Neurologic Withdrawal Symptoms Following Abrupt Discontinuation of a Prolonged Dexmedetomidine Infusion in a Child

INTRODUCTION

Sedation and analgesia are important considerations for children admitted to the pediatric intensive care unit (PICU). There are numerous agents available for sedation and analgesia in this patient population including opioids, benzodiazepines, ketamine, and dexmedetomidine. Dexmedetomidine is an α₂-adrenergic agonist which possesses sedative, analgesic, and anxiolytic properties. The affinity of dexmedetomidine for the α₂ receptor is approximately 6–8 times that of clonidine.¹ Its highly-selective properties have shown promise as a means to decrease opioid requirements for adequate sedation and to facilitate extubation because of its minimal effect on respiratory depression. It is approved by the Food and Drug Administration for short-term sedation in intubated adult patients requiring mechanical ventilation and for non-intubated adults undergoing procedural sedation/surgery.²

Limited case reports and studies have evaluated dexmedetomidine use in the pediatric patient population.^3–11 These reports have described similar adverse effects (e.g., hypotension, hypertension, and bradycardia) to those reported in adults. Although use of dexmedetomidine is recommended only for a short duration (<24 hours) for sedation in patients requiring mechanical ventilation, a few reports describe its efficacy and safety following prolonged use.^5–6,¹¹ We report a 2-year-old male who received a dexmedetomidine infusion for 11 days (263 hours) and developed possible withdrawal symptoms following abrupt discontinuation of therapy.

CASE REPORT

A 2-year-old (12 kg) male with a history of pulmonary atresia, ventricular septal defect (VSD), and Tetrology of Fallot (TOF) was admitted for surgical repair of his TOF and VSD patch closure. Following the surgical procedure, the patient remained intubated. Continuous infusions of fentanyl (3 mcg/kg/hr) and midazolam (0.05 mg/kg/hr) were initiated and quickly titrated to 5 mcg/kg/hr and 0.1 mg/kg/hr, respectively. The patient also required dopamine and milrinone postoperatively for treatment of low cardiac output syndrome. Both cardiac and ventilator support were weaned and discontinued on hospital day 3.

The following day, the patient required reintubation due to increased work of breathing and hypoxia. Chest tubes were placed to manage bilateral pleural effusions, one of which was thought to be chylous in nature. Continuous infusions of fentanyl (2 mcg/kg/hr) and midazolam (0.05 mg/kg/hr) were again initiated for sedation and analgesia. Dexmedetomidine (Precedex; Hospira, Lake Forest, IL) was initiated on day 4 in an effort to decrease opioid requirements and provide additional sedation. The patient was given a 9 mcg (0.75 mcg/kg) loading dose followed by a continuous infusion of 0.7 mcg/kg/hr. Despite the addition of dexmedetomidine, the patient required an upward titration of both fentanyl (5 mcg/kg/hr) and midazolam (0.2 mg/kg/hr) in order to maintain adequate sedation. Due to increased ventilatory peak pressures on hospital day 5, a vecuronium continuous infusion (0.1 mg/kg/hr) was initiated and the patient was paralyzed for a total of four days.

Enteral methadone (0.4 mg/kg q 6 hours) and diazepam (0.2 mg/kg q 6 hours) were initiated on hospital day 13 for prevention of opioid and benzodiazepine withdrawal following weaning of the continuous infusions and discontinuation of fentanyl and midazolam (Figure). On hospital day 14, fentanyl and midazolam were discontinued after 11 total days of therapy. The following day, the dexmedetomidine (0.7 mcg/kg/min) infusion was abruptly discontinued. At this time, the child had been treated with dexmedetomidine for a total of 263 hours and had been given a cumulative dose of 193.7 mcg/kg. The child remained normotensive throughout the duration of the infusion. There was no evidence of rebound hypertension at discontinuation of dexmedetomidine as evidenced by a blood pressure of 107/48 at the end of the infusion and a blood pressure 12 hours later of 106/39. The patient was extubated on hospital day 15.

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On hospital day 16, approximately five hours following discontinuation of dexmedetomidine, the PICU attending noted that the patient began demonstrating neurological symptoms such as episodes of blank staring, agitation, and decreased verbal communication. Although the patient's pupils remained equal and reactive throughout the infusions of fentanyl, midazolam, and dexmedetomidine, they were now asymmetric. Opioid and benzodiazepine withdrawal were not suspected since the patient continued on his initial dose of both methadone and diazepam. He also received intermittent doses of lorazepam and morphine, which produced a modest reduction in agitation. There were no significant changes in his staring episodes, pupil changes, and verbal communication. On hospital day 18, his parents noted that his verbal communication returned to baseline and that the staring episodes had resolved. Additionally, at this time, the pupils were again equal in reactivity upon examination. Because the patient was noted to have significant improvement, no further neurological workup was obtained.

On hospital day 24, he was transferred to the floor. Methadone and diazepam were gradually tapered by approximately 10% daily, and were discontinued on hospital days 33 and 34, respectively. He had full resolution of neurologic sequelae and was discharged on hospital day 38 in stable condition.

DISCUSSION

Dexmedetomidine is approved by the Food and Drug Administration for non-intubated patients undergoing procedural sedation/surgery and short-term (< 24 hours) in adults who are intubated and receiving mechanical ventilation in the intensive care setting.² Although not labeled for use in children, a number of case reports,^4–5 case series,³,^6–8 and studies^9–11 describe the use of dexmedetomidine as an adjunct sedative agent to decrease opioid requirements, facilitate extubation, and treat opioid withdrawal. Doses used in these previous reports range from 0.1–2.5 mcg/kg/hr. Diaz et.al reported that pharmacokinetic parameters in children >4 months of age are not significantly different from that of adults and suggested that children can be dosed according to the adult weight based recommendations of 0.2–0.7 mcg/kg/hr.³

The most commonly reported adverse effects of dexmedetomidine include bradycardia, hypotension, and hypertension, all of which appear to be dose related. A recent retrospective case series evaluated adverse effects associated with 74 infusions of dexmedetomidine in children.⁶ The authors reported an incidence rates of 9% for hypotension, 8% for hypertension, and 3% for bradycardia. These cardiovascular events resolved without treatment or responded to a decrease in the rate of infusion.⁶ A prospective observational study reported no statistically significant differences between baseline and ending mean arterial blood pressures or heart rates in 17 children receiving dexmedetomidine.¹¹ It is important to note that no patient received a loading dose in this study. Other studies have also reported no statistically significant increase in adverse effects or rebound hypertension with prolonged infusions; ^5–6 however, these reports failed to describe if dexmedetomidine was gradually tapered or if the infusion was abruptly discontinued.

The duration of dexmedetomidine use reported in pediatric patients range from 1–451 hours.^3–11 The patient described in this case received a continuous infusion of dexmedetomidine for a total of 263 hours. Our patient remained hemodynamically stable throughout the infusion and following completion of the infusion, but did experience adverse effects including blank staring episodes, asymmetric pupils, agitation, and decreased verbal communication approximately five hours following the abrupt discontinuation of dexmedetomidine. At this time, the patient was receiving methadone and diazepam for prevention of opioid and benzodiazepine withdrawal. He received intermittent doses of narcotics and benzodiazepines, but only had improvement in the level of his agitation. For this reason, the intensivist believed that these symptoms were related to dexmedetomidine withdrawal.

The onset of symptoms appeared to coincide with dexmedetomidine withdrawal, given that dexmedetomidine has a terminal half life of 2 hours.² In a prospective, open-label study involving adult patients receiving prolonged infusions (> 24 hours) of dexmedetomidine, Shehabi and colleagues¹² noted that adverse hemodynamic effects (e.g., increased heart rate and increased systolic blood pressure) occurred within 5 hours of abrupt discontinuation of dexmedetomidine. Our patient's symptoms continued to improve on hospital days 17 and 18, and he did not require any additional interventions.

The manufacturer product information states that the abrupt cessation of dexmedetomidine could potentially result in withdrawal symptoms similar to those seen with clonidine (i.e., agitation, irritability, rebound hypertension).² At least one case of neurological adverse events has been reported. Venn and colleagues report a case of an adult who developed dystonic movements while receiving a large dose of dexmedetomidine (1.5 mcg/kg/hr) for 24 hours.¹³ The authors attributed this adverse event to the central actions of α₂-adrenoceptor agonism. Others have suggested that clinicians could potentially avoid the development of withdrawal symptoms by using a gradual taper of dexmedetomidine in patients who received prolonged therapy (i.e., > 24 hours).¹⁴ It is unknown whether our patient's symptoms could have been avoided by gradually tapering the dexmedetomidine.

CONCLUSION

The use of dexmedetomidine in children is increasing. Although the manufacturer recommends that the medication be infused for < 24 hours, prolonged infusions are being used in the clinical setting. A limited number of published reports have noted adverse effects following the prolonged use of dexmedetomidine.^5–6,¹¹,¹²,¹⁴ Patients receiving prolonged continuous infusions of dexmedetomidine like our patient may be at risk for withdrawal symptoms following abrupt discontinuation. Clinicians should be aware of the potential for withdrawal symptoms, including rebound tachycardia and neurologic manifestations (e.g., agitation, speech abnormalities, irritability). Given that the half-life of dexmedetomidine is two hours, patients should be monitored for withdrawal symptoms for the first 12–24 hours following discontinuation. To prevent withdrawal, it may be prudent to taper dexmedetomidine in any patient who has received therapy > 24 hours. A reasonable approach is to taper dexmedetomidine by 0.1 mcg/kg/hr every 12–24 hours. Future prospective studies should be conducted to determine the incidence and severity of withdrawal symptoms associated with dexmedetomidine.