Paradoxical Hypertensive Urgency in a Child After Initiation of Guanfacine

Chief Complaint and Presenting Problem

J. was an 8-year-old, right-handed, second-grade student in a standard elementary school, with an individualized education plan, who carries a diagnosis of attention-deficit/hyperactivity disorder (ADHD), combined type, and oppositional defiant disorder (ODD). J. was referred for evaluation from school, at age 5 years, for disruptive and oppositional behavior, hyperactivity, and impulsivity.

History of Present Illness

J.'s parents initially became concerned about him within the first few years of life. As early as 2½ years of age, his parents noted that J. was exhibiting difficulty in ways that his peers were not. He had significant difficulty remaining still and seated, even when engaged in activities he found enjoyable. He was hyperenergetic “from morning to night” and as such, he required constant attention. Parents reported that he could not be brought on errands or out shopping as he would run away, wander off, touch everything in the store, and on multiple occasions was disruptive to employees by knocking things off shelves or displays. At home, he jumped from furniture, and as a result, frequently sustained cuts and scratches from impulsive activity. He was also noted to have poor frustration tolerance and easily cried or became angry when denied things he wanted. From this young age, J. was reported to have significant difficulty transitioning between tasks or locations and had tantrums that were difficult to control or calm, requiring significant redirection. In these moments, he became aggressive toward his parents, hitting and scratching, and was destructive to property on occasion, pushing pictures off shelves and trying to knock over furniture. These behaviors persisted into kindergarten, where he was also noted to demonstrate oppositional and disrespectful behavior toward teachers and school staff. His behavior worsened over the course of kindergarten as J. was increasingly more isolated by his classmates and was in frequent trouble with teachers. He was at times provocative as well, using foul language and inappropriate touch. Teachers also noted difficulty with attention to tasks. J.'s teachers assisted mother with referral to a child mental health clinic. An individualized educational plan (IEP) was put into effect for these complaints, and J. was placed in an integrated co-teaching (ICT) classroom setting.

Upon initial clinical assessment, at age 5, J. was found to have ADHD and ODD and was referred for treatment. J. was engaged in weekly individual therapy to develop coping skills and interpersonal strengths. Despite therapy, his symptoms persisted and so medical treatment was indicated; at the age of 6 years, he was started on mixed amphetamine salts (MAS) to target his hyperactivity, impulsivity, and attentional problems. J. started MAS 5 mg extended release in the morning and remained at this dose for several months. Over the course of time, benefits were noted. J. became somewhat less irritable, was notably more able to focus on schoolwork, and could remain seated for longer periods of time. There were also minimal reports of side effects; the only complaint was mild gastrointestinal upset for an hour on the first two mornings of use, which subsequently remitted. Parents and teachers noted, however, that J. still had significant residual symptoms, and after several months, his dose of MAS extended release was increased to 10 mg every morning.

This dose increase initially seemed to be helpful both at home and at school. J. showed significantly increased ability to maintain attention and a notable decrease in hyperactivity. However, over several weeks after this dose increase, mother became concerned about J.'s decreased appetite. J. was a “picky” eater to start and was small and thin for his age, and now was showing further decrease in appetite on the increased dose. He was refusing lunch entirely on most days and had poor dinner time appetite as well. Additionally, J.'s moodiness and behavioral difficulties persisted and he continued to demonstrate oppositional behavior. Thus, parents agreed to a switch of medication. J. was titrated off the stimulant over a week and guanfacine was initiated. Guanfacine was considered for its lack of significant effect on appetite, as well as its known benefit for irritability and opposition in children with ADHD. J. was started on 0.5 mg guanfacine daily, with intention to titrate over several weeks to an effective dose.

Within 2 days of initiation, J. developed adverse effects to the guanfacine. Most significantly, J. reported evening headaches that persisted until bedtime. He reported this on the very first day of guanfacine use as well as the next 2 days. On day 4, J.'s headache was significant and he was flushed, sweaty, and lethargic, so mother brought him to an urgent care facility for evaluation. On screening, J. was found to have a blood pressure (BP) of 180/110 in the seated position. His urgent care physician speculated, due to timing and recent history, that guanfacine was the likely cause of J.'s symptoms.

J. was observed and monitored without intervention and medically cleared to return to home that same night. Follow-up with his pediatrician the next morning demonstrated BP that was within normal limits. Treatment with guanfacine was immediately discontinued, and there have been no significant headaches or elevated BP readings since that time.

Psychiatric History

J. had no psychiatric history other than described above. Psychoeducational testing at the age of 6 years documented an average intelligence quotient (IQ) and otherwise supported his clinical diagnosis. J. had no history of emergency department (ED) visits, inpatient admissions, substance abuse, legal interventions, or self-harm.

Developmental History

The pregnancy was reported to be planned but difficult due to gestational diabetes. J. was delivered via scheduled Caesarean section at 38 weeks for macrosomia. Birth weight was 9 pounds, 10 ounces.

J.'s developmental progression for language and motor skills was within normal limits.

Educational History

J. attended a regular education class for kindergarten but was placed in an ICT classroom for first grade. He had thrived in this setting, met all his IEP requirements, and was returned to a standard classroom setting for second grade. He also received some educational modifications such as extra time for tests and in-school behavioral therapies.

Social History

J. lived with his biological parents: mother was age 47 and father age 53. He had a 21-year-old brother who intermittently lived with the family when in the state for extended periods of time. J. had no close relatives in his age range and had few neighborhood peers before starting school. In school, he was reported to be open and friendly, but had difficulty socializing due to his hyperactivity and impulsivity. He had been ostracized to an extent, but there was no reported history of bullying.

Family History

J. had a 21-year-old brother with ADHD-combined presentation, who had similar but “less significant” symptoms when he was J.'s age. Mother had generalized anxiety disorder. Extended family history was significant for bipolar disorder and depression.

Medical History

J. had no serious medical problems, hospitalizations, or surgery. He had no history of any major childhood illnesses and had received all his appropriate vaccinations. He had no significant allergies to food or drugs.

Mental Status Examination

Mental status examination revealed a cooperative child, dressed appropriately, with no dysmorphic features, whose response to questions was well related and elaborate. J. was very active but could be relaxed and still when urged. No tics or other abnormal movements were apparent. Eye contact was appropriate and comfortable. His speech was clear, with occasional tone of a younger child, but this was corrected when pointed out. Language was fluent. J. was oriented to time, day, place, and situation. J. was able to abstract. His memory was intact. His thought process was linear and content was without abnormality. J. denied any auditory or visual hallucinations. Insight was somewhat impaired, as J. denied his role in interpersonal conflicts; judgment was age appropriate, but limited.

Brief Formulation

In summary, J. was an 8-year-old boy who met diagnostic criteria for ADHD, combined presentation, and ODD. From a biological perspective, there was a known family history of ADHD, which rendered him vulnerable to ADHD, but no other potentially contributing medical problems. From a psychosocial perspective, J. was moderately isolated, as his ADHD symptoms made it difficult for him to develop appropriate social skills and to master academic tasks and classroom behavior. Initial treatment with a long-acting amphetamine was helpful, but intolerable, in that he experienced persistent irritability and oppositionality and significant loss of appetite. A switch to low-dose guanfacine resulted in headache, malaise, and diaphoresis, and signs and symptoms of hypertensive urgency with a BP 180/110. Guanfacine was immediately discontinued, and headache and hypertension resolved.

Multiaxial Diagnoses

Discussion

This case represents an interesting and uncommon response to guanfacine in a child. It is particularly surprising to see development of hypertension, as guanfacine is an α2-adrenoreceptor agonist, and indicated for treatment of essential hypertension as well as ADHD (Zamboulis and Ried 1980). Activation of postsynaptic adrenoreceptors in the medulla causes reduced sympathetic outflow. By this primary mechanism, one would expect a hypotensive response, decreased cardiac output, and decrease in BP to be the more likely adverse reaction, and this is much more extensively demonstrated in the literature.

This unusual adverse effect has been described in a recent review on presentation and management of overdose on several ADHD medications (Spiller et al. 2013). Interestingly, documentation of hypertensive adverse effects does exist, but these clinical descriptions have typically been in the context of overdose. One article cites a case of a 12-year-old boy who overdosed on 12 mg of extended-release formulation guanfacine (Fein et al. 2013). Another clinical description is of a 16-year-old girl who acutely ingested 25 mg of immediate-release guanfacine (Minns et al. 2010). Both these cases described similar responses of lethargy and somnolence, diaphoresis, and initial hypertension with subsequent orthostatic hypotension. These responses are plausible, as primary and adverse effects of guanfacine have been demonstrated to be dose dependent (Frisk-Holmberg and Wibell 1986). At lower recommended doses and intervals, guanfacine stimulates the previously mentioned adrenoreceptors causing the anticipated antihypertensive effect. However, at larger doses, this effect has been found to decline, and guanfacine-induced hypertension has been described. This is due to stimulation of postjunctional peripheral adrenoreceptors that induce a pressor-like response (Frisk-Holmberg and Wibell 1986). Due to lower receptor affinity, these are only activated when recommended dosing is exceeded, as in the reports of overdose.

One report describes a case that is clinically similar to that of J. (Tsze and Dayan 2012). The authors describe a 4-year-old boy referred to the ED 38 hours after ingestion of 1 mg extended-release guanfacine; he experienced initial hypertension followed by hypotension, as well as significant somnolence and bradycardia. In this case, peak reported BP was 126/81. This case report also described the use of naloxone for treatment.

Taken together, then, aspects of J.'s interesting presentation have been described in the literature, but not fully explored. Here, a healthy boy within the Food and Drug Administration (FDA)-approved age limits for use of guanfacine was given a low starting dose and developed an unusual and potentially dangerous adverse effect of hypertension, only documented previously in overdose reports. Fortunately, he required only close monitoring and experienced rapid resolution of symptoms after discontinuation of the medication.

Further exploration of the causes of this phenomenon in children is warranted. Perhaps most importantly, however, bringing this to the attention of child and adolescent psychiatrists and pediatricians may be helpful in addressing potentially unexpected or paradoxical adverse effects.