Two case reports of extended- release guanfacine overdose in children

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Received: 17 April 2022    Revised: 21 October 2022    Accepted: 21 November 2022 DOI: 10.1111/ped.15424

CLINICAL NOTE

Two case reports of extended-­release guanfacine overdose in children Asuka Shimozato | Kei Ohashi  | Shinji Saitoh Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan Correspondence Kei Ohashi, Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-­Cho, Mizuho-­Ku, Nagoya 467-­8601, Japan. Email: [email protected] Keywords: attention-­deficit hyperactivity disorder, autism spectrum disorder, drug overdose, guanfacine, hypotension

Guanfacine (GXR) is a central, alpha-­2 agonist that can cause hypotension and bradycardia. Extended-­ release GXR is commonly used to treat patients with attention-­ deficit hyperactivity disorder (ADHD) in Japan. It has a half-­life of 28 h and the time to achieve a maximum concentration is 5–­8 h. We present two cases of extended-­ release GXR overdose. Case 1 was 5-­year-­old male diagnosed with ADHD and autism spectrum disorder (ASD). His full-­scale intelligence quotient (FSIQ; Wechsler Intelligence Scale for Children, 4th Edition [WISC-­IV]) was 80 at 9 years 1 month of age. His peak score and current score at 5 years of age on the Parent-­interview ASD Rating Scale -­Text Revision (PARS-­TR) were 14 and 10, respectively. He had been treated with atomoxetine and methylphenidate but these were discontinued because of decreasing appetite and difficulty with taking the drugs. Therefore, he started taking 1 mg per day of extended-­release GXR at 9 years 5 months of age, which was successful. His mother was divorced and raising the child on her own which made it difficult for her to check his daily medications. She, therefore, prepared a week's worth of medications in advance in a special box to keep track of them. At 10 years of age, the boy forgot to take his medication for six days and his mother reminded him to take it promptly. The patient misunderstood the instruction and took 6 days' worth of GXR that evening. Although he developed no symptoms that night, he was hospitalized the next morning because of drowsiness. His blood pressure (BP) and heart rate (HR) were 74/33 mmHg and 55 beats/min, respectively. His electrocardiogram (EEG) demonstrated sinus bradycardia with normal QTc at 410. Intravenous fluids were sufficient to gradually improve his hypotension and bradycardia. Two days later, his BP and HR were 101/61 mmHg and 61 beats/min, respectively and he was discharged from the hospital. Pediatr Int. 2023;65:e15424. https://doi.org/10.1111/ped.15424

Case 2 was a 15-­year-­old boy diagnosed with ADHD and oppositional defiant disorder (ODD). Although he had exhibited ADHD traits since childhood, including forgetfulness and difficulty concentrating in class, he had never sought medical attention, therefore, he was not diagnosed with a neurodevelopmental disorder until he presented with a complaint of inattention at age 15. His WISC-­IV profile at 15 years of age, with discrepancy in the sub-­items, was as follows: FSIQ 101, Verbal Comprehension Index 93, Perceptual Reasoning Index 127, Working Memory Index 97, and Processing Speed Index 83. His peak score and current score on the adolescence of PARS-­TR were 5 and 12, respectively. On the Conners 3 rating scale, his ADHD inattention score, DSM-­5 scores for impulsivity of ADHD, ODD, and conduct disorder were 74, 53, over 90, and 80, respectively. He started to take 2  mg of extended-­release GXR at 15 years 10 months of age, and his inattentiveness and emotional stability improved. At 16 years of age, his mother reprimanded him as he had become addicted to the Internet because of forgetting to take his medication. Thus, he impulsively ingested 12 mg of extended-­release GXR that day, 6 mg the next day, and 3 mg 2 days later as an act of rebellion against his mother. Three days after the first overdose, his mother called the hospital because the boy exhibited severe drowsiness and difficulty standing up. For family reasons, he was not hospitalized but was closely monitored by phone. His BP and HR were 89/49 mmHg and 55 beats/min, respectively. Four days later, his BP normalized at 120/80 mmHg. He was not administrated an EEG. Extended-­release GXR is commonly prescribed to inattentive and impulsive patients with ADHD, in whom medication intake errors are common. The two present cases and three previously related cases are summarized in Table  1.1–­3 All patients exhibited hypotension

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Impulsivity and anger Misunderstanding of words Cause of overdose

ODD ASD

Abbreviations: ADHD, attention-­deficit hyperactivity disorder; ASD, autism spectrum disorder; BP, blood pressure; GXR, guanfacine; HR, heart rate; NA, not available; ODD, oppositional defiant disorder; QTc, corrected QT interval; WNL, within normal limits.

Accidental ingestion Misadministration by parents

Desire for stronger effects

ASD Tourette syndrome

376

ADHD ADHD

416 WNL

ADHD

NA

ADHD

415

ADHD

QTc

Diagnoses

NA

45 36 3

45

24

96

12 Time to drop BP (h)

Time to recover BP (h)

48

85

45

114/60 70/26 80/40

40

89/49

55

74/33 Minimum BP (mmHg)

Minimum HR (bpm)

55

45

80

2 4 3 2

6 12

1

6

Prescribed dose of extended-­release GXR (mg)

Ingested dose of extended-­release GXR (mg)

20

Male

17 12

Male Male Sex

8

Male

16

Male

10 Age (years)

Case 53 Case 42 Case 31 Case 2 Case 1

T A B L E 1   Comparison of presently and previously reported cases of extended-­release GXR overdose

SHIMOZATO et al.

or bradycardia. One patient suffered from an overdose episode and developed symptoms lasting for several days. The effect of extended-­release GXR is prolonged, and GXR overdose results in symptomatic hypotension and bradycardia. Thus, even patients with less intake of GXR can develop symptoms, whereas GXR overdose may cause delayed symptoms in others. Fortunately, QTc prolongation was not observed in these cases, but GXR would be at the risk of severe arrythmia. Thus, it is important to educate patients and caregivers regarding the side effects of this drug. In a previous report, an overdose of extended-­released GXR resulted in a pulmonary hemorrhage and the patient required ventilator management and vasopressors.3 An overdose of extended-­release GXR causes significant impact on patients. In our two cases, the overdose was not triggered by suicidal ideation or self-­injurious behavior. Moreover, there are no known reports of a higher risk of overdose in ADHD. Besides patient characteristics, such as ASD and ODD, the miscommunication between the patients and their parents might have contributed to the overdose of extended-­release GXR in the two cases presented here. In the first case, the mother's nursing care was inadequate. In the second case, miscommunication coupled with ODD symptoms caused the patient to misunderstand the drug intake instructions. This type of error is common among impulsive patients with ASD and ADHD. In the three previously reported cases, the overdoses were related to suicide attempts. A study showed that depression, anxiety, and eating disorders were significantly associated with overdosing, but ADHD was not.4 Patients with neurodevelopmental disorders are likely to experience overdoses due to their condition and comorbidities, including depression and risk-­seeking behavior.4 Furthermore, an increase of illicit overdosing of ADHD medications has been was reported.5 Thus, ADHD medications should be prescribed more carefully. Finally, as patients with neurodevelopmental disorders may have a high potential for overdose, health care providers prescribing extended-­release GXR should provide adequate information about medications tailored to their specific characteristics. The patients’ parents should also be vigilant in their medication management. AU T HOR C ON T R I BU T ION S Asuka Shimozato drafted the initial manuscript. Kei Ohashi contributed to clinical management. Shinji Saitoh reviewed and revised the manuscript. All authors read and approved the final manuscript. I N F OR M E D C ON S E N T Informed consent for the studies and for the reporting of these cases was obtained from the patients’ parents. C ON F L IC T OF I N T E R E ST The authors declare no conflicts of interest.

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ORC I D Kei Ohashi  https://orcid.org/0000-0001-6910-3591 Shinji Saitoh  https://orcid.org/0000-0001-6911-3351 R EF ER ENCE S 1. Walton J, Byrum M, Shumaker A, Coury DL. Prolonged bradycardia and hypotension following guanfacine extended release overdose. J Child Adolesc Psychopharmacol. 2014;24:463–­5. 2. Fein DM, Hafeez ZF, Cavagnaro C. An overdose of extended-­ release guanfacine. Pediatr Emerg Care. 2013;29:929–­31. 3. Bridwell RE, Larson NP, Rosenthal JB, Wray J, Baker Z, Cibrario A, et al. Guanfacine toxic ingestion with subsequent cardiogenic pulmonary edema. Am J Emerg Med. 2021;39:256.e5–­8. 4. Yule AM, Carrellas NW, Fitzgerald M, McKowen JW, Nargiso JE, Bergman BG, et al. Risk factors for overdose in

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treatment-­seeking youth with substance use disorders. J Clin Psychiatry. 2018;79:7m11678. 5. Cairns R, Daniels B, Wood DA, Brett J. ADHD medication overdose and misuse: the NSW Poisons Information Centre experience, 2004-­2014. Med J Aust. 2016;204:154.

How to cite this article: Shimozato A, Ohashi K, Saitoh S. Two case reports of extended-­release guanfacine overdose in children. Pediatr Int. 2023;65:e15424. https://doi.org/10.1111/ped.15424

1442200x, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ped.15424 by Northern Kentucky University, Wiley Online Library on [02/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

TWO CASES OF GUANFACINE OVERDOSE