs, hemodialysis may be Potential resources for caring for necessary (however, dialysis does other agents, and combinations these patients include toxicologists, of medicines or agents that can not remove antipsychotics that are a poison control center, and the protein bound). For agitation, experts cause serotonin syndrome all may NMS Information Service, which contribute to missed diagnoses. 93, 97, 98 suggest benzodiazepines as the first- can be accessed through its Web line agent. Fever can be treated with site (http:// www. nmsis. org/ index. Pathophysiology external cooling measures, such as asp). Staffed by NMS experts, the 72,75 cooling blankets. NMS Information Service provides In the CNS, serotonin Suggestions for NMS treatment are information, education, and phone (5-hydroxytryptamine) regulates based on case reports and clinical consultation regarding the diagnosis temperature, attention, and experience, not rigorous clinical and treatment of NMS. behavior. Peripherally, serotonin

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 138 , number 3 , September 2016 e9 TABLE 6 Medications and Other Agents Associated With Serotonin Syndrome modulates gastrointestinal Psychiatric drugs tract motility, vasoconstriction, Antianxiety drugs: direct serotonin antagonists bronchoconstriction, and platelet Buspirone aggregation. Seven families of Antimanic drugs: increased postsynaptic receptor sensitivity serotonin receptors have been Lithium Antidepressants identified, with serotonin syndrome Antidepressants: tricyclic antidepressants resulting from excess CNS Amitriptyline serotonin, 98, 99 primarily caused Clomipramine by overstimulation of serotonin Nortriptyline 2A 100,101 Antidepressants: monoamine oxidase inhibitors receptors. Phenelzine Antidepressants: SSRIs Excessive serotonin activity may Citalopram result from myriad mechanisms, Fluoxetine including increased release Paroxetine of serotonin (eg, cocaine, Sertraline amphetamines), increased Antidepressants: 5HT2A receptor blockers Nefazodone production of serotonin (eg, Trazodone L-tryptophan in stimulant Antidepressants: serotonin-norepinephrine reuptake inhibitors products), inhibiting reuptake of Venlafaxine Duloxetine synaptic serotonin (eg, tricyclic Nonpsychiatric drugs antidepressants, SSRIs), decreased Skeletal muscle relaxants neuronal metabolism of serotonin Cyclobenzaprine via inhibition of monoamine oxidase Opioid analgesics Fentanyl inhibitors, direct stimulation of Meperidine serotonin receptors (eg, lysergic Oxycodone acid diethylamide, migraine drugs Pentazocine such as sumatriptan, buspirone), Tramadol Hydrocodone and increased postsynaptic receptor Antibiotics responsivity (eg, lithium). 93, 95 Linezolid Antiretroviral (protease inhibitor) A single dose of a single Ritonavir proserotonergic agent may Anticonvulsants precipitate serotonin syndrome. Carbamazepine Valproic acid However, many cases occur after Antiemetics exposure to 2 or more drugs that Metoclopramide (Reglan) increase the serotonin activity. 5HT3 receptor antagonists Examples of combinations of Ondansetron Antimigraine drugs proserotonergic medications Ergot alkaloids: ergotamines causing serotonin syndrome include

Triptans (5 HT1B and 5HT1B receptor agonists; eg, sumatriptan) reports of SSRIs and fentanyl Antiparkinsonian drugs (given during procedural sedation),102 Carbidopa/levodopa erythromycin, 96 and St John’s Bariatric medications (weight reduction) Sibutramine wort (an over-the-counter herbal Over-the-counter medications supplement). 95 In addition, serotonin Dextromethorphan (cough suppressants and cold remedies) syndrome has also been reported Drugs of abuse in a patient withdrawing from a 3,4–Methylenedioxymethamphetamine (Ecstasy) 100 Cocaine serotonergic agent. Lysergic acid diethylamide Methamphetamine Clinical Presentation Herbals Hypericum perforatum (St John’s wort) The clinical triad of the serotonin Dietary supplements syndrome consists of mental status Panax ginseng (ginseng) changes, autonomic hyperactivity, L-tryptophan 5-hydroxytryptophan and neuromuscular abnormalities. This is not an all-inclusive list but gives an overview of the wide range of agents that can trigger the serotonin syndrome. One of the greatest challenges Drugs are listed by their therapeutic category. This list is not intended to endorse any given drug or product. of this diagnosis is its extremely

Downloaded from www.aappublications.org/news by guest on September 26, 2021 e10 FROM THE AMERICAN ACADEMY OF PEDIATRICS variable presentation. Many patients the most common cause of death have a higher sensitivity (84% do not exhibit all these clinical being inadequate management of vs 75%) and specificity (97% vs characteristics. 103 Some patients hyperthermia. 98 96%) than Sternbach criteria. 105 In will have severe symptoms, such addition, the use of the Sternbach as high fever (up to 41.1°C), severe Diagnosis criteria may exclude mild, early, hypertension, and tachycardia that The differential diagnosis of or subacute serotonin syndrome. may deteriorate into hypotension, serotonin syndrome includes Others prefer modified Dunkley 100,104 shock, agitated delirium, muscular other disorders precipitated criteria. According to the rigidity, and hypertonicity. Mild cases by medications or drug toxicity modified Dunkley criteria, the may range from tremor and diarrhea reactions (eg, NMS and malignant diagnosis can be made if the patient to tachycardia and hypertension but hyperthermia, anticholinergic has taken a serotonergic drug within no fever. Symptom onset is generally syndrome, and withdrawal the last 5 weeks and has any of the rapid, often within minutes of syndromes including delirium following: tremor and hyperreflexia; exposure to the precipitating agent, tremens); CNS disorders spanning spontaneous clonus; muscle rigidity, with most patients presenting within infection (meningitis, encephalitis), temperature >38°C, and either 100 6 to 24 hours. tumors, and seizures; and psychiatric ocular clonus or inducible clonus; ocular clonus and either agitation or Agitated delirium is the most disorders such as acute catatonia. diaphoresis; or inducible clonus and common form of mental status Differentiating between serotonin either agitation or diaphoresis. 100 change, although this too has a wide syndrome and other medication- Other variations of these diagnostic spectrum of severity, including mild induced syndromes can be criteria have been proposed. They all agitation, hypervigilance, slightly challenging and may be important, include a serotonergic drug having pressured speech, and easy startle. given that treatment may differ been started or the dosage increased Diaphoresis, shivering, mydriasis, depending on the underlying and other possible etiologies (eg, increased bowel sounds, and diarrhea etiology. Table 7 details both the NMS, substance abuse, withdrawal, are common signs of autonomic similar and differentiating features infection, other toxidromes) having dysfunction. 95, 100 Myoclonus is of these syndromes. The most been ruled out, plus the presence of the most common neuromuscular common clinical finding of serotonin specific signs and symptoms. 95, 106, 107 finding, 98 but other abnormalities syndrome is myoclonus, which occurs are possible, including muscular in slightly more than half (57%) Treatment rigidity, hypertonicity (which may of cases. 98 Some experts believe Treatment often involves in turn contribute to hyperthermia), that clonus and hyperreflexia are discontinuing the precipitating hyperreflexia and clonus (which “highly diagnostic for the serotonin agent and providing supportive are more pronounced in the lower syndrome and their occurrence in care. Supportive care may include than the upper extremities), the setting of serotonergic drug use treatment of agitation (eg, horizontal ocular clonus, tremor, establishes the diagnosis.” 100 and akathisia. In some cases, muscle benzodiazepines), amelioration of hypertonicity may be so severe that it As with NMS, there are no hyperthermia, and management overpowers and obscures tremor and pathognomonic laboratory or of the autonomic instability (eg, IV hyperreflexia. radiographic findings of serotonin fluids and other agents to address syndrome. Testing may be obtained abnormal vital signs). In addition, Significant morbidity and mortality on the basis of clinical suspicion for those with severe serotonin are associated with serotonin and may include a complete blood syndrome (eg, temperature >41.1°C), syndrome. Severe cases are cell count, electrolytes, serum emergency sedation, neuromuscular characterized by rhabdomyolysis urea nitrogen, creatinine, arterial paralysis, and intubation may be with an elevated creatine kinase, blood gas (checking respiratory considered. Physical restraints may metabolic acidosis, elevated serum status and for metabolic acidosis), be detrimental, because they may aminotransferase, renal failure hepatic transaminases, creatine exacerbate isometric contractions, with an elevated serum creatinine, kinase, urinalysis, toxicology thereby worsening hyperthermia seizures, and disseminated screens, coagulation studies, and lactic acidosis and increasing intravascular coagulopathy. electrocardiography, EEG, and brain mortality. 98 Approximately one-quarter of imaging studies. patients are treated with intubation, In severe cases, serotonin2A mechanical ventilation, and Clinical diagnostic criteria for antagonists may be considered, admission to an ICU. The mortality serotonin syndrome have been with cyproheptadine being most rate is approximately 11%, with proposed.104, 105 Hunter criteria 104 commonly used. The adult dosage of

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 138 , number 3 , September 2016 e11 TABLE 7 Differentiation of the Drug Toxicity Syndromes Serotonin Syndrome NMS Malignant Hyperthermia Anticholinergic Poisoning Etiology Excessive serotonin Decreased Calcium release from Inhibit acetylcholine binding to muscarinic dopamine sarcoplasmic reticulum receptors Precipitant Proserotonergic drugs Dopamine Inhalational anesthetic with Anticholinergic drugs or antimuscarinic drugs antagonist or or without succinylcholine withdrawal of dopaminergic drug History Nonidiosyncratic, add new Idiosyncratic, Inherited (+ family history) or Anticholinergic drug exposure antihistamines, drug, ↑ dosage of drug, exposure to new genetic mutation tricyclic antidepressants, sleep aids, cold or add second drug dopamine preparations, diphenhydramine, atropine antagonist drug or withdrawal from dopaminergic drug Onset Minutes to hours Days Hours Minutes to hours Usual: 6–24 h Usual: 1–7 d Usual: <12 h Usual: 0.5–24 h Vital signs Temperature Elevated (≤41.1°C) Elevated (≤41.1°C) Elevated (≤46°C) Mild elevation (<38.8°C) Heart rate Tachycardia Tachycardia Tachycardia Tachycardia Respirations Tachypnea Tachypnea Tachypnea Tachypnea Blood pressure Hypertension (may Hypertension Hypertension Hypertension (mild) deteriorate to hypotension) Mental status Agitated delirium Variable: alert, Agitation Agitated delirium mutism, stupor, coma Neuromuscular abnormalities Muscle tone Increased, lower “Lead pipe” rigidity Rigor mortis–like rigidity Normal extremities greater (masseters or generalized) than upper extremities Muscle refl exes Hyperrefl exic, clonus; Slowed, Hyporefl exic Normal may be masked by bradyrefl exic hypertonicity Physical examination Skin Diaphoretic Diaphoretic Diaphoretic, mottled Hot, dry, erythemaa Pupils Mydriasis Normal Normal Mydriasis Mucous membranes Sialorrhea Sialorrhea Normal Drya Gastrointestinal Hyperactive bowel sounds, Normal or Hypoactive bowel sounds Hypoactive or absent bowel sounds motility may have diarrhea hypoactive bowel sounds Treatment considerations General Discontinue precipitant drug, supportive care, benzodiazepine for agitation

Specifi c If severe: serotonin2A If severe: smooth If severe: dantrolene Sodium bicarbonate for prolonged QRS antagonists (eg, muscle relaxant or dysrhythmias, treat hyperthermia, cyproheptadine) (eg, dantrolene), physostigmine dopamine agonists (eg, bromocriptine, amantadine) All of these drug toxicity syndromes can present with altered mental status, autonomic dysfunction, and neuromuscular abnormalities as manifested by abnormal vital signs including fever, hypertension, and tachycardia. Treatment in all 4 syndromes may include removing the precipitating agent and providing supportive care. Other specifi c therapy may differ depending on the disorder. Not all patients will have all the classic signs and symptoms. For example, a patient with mild serotonin syndrome may be afebrile but have tachycardia and hypertension. Typical fi ndings are listed in this table. a Anticholinergic syndrome described as “Red as a beet, dry as a bone, hot as a hare, blind as a bat, mad as a hatter, full as a fl ask.” cyproheptadine is usually 12 to 24 every 6 hours, given orally. There is divided into 2 or 3 doses daily, up to a mg over 24 hours, typically starting no parenteral form, but tablets have maximum of 12 mg. Chlorpromazine, with 12 mg, followed by 2 mg every been crushed and administered via an antagonist of serotonin2A receptors 2 hours for continuing symptoms, a nasogastric tube. The pediatric as well, is available in a parenteral and a maintenance dose of 8 mg dosage is usually 0.25 mg/kg per day, form but has the disadvantage that

Downloaded from www.aappublications.org/news by guest on September 26, 2021 e12 FROM THE AMERICAN ACADEMY OF PEDIATRICS it can cause hypotension and may CHILDREN WITH SPECIAL NEEDS work with their children (eg, which increase muscle rigidity, decrease the words, actions, or stimuli calm and seizure threshold, and worsen NMS.98 Autism Spectrum and Developmental help their child and which have the Both drugs may be effective,108 but Disorders opposite effect). Parents can also cyproheptadine is preferred by most In recent years, there has been a be “interpreters” for ED clinicians, experts.99, 100 sharp increase in the incidence deciphering the significance of their 109 Low dosages of direct-acting of ASDs and DDs, with child’s actions and behaviors and sympathomimetic amines (eg, corresponding interest and growth facilitating communication with their phenylephrine, norepinephrine, and in treatment strategies. Investigated child. Spending some time asking epinephrine) or short-acting drugs therapeutic modalities include parents about their child is likely to 110–115 such as esmolol or nitroprusside psychobehavioral therapies, be a productive, efficient method for 116–118 have been used to manage fluctuating psychopharmacology, tailoring effective ED care for these blood pressure and heart rate. Use occupational and language patients. 119–121 of indirect agents (eg, dopamine) therapies, and complementary and alternative medicines. 122 Strategies for ASD-DD–Sensitive ED may not be efficacious, because the Care mechanism of action of these drugs Unfortunately, many studies have includes intracellular metabolism via had methodologic limitations (eg, Typical strategies for caring for catecholamine-O-methyl transferase small sample sizes, variability in children with ASD-DD are listed in 128 to metabolize the dopamine to study populations, methods or Table 8. Children with ASD-DD are epinephrine and norepinephrine, interventions used, and outcomes often hypersensitive to environmental which may result in overshooting the measures) and are not applicable stimuli (eg, light, sound, and activity). 123–125 desired effect. to the medical setting. Three Simple solutions include using a evidence-based reviews of this topic quiet office or counseling room Management of hyperthermia often conclude that there is adequate (if available) instead of a loud, involves terminating the extreme evidence for only a limited number stimulating examination room. If this muscle activity. In addition to treating of therapies (eg, pharmacotherapy), type of patient space is not available, agitation, benzodiazepines may be although several other strategies an alternative solution may be to use useful in controlling muscular activity show promise (eg, early and a quiet examination room, away from in moderate cases. In severe cases, intensive behavioral therapy, the busy, noisy areas of the ED, with paralysis with nondepolarizing drugs social skills training, and visual dimmed lighting (eg, turning off some (eg, vecuronium or rocuronium) and 125–128 communication systems). lights or using a single lamp). intubation may be considered. Some Given these limitations, the strategies Studies have demonstrated that experts suggest that succinylcholine discussed below are based primarily visual communication systems may be risky with these patients, on expert, consensus opinion. secondary to hyperkalemia and (VCSs) can improve communication rhabdomyolysis, which may be with children with language ASD-DD–Sensitive Care Resources 129–132 present and ultimately result in disabilities. VCS products dysrhythmias. Because the fever A wide range of ED health are the most commonly used of NMS is secondary to muscular professionals can champion, communication adjuncts and are hyperactivity and not effects on the organize, design, and coordinate widely available. There are numerous hypothalamic thermoregulation set ASD-sensitive ED care, including commercial or free and print and point, antipyretics typically are not physicians, nurses, nursing electronic products (eg, Web sites, efficacious.96, 99, 108 assistants, nurse practitioners and “apps,” devices). A visual schedule physician assistants, social workers, (Fig 1) exemplifies how a VCS can Patients with serotonin syndrome and child life specialists. Non-ED be used to prepare a child with can deteriorate rapidly; therefore, professionals who may be helpful ASD-DD for an upcoming event close observation and preparation include developmental–behavioral or activity. Visual schedules help for rapid intervention may be pediatricians, child psychologists children organize themselves, considered. In milder cases, and psychiatrists, special education understand what will happen next, evaluation, observation, and teachers, speech–language therapists, highlight or introduce activities that discharge with close, additional and occupational therapists. are unfamiliar to them, and create outpatient management may be smoother transitions, all of which considered. As mentioned previously, Often, the most important ASD-DD may decrease children’s anxiety. discussing these patients’ care with a “experts” to consult are the child’s toxicologist or poison control center parents. Parents of children with If a child has his or her own personal may be helpful. ASDs or DDs know what strategies VCS, it may be advantageous to use

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 138 , number 3 , September 2016 e13 TABLE 8 Nonpharmacologic Strategies for Caring for Children With ASD-DD Environmental modiﬁ cation (light, noise, other stimuli) Visual communication systems Transition planning Occupational or physical therapy techniques the VCS, because the child will be familiar with pictures. A potential disadvantage of a personal VCS is that the set of images may not have FIGURE 1 the necessary medical pictures. A Digital photograph visual schedule. Photo credit: Thomas H. Chun, MD, MPH, FAAP. simple and inexpensive solution to this problem is to create a custom set of images of the ED setting. This can easily be done with clip art or digital photography images, which are then printed and laminated. If digital photography is used, taking pictures of the ED staff, equipment, and commonly performed procedures is a simple method for creating a customized VCS for your setting (Fig 2).

Transitions are often problematic for children with ASD-DD, including FIGURE 2 changing from 1 activity to the next, Clip art visual schedule. moving from 1 setting to another (especially new settings), and breaks the ED visit this may still be a time- Other children with ASD-DD are very or deviations from their usual neutral strategy relative to the time sensitive about their personal space. routines. For these reasons, a medical consumed by unsuccessful strategies. Starting at the periphery (ie, toes and visit may be upsetting or unsettling At the least, this strategy is likely to fingers) and slowly moving centrally to these children. Fortunately, many be more satisfactory to children, their may help relax children and facilitate parents are familiar with anticipating parents, and ED clinicians. the examination. These types of and planning for these types of desensitization strategies have been Desensitization strategies that are transitions. For example, these successfully used for phlebotomy used with all children (eg, gradually parents talk to their children before attempts in children with ASD-DD. 133 approaching and engaging with a new experience, describe what will children, bending down to interact Many children with ASD-DD find happen and the sequence of events, at children’s level, allowing children value in occupational therapy (OT). and explain what might be upsetting to play with medical instruments OT techniques that are directly to the children and how they will or to use them on you or their applicable to medical settings involve handle these stressful situations. parent first, distracting them with sensory integration and tasks that Preparing children with ASD-DD for a toy or game, and having children can be used as distraction techniques. a medical visit ideally begins before held or comforted by parents while Children with ASD-DD have variable or while en route to the visit and is an they are examined) also may help responses to touch, with some ongoing process once they arrive. with children with ASD-DD. For finding it soothing and others Anticipating and building breaks some, however, the same strategies becoming distressed by touch. Some in a schedule may be helpful. Many may benefit from significant find “deep pressure” (ie, the feeling children with ASD-DD are able to augmentation, literally breaking each of weight on their bodies) relaxing, remain on task for only short periods step down into several incremental, but others respond to light touch. of time. Regular, brief breaks in the smaller steps. It may take several Devices such as weighted blankets or schedule may be helpful to these visits and interactions and multiple shawls for deep pressure and gentle children. As time consuming as it may attempts before children will allow massaging devices for light touch be, in the total calculus of planning you to approach and examine them. frequently are used. These products

Downloaded from www.aappublications.org/news by guest on September 26, 2021 e14 FROM THE AMERICAN ACADEMY OF PEDIATRICS can be purchased through OT supply Academy of Pediatrics clinical report vendors, but simple substitutes can on screening for behavioral and be found easily in medical settings. emotional problems. 135 For example, a radiology lead vest or apron is an easy facsimile of a The Advantages of the ED Setting weighted blanket. Gently stroking The ED may be an ideal setting for the child with gauze or cast screening and identifying high- underpadding provides an excellent risk, difficult-to-reach pediatric light touch massage. populations with mental health Distraction may be a useful adjunct problems. Many teenagers either do in children with ASD-DD. Occupying not have a primary care provider FIGURE 3 a child’s hands or body with “fidget or face significant barriers to Example of rocking in a sports chair. Photo toys” is a typical strategy. OT devices accessing such health care. For credit: Thomas H. Chun, MD, MPH, FAAP. (eg, grip strengthening and manual these adolescents, the ED often is dexterity devices, devices to improve their main or only source of medical acceptable to adolescents, their balance) also may serve this function. care. 136, 137 Other high-risk groups parents, and ED clinicians. Numerous With appropriate supervision, simple for mental health and substance use studies have shown the acceptability substitutes for these devices are also problems are homeless adolescents of such screening. Teenagers and easily made (eg, a loosely wound roll and school dropouts, 138 – 143 both parents both report favorable of gauze or cast underpadding can of whom disproportionately seek attitudes toward mental health be a substitute for a squeeze toy). medical care in the ED. screening during an ED visit. 153, 154 Rocking in a rocking chair or nylon Finally, male adolescents may In this study, suicide and drug and folding sports stadium seat also can preferentially seek care in EDs alcohol screening rated as more calm children ( Fig 3). because they are less likely to important than other mental health participate in primary or mental problems. Female adolescents Psychopharmacology and ASD-DD health care. 144, 145 and their parents, more than male There are no rigorous evidence- adolescents, expressed positive based guidelines regarding Feasibility and Acceptability of ED views on screening. In another study, Mental Health Screening psychotropic medications for both teenagers and their caregivers children with ASD-DD. Although Several rapid, efficient, and accurate perceived ED depression screening there is strong evidence for the use ED mental health screening tools as a sign of caring and concern for the 155 of psychotropic medications in have been developed and show adolescent. Suicide screening has ASD-DD,116, 117, 125 there are no promising results. As few as 2 been found to be acceptable to 60% controlled trials of these medications screening questions have been found to 66% of patients and parents, with for acute agitation or sedation. to be helpful in detecting depression 96% of participants agreeing that Currently, there are no known in both adult and pediatric ED suicide screening is appropriate in 149, 150,156 contraindications to using common settings as well as problematic the ED. 146–148 sedating medications for children adolescent alcohol use. What do ED clinicians think about with ASD-DD, although some experts A 4-question adolescent suicide mental health screening in the ED? believe that atypical medication screen has been shown to have good Is such screening acceptable to responses may be more common sensitivity, specificity, and predictive them? Perceived and real barriers (eg, idiosyncratic, disinhibition, or value across a range of teenagers to such screening exist, including paradoxical reactions). Inquiring seeking care in the ED and can be lack of training, time constraints, about the previous reaction to accurately administered by non– and increasing ED patients’ length of 149–151 medications often is helpful, as may mental health professionals. stay. Williams et al 154 investigated be beginning with lower medication Similarly, an 8-question screen was this question and found that 99% of dosages to observe and determine the shown to have excellent predictive physicians and 97% of nurses stated 134 child’s response to the medication. characteristics for detecting that a brief, validated screening tool posttraumatic stress symptoms in did not interfere with patient care. children who sustained traffic-related In addition, research staff endorsed MENTAL HEALTH SCREENING 152 injuries. “no difficulty” in administering the For a discussion of mental health Given the clinical and time pressures screen to 73% of participants. Lastly, screening strategies in primary care of the ED setting, it is important a significant and important finding settings, please refer to the American that mental health screening be of the study by Horowitz et al 149 was

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 138 , number 3 , September 2016 e15 that real-time evaluation of positive Both depression and alcohol partner violence, 165, 166 weapons, 167 suicide screens did not increase ED abuse may be screened for with 2 injury prevention, 168 and HIV risk patients’ length of stay. questions. Rutman et al 147 found behaviors. 169 Adolescents not that the 2 questions “During the only rated these screens as highly ED Mental Health Screens past month, have you often been acceptable but also may prefer such bothered by feeling down, depressed, health interventions. 170– 172 Fein and Many mental health screening tools or hopeless?” and “During the past Pailler 140, 173 have developed and have been developed or tested in the month, have you often been bothered implemented an electronic tool for ED setting. Although not validated by little interest or pleasure in doing universal screening of ED adolescent in general ED populations, they have things?” were 78% sensitive (95% physical and mental health risks. The the potential to increase ED mental CI, 73%–84%) and 82% specific screen was presented to patients health screening. One example is an (95% CI, 77%–87%) for adolescent by a nurse or medical technician. abbreviated version of the Home, depression. These 2 questions have After the screen was scored, the Education/School, Activities, Drugs, similar screening properties in adult adolescent’s results were printed Depression, Sexuality, Suicide, ED patients as well. 146 Both Newton out and reviewed by the treating Safety (HEADDSSS) mnemonic for et al and the National Institute physicians. This method resulted adolescent psychosocial assessment, of Alcohol Abuse and Alcoholism in a 68% increase in identification which was adapted for and tested (NIAAA) have developed 2-question of psychiatric illnesses and in an ED. 157 The Home, Education, screens for problematic teenage subsequently a 47% increase in Activities and Peers, Drugs and alcohol use. 148, 160 Newton et al also mental health assessments. Alcohol, Suicidality, Emotions and believe that a single question may Behaviors, Discharge Resources efficiently screen for marijuana use. LEAD AUTHORS (HEADS-ED) was found to be They used the following questions: reliable and accurate, with good Thomas H. Chun, MD, MPH, FAAP “In the past year, have you sometimes Sharon E. Mace, MD, FAAP, FACEP concurrent and predictive validity been under the influence of alcohol Emily R. Katz, MD, FAAP for future psychiatric evaluation and in situations where you could have hospitalization. 158 caused an accident or gotten hurt?”, AMERICAN ACADEMY OF PEDIATRICS COMMITTEE ON PEDIATRIC EMERGENCY Horowitz et al 149, 151, 159 have “Have there often been times when MEDICINE, 2014–2015 performed several studies on ED you have a lot more to drink than suicide screening, most recently by you intended to have?”, and “In the Joan E. Shook, MD, MBA, FAAP, Chairperson James M. Callahan, MD, FAAP past year, how often have your used using multiple logistic regression Thomas H. Chun, MD, MPH, FAAP modeling to determine which suicide cannabis: 0 to 1 time, or greater than Gregory P. Conners, MD, MPH, MBA, FAAP screening questions best screen for 2 times?” Teenagers who answer Edward E. Conway Jr, MD, MS, FAAP and identify occult suicidal youth. 150 “yes” to 1 alcohol question or to the Nanette C. Dudley, MD, FAAP A 4-question model was found to marijuana question have an eightfold Toni K. Gross, MD, MPH, FAAP Natalie E. Lane, MD, FAAP and sevenfold increased risk of optimize sensitivity (97%; 95% CI, Charles G. Macias, MD, MPH, FAAP 91%–99%), specificity (88%; 95% CI, having a substance use disorder, Nathan L. Timm, MD, FAAP 84%–91%), and negative predictive respectively. The 2 NIAAA questions value (99%, 95% CI, 98%–99%) vary according to the patient’s age for ED patients presenting with and explore the patient’s and their LIAISONS both psychiatric and nonpsychiatric friends’ experience with alcohol. The Kim Bullock, MD – American Academy of Family conditions. The 4 domains of suicidal NIAAA currently is investigating the Physicians Elizabeth Edgerton, MD, MPH, FAAP – Maternal reliability as well as the concurrent, ideation are current suicidal ideation, and Child Health Bureau past suicide attempts, current wish convergent, discriminant, and Tamar Magarik Haro – AAP Department of to die, and current thoughts of being predictive validity of this screen.161 Federal Affairs better off dead. Given the prevalence Madeline Joseph, MD, FACEP, FAAP – American of suicidal ideation and attempts Computerized screening may add College of Emergency Physicians Angela Mickalide, PhD, MCHES – EMSC National and the morbidity and mortality advantages and efficiency to ED Resource Center associated with attempts, screening mental health screening. They can be Brian R. Moore, MD, FAAP – National Association patients with unclear or high risk administered with little ED clinician of EMS Physicians of suicide (eg, those presenting time or effort and have been used Katherine E. Remick, MD, FAAP – National with ingestions, acute intoxication, successfully in both pediatric and Association of Emergency Medical Technicians Sally K. Snow, RN, BSN, CPEN, FAEN – Emergency single-car motor vehicle crashes, general ED settings for general health Nurses Association and significant falls) also may be and mental health screening, alcohol David W. Tuggle, MD, FAAP – American College of important. use, 162 – 164 interpersonal and intimate Surgeons

Downloaded from www.aappublications.org/news by guest on September 26, 2021 e16 FROM THE AMERICAN ACADEMY OF PEDIATRICS Cynthia Wright-Johnson, MSN, RNC – National Marianne Gausche-Hill, MD, FACEP, FAAP STAFF Association of State EMS Ofﬁ cials Michael Gerardi, MD, FACEP, FAAP Dan Sullivan Charles J. Graham, MD, FACEP Stephanie Wauson FORMER MEMBERS AND LIAISONS, Doug K. Holtzman, MD, FACEP 2013-2015 Jeffrey Hom, MD, FACEP Paul Ishimine, MD, FACEP Alice D. Ackerman, MD, MBA, FAAP Hasmig Jinivizian, MD Lee Benjamin, MD, FACEP, FAAP - American College ABBREVIATIONS Madeline Joseph, MD, FACEP of Physicians Sanjay Mehta, MD, MEd, FACEP ASD: autism spectrum disorder Susan M. Fuchs, MD, FAAP Aderonke Ojo, MD, MBBS Marc H. Gorelick, MD, MSCE, FAAP CI: confidence interval Audrey Z. Paul, MD, PhD Paul Sirbaugh, DO, MBA, FAAP - National CNS: central nervous system Denis R. Pauze, MD, FACEP Association of Emergency Medical Technicians Nadia M. Pearson, DO DD: developmental disorder Joseph L. Wright, MD, MPH, FAAP Brett Rosen, MD ED: emergency department W. Scott Russell, MD, FACEP FDA: US Food and Drug Adminis- STAFF Mohsen Saidinejad, MD tration Sue Tellez Gerald R. Schwartz, MD, FACEP IV: intravenous Harold A. Sloas, DOOrel Swenson, MD AMERICAN COLLEGE OF EMERGENCY Jonathan H. Valente, MD, FACEP NIAAA: National Institute of PHYSICIANS PEDIATRIC EMERGENCY Muhammad Waseem, MD, MS Alcohol Abuse and MEDICINE COMMITTEE, 2013–2014 Paula J. Whiteman, MD, FACEP Alcoholism Dale Woolridge, MD, PhD, FACEP Lee S. Benjamin, MD, FACEP, ChairpersonKiyetta NMS: neuroleptic malignant Alade, MD syndrome FORMER COMMITTEE MEMBERS Joseph Arms, MD OT: occupational therapy Jahn T. Avarello, MD, FACEP Carrie DeMoor, MD PNES: psychogenic nonepileptic Steven Baldwin, MD James M. Dy, MD seizures Isabel A. Barata, MD, FACEP, FAAP Sean Fox, MD Kathleen Brown, MD, FACEP Robert J. Hoffman, MD, FACEP SSRI: selective serotonin Richard M. Cantor, MD, FACEP Mark Hostetler, MD, FACEP reuptake inhibitor Ariel Cohen, MD David Markenson, MD, MBA, FACEP VCS: visual communication Ann Marie Dietrich, MD, FACEP Annalise Sorrentino, MD, FACEP system Paul J. Eakin, MD Michael Witt, MD, MPH, FACEP

FINANCIAL DISCLOSURE: The authors have indicated they have no ﬁ nancial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conﬂ icts of interest to disclose.

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Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2016/08/18/peds.2 016-1573 References This article cites 148 articles, 15 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2016/08/18/peds.2 016-1573#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Emergency Medicine http://www.aappublications.org/cgi/collection/emergency_medicine_ sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 26, 2021 Evaluation and Management of Children With Acute Mental Health or Behavioral Problems. Part II: Recognition of Clinically Challenging Mental Health Related Conditions Presenting With Medical or Uncertain Symptoms Thomas H. Chun, Sharon E. Mace, Emily R. Katz, AMERICAN ACADEMY OF PEDIATRICS Committee on Pediatric Emergency Medicine and AMERICAN COLLEGE OF EMERGENCY PHYSICIANS Pediatric Emergency Medicine Committee Pediatrics originally published online August 22, 2016;

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