Two cases of acute dexmedetomidine withdrawal syndrome following prolonged infusion in the intensive care unit

Abstract

Prolonged infusion of dexmedetomidine, an α₂-adrenoreceptor agonist anesthetic used in the intensive care unit, produces a withdrawal syndrome of sympathetic over-activity, characterized by tachycardia, hypertension and agitation, but there is no recommended standard treatment for this syndrome. We describe two patients with a clinical diagnosis of acute dexmedetomidine withdrawal and its management with oral clonidine. We utilized the principle of managing acute drug withdrawal with longer acting medications. These two cases demonstrated the benefit of using oral, longer acting clonidine to manage acute withdrawal from shorter-acting, intravenous dexmedetomidine.

Introduction

Dexmedetomidine hydrochloride (Precedex™ Primadex™) is a potent central α₂-adrenoceptor agonist that is used as an intravenous, sedative-anesthetic agent. Its chemical structure is similar to clonidine and it is a member of the imidazole chemical family, which pharmacodynamically produces decreased sympathetic tone, sedation and analgesia. ¹ Its relative selectivity ratio for α₂- versus α₁-adrenoceptor is 1620 ² and in vitro work suggested that the α₂-/α₁-adrenoceptor selectivity is eightfold greater for dexmedetomidine when compared to clonidine. ³ Dexmedetomidine was approved by the Food and Drug Administration (FDA) in 1999 for the sedation of intubated and mechanically ventilated adult patients who experience agitation in the intensive care unit (ICU) ⁴ but only for short-term (<24 h) use. Other approved indications include sedation and analgesia in nonintubated patients prior to and/or during surgical and other painful procedures. ⁴ The safety of prolonged use (>24 h) of dexmedetomidine infusions has been reported in critically ill pediatric and adult patients ^3,5 despite the current labeling approved by the FDA.

The manufacturers of dexmedetomidine (Precedex^TM) warn about the possibility of developing a withdrawal syndrome characterized by nervousness, agitation, headaches, a rise in blood pressure and elevated catecholamine concentrations on abrupt cessation after a period of prolonged administration (>24 h) ⁴ and that this clinical picture was reported in earlier clinical trials. There have been case reports of dexmedetomidine withdrawal after prolonged use in pediatric patients ^6,7 and the management of this syndrome with reinstitution of dexmedetomidine infusion and then a gradual taper. It has also been suggested that pediatric patients who receive dexmedetomidine infusions for longer than 4–5 days might benefit from a switch to an orally/transdermally equivalent dose of clonidine. ⁸ However, based on our review of the current literature, there have not been reports of dexmedetomidine withdrawal in the adult population (outside a clinical trial setting) or the use of oral clonidine in treating an apparent withdrawal syndrome.

Here, we report two cases of adult patients who, following their periods of treatment in the ICU, experienced the sudden onset of hypertension, tachycardia, agitation and anxiety after rapid discontinuation of prolonged (5–7 days) infusions of dexmedetomidine. Both the patients experienced either complete resolution or significant improvement in their symptoms and signs within 12 h of starting oral clonidine given on a fixed schedule as an alternative substituted α₂-adrenoceptor agonist.

Case reports

Case 1

A 61-year-old Caucasian female was transferred to our ICU for management of sepsis secondary to ascending cholangitis. Medical history was significant for emphysema, scleroderma, lichen sclerosis, supraventricular tachycardia and osteoporosis. Her outpatient medication use included verapamil, ipratropium, albuterol, amitriptyline and risedronate. The patient did not have a prior history of ethanol abuse, opiate or benzodiazepine use or abuse. She arrived intubated and goal-directed resuscitation was initiated. Sedation was maintained with fentanyl 100 mcg/h, midazolam 2 mg/h and propofol 75 mcg/kg/min, and a biliary sphincterotomy was undertaken.

On ICU day 3, her ventilator requirements decreased and hemodynamic stability improved. Fentanyl and midazolam infusions were changed to an ‘as-needed’ basis and dexmedetomidine was started (loading dose 1 mcg/kg, continuous infusion of 0.7 mcg/kg/h and titrated to 1.4 mcg/kg/h) in the anticipation of prompt extubation.

By ICU day 5, she was successfully extubated and placed on bilevel positive airway pressure (BiPAP) ventilation; the dexmedetomidine infusion was continued without the requirement of opiates or benzodiazepines. By ICU day 8, her dexmedetomidine infusion was decreased to 0.5 mcg/kg/h; on ICU day 9, after a total of 7 days (~168 h) of continuous infusion, dexmedetomidine was discontinued by progressive dose reduction over 8 h. She was initially afebrile, hemodynamically stable and requiring BiPAP intermittently. Her heart rate remained between 80 and 100 beats/min and blood pressure was between 120/80 and 150/100 mmHg.

Approximately 6 h (three terminal elimination half-lives) after, dexmedetomidine was discontinued, she became acutely agitated and combative. Her blood pressure and heart rate rose to 190/120 mmHg and 110–120 beats/min, respectively. Her peripheral oxygen saturation fell to <90% requiring continuous BiPAP. She was acutely managed with a 5-mg dose of intravenous metoprolol and intermittent administration of haloperidol without the resolution of agitation. With a suspicion of a possible acute withdrawal syndrome from dexmedetomidine and the absence of other identifiable causes of agitation and hypertension, the Clinical Pharmacology Service was consulted. On the recommendations by the Clinical Pharmacology Service, she was started on an oral clonidine taper starting with 0.6 mg on the day 2 (0.2 mg by mouth every 8 h), followed by a 0.1-mg/d reduction over 6 days. It was also recommended to avoid alpha and dopaminergic blockade with haloperidol and adrenergic antagonists. Benzodiazepines were not prescribed.

Within 12 h of receiving her first dose of oral clonidine (0.2 mg), the patient was noted to be markedly less agitated, somnolent but verbally interactive. Her blood pressure ranged from 120/60 to 160/90 mmHg with a heart rate of 80–110 beats/min. By day 2 of the clonidine taper, her blood pressure and heart rate ranged from 110/40 to 130/60 mmHg and 70–90 beats/min, respectively. Her mental status had significantly improved and she became more interactive; she was later transferred to the medicine ward.

Case 2

A 46-year-old woman was admitted to the Hematology/Oncology service for induction chemotherapy to treat a cervical granulocytic sarcoma. Her past medical history revealed no evidence of ethanol, opiate or benzodiazepine use or abuse. Five days following her first cycle of cisplatin, paclitaxel and ifosfamide chemotherapy, she developed a neutropenic fever, nausea, vomiting, abdominal pain and subsequent sepsis requiring ICU management. She was started on broad spectrum antibiotics and eventually required intubation. Sedation was achieved with fentanyl 100 mcg/h and midazolam 2 mg/h. Imaging studies revealed an infected or inflamed cecum that had subsequently perforated resulting in sepsis. She underwent surgical resection of the cecum on ICU day 2. She remained intubated over the next 10 days of her ICU stay.

Midazolam was weaned off on ICU day 3 and fentanyl discontinued on ICU day 11. On ICU day 11, she was started on dexmedetomidine 0.2–0.7 mcg/kg/h, titrated up to 1.4 mcg/kg/h to provide sedation in anticipation of extubation. On ICU day 15, she was successfully extubated, and on day 16, she underwent weaning off of dexmedetomidine over 6 h. She was transferred to the hematology/oncology ward that day but remained tachycardic (120–150 beats/min) with BP ranging between 120/80 to 150/100. She was intermittently febrile (without positive cultures) and experienced occasional episodes of agitation and diaphoresis. The persistence of these symptoms and signs for 5 days resulted in a Clinical Pharmacology Service consultation. Further examination revealed markedly dilated pupils, and her clinical presentation was diagnosed as a ‘hyper-sympathetic syndrome’. A dexmedetomidine withdrawal syndrome was suspected based on the knowledge of its sympatholytic effects and the extended (~144 h) treatment she had received. She was started on clonidine 0.1 mg orally every 8 h with close monitoring of her blood pressure. By the next day, she was noted to be substantially less anxious and had mild improvement in heart rate (110–125 beats/min) and the blood pressure had reduced to 115/75 mmHg.

Her clonidine was tapered to 0.1 mg twice daily on day 2 of therapy and to 0.1 mg by mouth once daily before it was discontinued after 4 days of treatment. The condition of the patient remained stable and she was discharged 24 h after completion of the oral clonidine taper.

Discussion

Selective α₂-adrenoceptor agonists such as dexmedetomidine are able to induce analgesia, sedation and anxiolysis ¹ in clinical situations without hypertension and other adverse effects associated with α₁-adrenoceptor and opioid receptor stimulation. With a distribution half-life of approximately 6 min and terminal half-life of 2 h, ⁴ dexmedetomidine is increasingly being used in the ICU and operating rooms for its ‘rapid-on and rapid-off’ pharmacodynamics.

Pharmacokinetic properties of clonidine, such as a variable and long elimination half-life (12–16 h in patients with normal, and up to 41 h in patients with varying degrees of renal dysfunction), make it unsuitable for use as an anesthetic in the critical and surgical care setting. It has been well established that abrupt termination of clonidine after prolonged use as an antihypertensive results in a withdrawal syndrome that includes rapid blood pressure elevation, tachycardia, agitation and diaphoresis. These signs and symptoms can develop after missing even a single dose of clonidine therapy. ⁹ Considering the common adrenoreceptor-binding targets of clonidine and dexmedetomidine, it is logical to hypothesize that similar signs and symptoms would develop after a rapid weaning off of dexmedetomidine, especially since it has a shortened half-life. Lending further scientific credence to this hypothesis are the few case reports in the pediatric literature, which described a clonidine-like withdrawal syndrome after abrupt termination of dexmedetomidine for sedation. One of the pediatric cases reported tachycardia, hypertension and emesis within an hour of discontinuing dexmedetomidine following 6 days of therapy. This syndrome was unresponsive to benzodiazepine administration but abated within an hour of reinitiating dexmedetomidine therapy. ⁷ A similar withdrawal syndrome occurred in an 8-week-old infant 2 h after completing a rapid 6-hour weaning off of dexmedetomidine, following 84 h of continuous infusion. This infant also developed a generalized seizure occurring 7 h after stopping dexmedetomidine. ⁵ Neurological withdrawal symptoms associated with dexmedetomidine discontinuation have also been reported in a 2-year-old child; these were managed with opiates and benzodiazepines. ¹⁰

In our two cases, the temporal relation of the onset of agitation, confusion, tachycardia and hypertension (along with mydriasis in the second patient) with the discontinuation of dexmedetomidine, although not as striking as that reported by Weber et al., ⁷ was still sufficient to consider dexmedetomidine withdrawal as the most likely diagnosis. Utilizing the knowledge of the pharmacodynamic target of dexmedetomidine, oral clonidine was successfully used to treat the patients’ presumed withdrawal symptoms and signs. Clonidine offered an inexpensive, orally administered and less sedating alternative to the reinstitution of dexmedetomidine therapy in our patients. When compared with dexmedetomidine, oral clonidine has a longer elimination half-life of 12–16 h, which facilitates slower dose tapering, less frequent dosing and use outside the ICU. Antihypertensive effects are observed within 30–60 min of administration and peak within 2–4 h. ¹¹ Finally, we are not sure of the optimal dose or the duration of oral clonidine replacement therapy, but total daily oral doses of 0.3–0.6 mg tapered down over 4–7 days were therapeutically effective in the two patients we report here.