Selective serotonin reuptake inhibitors (SSRIs) are a widely prescribed class of medications used most commonly as antidepressants.‍1 Side effects can include benign manifestations such as drowsiness or gastrointestinal upset and agitation to more severe complications including purpura, bleeding, increased suicidality, and serotonin syndrome (SS).‍2 –5 In adults, rhabdomyolysis is an extremely rare complication of SSRIs6 – 9 and, apart from SS, is an unreported phenomenon in children.‍ We report the first known case of sertraline-induced rhabdomyolysis with associated renal failure, trismus, and cardiopulmonary arrest in a pediatric patient.‍

HISTORY AND FINDINGS

A 13-year-old boy presented to the emergency department (ED) with 2 weeks of generalized weakness, myalgias, fatigue, headache, intermittent abdominal pain, neck pain, and diffuse erythematous rash.‍ He was hemodynamically stable, febrile at 38.‍7°C, and had normal mental status.‍ An examination revealed diffuse erythroderma of

the thorax, a heliotrope periorbital rash, mild neck pain with flexion, and extension and pain and weakness in the calf and thigh muscles with impaired ambulation.‍ A laboratory workup revealed elevated creatine kinase (CK) 2447 U/L and aspartate aminotransferase (AST) 154 U/L, but normal electrolytes, complete blood count, and lipase.‍ The results of a head computed tomography were negative.‍ Lumbar puncture revealed normal cerebrospinal fluid indices (glucose 48 mg/dL, protein 25 mg/dL, and negative xanthochromia).‍ Fentanyl, ibuprofen, and a liter of normal saline were provided with slight improvement in symptoms.‍ The differential diagnosis included infectious or autoinflammatory processes including dermatomyositis, polymyositis, or reactive myositis.‍

Past medical history was significant for attention-deficit/hyperactivity disorder and adjustment disorder with depressed mood, which were treated with methylphenidate 20 mg 3 times daily and sertraline (Zoloft) 100 mg nightly, respectively.‍ Thirteen weeks before index ED visit, the patient was started on a titration of sertraline

Sertraline-Induced Rhabdomyolysis, Trismus, and Cardiac Arrest in a ChildPeter J. Holmberg, MD, FAAP, a Grace Arteaga, MD, b Brenda M. Schiltz, MD, MS, MA, FAAP, b James Homme, MDc

Selective serotonin reuptake inhibitors are a commonly used and often effective class of medications in the treatment of mood disorders such as anxiety and depression.‍ Sertraline (1S, 4S-N-methyl-4-[3, 4-dichlorophenyl]-1, 2, 3, 4-tetrahydro-1-naphthylamine [Zoloft; Pfizer, New York City, NY]) is a frequently used selective serotonin reuptake inhibitor that has shown efficacy in children, adolescents, and adults.‍ We report the case of a 13-year-old boy with sertraline-induced rhabdomyolysis and renal failure, trismus, and cardiopulmonary arrest.‍ Pharmacogenetic testing later revealed our patient had serotonin transporter polymorphisms and enzymatic alterations that put him at risk for increased levels of sertraline and greater likelihood for untoward side effects.‍

abstract

To cite: Holmberg PJ, Arteaga G, Schiltz BM, et al. Sertraline-Induced Rhabdomyolysis, Trismus, and Cardiac Arrest in a Child. Pediatrics. 2018; 142(4):e20180804

Divisions of aPediatric Hospital Medicine and bPediatric Critical Care Medicine, Department of Pediatric and Adolescent Medicine, and cDivision of Pediatric Emergency Medicine, Department of Emergency Medicine, Mayo Clinic, Rochester, Minnesota

Dr Holmberg conceptualized the report and drafted the initial manuscript; Dr Homme reviewed and revised the manuscript; Drs Arteaga and Schiltz collected patient data and conceptualized the report and reviewed the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

DOI: https:// doi. org/ 10. 1542/ peds. 2018- 0804

Accepted for publication Jul 5, 2018

Address correspondence to Peter J. Holmberg, MD, FAAP, Department of Pediatric and Adolescent Medicine, Mayo Clinic Children’s Center, 200 First St SW, Rochester, MN 55905. E-mail: holmberg.peter@mayo.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2018 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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25 mg daily up to 75 mg daily over 10 days.‍ The dose was increased from 75 to 100 mg daily 6 weeks before symptom onset.‍

CLINICAL COURSE AND MANAGEMENT

The patient was admitted from the ED to the pediatric service.‍ MRI of the lower extremities revealed diffuse muscle inflammation consistent with dermatomyositis versus reactive myositis.‍ Muscle biopsy demonstrated nonspecific rare necrotic fibers with occasional macrophage invasion.‍ During admission, he was mildly pancytopenic with nadirs in leukocytes (white blood cells) 2.‍2 × 109/L, platelets 109 × 109/L, hemoglobin 11.‍3 g/dL, and mean corpuscular value 82.‍8 fL.‍ Elevations in CK 2144 U/L, AST 131 U/L, and aldolase 27.‍8 U/L persisted.‍ Symptoms improved during the 4 days of hospitalization, and he was discharged with follow-up in the pediatric rheumatology clinic 4 days later.‍

At follow-up, he had increasing myalgias, weakness, difficulty ambulating, and positive Gowers sign, as well as new dysphagia with solids.‍ The heliotrope rash was more pronounced, and erythroderma now included the upper and lower extremities.‍ Given these findings, he was readmitted for inpatient treatment of dermatomyositis.‍ Laboratory results on admission revealed persistently elevated CK 5386 U/L and transaminases (AST 1291 U/L and alanine aminotransferase 428 U/L) as well as a ferritin of 1137 μg/L.‍ The patient was started on intravenous (IV) methylprednisolone 1 g daily for 5 days and received a dose of IV immunoglobulin (Gamunex-C; Grifols, Barcelona, Spain) 80 g.‍ After initial steroid burst, he was continued on 60 mg oral prednisone alternating daily with 1 g IV methylprednisolone.‍ Omeprazole was started for gastric

protection.‍ Because of a concern for macrophage activation syndrome, twice daily cyclosporine was started on hospital day (HOD) 5.‍

His clinical condition failed to improve; despite therapy, a severe inflammatory process persisted, with elevation in ferritin to a peak of 1805 μg/L.‍ Fourteen days into the second hospitalization, his symptoms abruptly worsened with tachycardia, hypertension, hypothermia, peripheral mottling, increasing weakness, and the development of hematuria, leukocytosis (white blood cells 25.‍5 × 109/L), increasing CK 16 546 U/L, and elevated lactate 8.‍5 mmol/L, prompting transfer to the PICU.‍ In the PICU, he had evolving respiratory distress as well as hypertensive encephalopathy without clear etiology.‍ Renal ultrasound with Doppler revealed normal renal vessels, the results of a head computed tomography were negative, and an echocardiogram revealed no cardiac cause of hypertension.‍ Sepsis workup was initiated, but serial blood culture results were negative.‍

Cyclosporine therapy was stopped but steroids and IV immunoglobulin were continued.‍ An active myopathy persisted, and CK peaked at 31 600 U/L.‍ He developed oligoanuric renal failure despite fluid resuscitation, IV furosemide, and metolazone.‍ A hemodialysis catheter was placed on PICU day 7 (HOD 21) and continuous renal replacement therapy by venovenous hemodialysis was begun.‍ On PICU day 9 (HOD 23), he developed sudden respiratory and cardiac arrest with wide complex bradycardic pulseless electrical activity requiring chest compression and ventilation for 5 minutes and 1 dose of epinephrine before return of spontaneous circulation.‍ Endotracheal intubation was unsuccessful because of a first occurrence of severe trismus, despite the use of 60 mg rocuronium (Fig 1).‍ He was fiberoptically

intubated through the right naris.‍ Trismus persisted despite the use of dantrolene, necessitating tracheostomy.‍

At this point, concern for SSRI-induced rhabdomyolysis arose and sertraline was discontinued, 4.‍5 months after initiation.‍ His course improved dramatically and by 2 weeks after cessation of sertraline, and without other medical intervention, CK had decreased to normal (Fig 2) and trismus improved.‍ The renal failure resolved, and his last dialysis was on PICU day 21 (HOD 35).‍ Decannulation occurred on PICU day 36 (HOD 50) and he was transferred to inpatient rehabilitation the next day.‍

FINAL DIAGNOSIS

Dermatomyositis with concomitant sertraline-induced rhabdomyolysis, renal failure, trismus, and cardiac arrest.‍

DISCUSSION

Rhabdomyolysis is a rare complication of SSRI therapy in adults and has been reported, independently of SS, 6 times in the setting of sertraline use.‍9 –13 However, to our knowledge, it has not yet been recorded as a direct consequence of sertraline use in children.‍ The adult cases involved confounding variables and an exact description or relationship for sertraline-induced myocyte injury and rhabdomyolysis

HOLMBERG et al2

FIGURE 1Maximum opening after return of spontaneous circulation (16 mm).

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has not been clearly elucidated.‍ On the basis of our review of the literature, we put forth mechanisms that likely affected our patient’s clinical course.‍

SSRIs are central nervous system agents but can act directly on peripheral organs through various serotonin receptors, including the 5-HT2A receptor, which is localized to skeletal muscle.‍11, 14, 15 The 5-HT2A receptor is coupled to a G-protein that, when activated by serotonin or other agonist, triggers the release of calcium from endoplasmic stores within the cell.‍16 Pathologic increases in intracellular Ca2+ cause cell death and muscle breakdown, similar to the pathophysiology in malignant hyperthermia.‍17 In vivo studies reveal that agonists of the 5-HT2A receptor induce muscle rigidity, increase lactate, and decrease pH, and in vitro induces skeletal muscle contraction.‍18 Potent 5-HT2A receptor antagonists can prevent and even reverse these effects, 14, 19 underscoring a clear link between peripheral serotonin receptor activation and myocyte injury.‍ These findings reveal that increased plasma levels of serotonin can act directly on skeletal muscle, elevating

intracellular Ca2+ and triggering cell injury and death.‍

In lieu of this information, it is important to consider the effective drug levels in our patient and the possible effects on skeletal muscle.‍ Gareri et al12 and Richards et al20 both report putative relationships between elevated drug levels of sertraline and rhabdomyolysis.‍ In addition, muscle breakdown has been seen in children who overdose with SSRIs, 21 implicating dose-dependent myocyte toxicity.‍ For several reasons, we believe that our patient had unanticipated elevations in his serum sertraline levels and propose that this was responsible for much of his disease process.‍

Genetic alterations in cytochrome P enzyme activity and phenotypic differences in the metabolism of sertraline have both been proposed as causes of increased serum sertraline concentrations.‍12, 20 Our patient was found to be an intermediate metabolizer at CYP2C19 (Genesight; Assurex Health, Mason, OH), the primary enzyme responsible for the breakdown of sertraline.‍22, 23 Patients who have loss-of-function changes at 1 or both of the CYP2C19 alleles have increased serum concentrations of sertraline, 24, 25

predisposing them to toxicity.‍ In fact, in patients who are known to be poor metabolizers, a reduction in sertraline dose of up to 50% is recommended.‍26

In addition to decreased CYP2C19 activity, our patient was found to be homozygous for the short promoter polymorphism of the serotonin transport gene SLC6A4 (Assurex Health).‍ This genotype results in decreased expression of the serotonin transporter (5HTT) that regulates serotonin uptake into the presynaptic neuron.‍ The short promoter leads to increased serotonin in extrasynaptic sites and was shown in a meta-analysis to result in greater risk for medication side effects.‍27, 28

The cardiac arrest and trismus experienced by our patient are likely the result of the interplay between the patient’s underlying medical condition (dermatomyositis) and the drug induced rhabdomyolysis and renal failure.‍ Trismus has been reported as an adverse effect of SSRI therapy in an adult taking fluoxetine and was thought be a result of the interplay between the serotonergic and dopaminergic pathways within the basal ganglia.‍29 It has also been associated in an adult

PEDIATRICS Volume 142, number 4, October 2018 3

FIGURE 2Trend in CK levels (U/L) over time and in relation to sertraline therapy. It should be noted that after sertraline wean was started, the CK level dropped dramatically and returned to normal only after sertraline was completely discontinued. CVVH, continuous venovenous hemodialysis.

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patient suffering from SS secondary to moclobemide-clomipramine overdose30 as well as in an individual with SS from cocaine use while taking escitalopram.‍31

The clinical course of our patient reveals the pharmacologic and physiologic complexity associated with SSRIs and identifies an otherwise unknown complication of sertraline use in a child.‍ The strength of association of this particular adverse drug reaction is supported by causality tools such as the Hill32 criteria and the Naranjo et al33 probability.‍ The temporal relation, plausible pathophysiologic mechanism, rarity of rhabdomyolysis in children, and clear dose-response enforces this fact and necessitates that prescribers be cognizant of it, particularly in children with underlying myopathies or inflammatory muscle disease.‍ When discussing side effects of SSRI therapy, providers should consider including a description of possible muscle toxicity as well as the signs and symptoms that would be suggestive of such an adverse effect.‍

In addition, genetic differences are increasingly found to play an important role in both medication efficacy and side effects.‍ Clinicians need to be aware of the importance of pharmacogenetic variations in drug transport and metabolism.‍ Specifically, given the high prevalence of SSRI use, further research is needed for a better understanding of the complex genetic and pharmaco-pathophysiologic relationship between serotonin, SSRIs, and skeletal muscle.‍

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ABBREVIATIONS

AST:  aspartate aminotransferaseCK:  creatine kinaseED:  emergency departmentHOD:  hospital dayIV:  intravenousSS:  serotonin syndromeSSRI:  selective serotonin

reuptake inhibitor

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DOI: 10.1542/peds.2018-0804 originally published online September 7, 2018; 2018;142;Pediatrics 

Peter J. Holmberg, Grace Arteaga, Brenda M. Schiltz and James HommeSertraline-Induced Rhabdomyolysis, Trismus, and Cardiac Arrest in a Child

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DOI: 10.1542/peds.2018-0804 originally published online September 7, 2018; 2018;142;Pediatrics 

Peter J. Holmberg, Grace Arteaga, Brenda M. Schiltz and James HommeSertraline-Induced Rhabdomyolysis, Trismus, and Cardiac Arrest in a Child

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