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Hypoglycemia associated with dexmedetomidine overdose in a child?
Journal of Clinical Anesthesia (2009) 21, 50–53
Case report
Hypoglycemia associated with dexmedetomidine overdose in a child? Philip A. Bernard MD (Assistant Professor of Pediatrics)⁎, Carrie E. Makin RN (Research Nurse), Heinrich A. Werner MD, FCCM (Professor) Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, USA Department of Pediatrics, Kentucky Children's Hospital, Lexington, KY 40536, USA Received 6 September 2007; revised 2 June 2008; accepted 9 June 2008
Keywords: Anesthesia, pediatric; Children; Conscious sedation; Dexmedetomidine, overdose; Hypoglycemia
Abstract The case of an asymptomatic 20 month-old, 10.7-kg girl, scheduled for interventional cardiac catheterization to close a patent ductus arteriosus, who suffered significant hypoglycemia possibly related in part to an overdose of dexmedetomidine, is reported. An infusion of dexmedetomidine was started using a programmable syringe pump at the intended administration rate of one mcg/kg/hr, but was actually incorrectly programmed at the rate of one mcg/kg/min. The infusion continued for 36 minutes until a total of 380 mcg (36 mcg/kg) had been given, and was stopped when the error was discovered. A peripheral blood sugar level was found to be 26 mg/dL. The significant hypoglycemia likely was due to substrate deficiency, with a possible dexmedetomidine effect. © 2009 Elsevier Inc. All rights reserved.
1. Introduction Sedation or general anesthesia is required during cardiac catheterization of children in order to provide safe and efficient conditions for the procedure [1]. Any major, sedation-related cardiorespiratory alteration impacts hemodynamic measurements and should be avoided [2]. Recently dexmedetomidine was reported to be a suitable drug for sedation in spontaneously breathing children undergoing cardiac catheterization [3]. Dexmedetomidine, which is chemically related to clonidine, is a selective α2-adrenergic receptor agonist that
⁎ Corresponding author. Medical Transport Service, Kentucky Children's Hospital, Lexington, KY 40536, USA. Tel.: +1 859 323 1496. E-mail address: [email protected] (P.A. Bernard). 0952-8180/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jclinane.2008.06.025
provides centrally mediated sympatholytic, sedative, and anxiolytic effects [4]. In a recent case series of 20 pediatric catheterizations, dexmedetomidine (one mcg/kg load over 10 min, followed by infusion at average dose of 1.15 mcg/kg/hr) did not cause airway obstruction or respiratory depression, and was associated with only mild hypotension and bradycardia [3]. Dexmedetomidine overdose has been reported in adults [5] and in a child [6].
2. Case report The patient was an asymptomatic, 20-month old, 10.7 kg girl who was scheduled for interventional cardiac catheterization to close a patent ductus arteriosus. Her last oral intake was 10 hours prior to the catheterization. The child had a routine preoperative evaluation. Physical examination was normal except for a murmur.
Hypoglycemia from dexmedetomidine overdose? The patient received 0.5 mg/kg midazalom orally, which provided appropriate anxiolysis. After peripheral intravenous (IV) catheter placement, she was given two mg/kg of propofol, followed by two mcg/kg of fentanyl, and femoral vascular access was established. Dexmedetomidine IV solution (100 mcg/mL) was diluted to a 4 mcg/mL solution. An infusion was started at the intended administration rate of one mcg/kg/hr, but was actually being administered at the rate of one mcg/kg/min. The infusion continued for 36 minutes until a total of 380 mcg (36 mcg/kg) had been given, and was stopped when the error was discovered. During this period, vital signs were recorded every 5 minutes (Fig. 1). The patient's heart rate (HR), which had been 126 beats per minute (bpm) prior to the procedure, decreased to 95 bpm during the dexmedetomidine infusion, and reached a minimum of 84 bpm 90 minutes after the end of the infusion. There was an immediate and sustained increase in HR with a dose of atropine (0.02 mg/kg). Hypertension developed during the high-dose dexmedetomidine infusion (blood pressure [BP] was 109/64 mmHg at baseline, and peaked at 152/85 mmHg 20 min into the infusion), and slowly resolved over the subsequent 90
Fig. 1
51 minutes. Respiratory rate (RR) remained unchanged, and no airway obstruction was observed. The child's end-tidal carbon dioxide (ETCO2) increased during the propofol induction but quickly returned to a normal range. The patient remained on room air with normal pulse oximetry saturation levels throughout the sedation. The patient remained deeply sedated with normal ETCO2 while breathing spontaneously throughout the procedure (Ramsay scale of 6) [7]. The child was transferred to the recovery room for close monitoring. During the initial recovery room monitoring, BPs returned to normal range, RR was unremarkable, and the patient remained sedated (Fig. 1). Three hours after the patient's dexmedetomidine infusion had been discontinued, the nurse observed two brief episodes of shaking. A peripheral blood sugar level was found to be 26 mg/dL. The patient was given a three mL/kg bolus of 10% glucose, and the blood sugar was then checked every 30 minutes. Following the glucose bolus, she had a blood sugar of 89 mg/ dL. An infusion of D50.25 NS was started at 40 mL/hr; subsequent blood sugar was 55 mg/dL; and the patient's infusion was changed to D100.25 NS. The remaining blood sugar, while asleep, was above 60 mg/dL.
Record of vital signs taken every 5 minutes.
52 At 4 hours after the end of the infusion, the child was responsive to painful stimuli with localization, withdrawal, and moaning. At 7 hours, the patient awakened and recognized her parents. She was monitored in the pediatric intensive care unit overnight, without any further events. She was at her baseline neurological status the following morning, and was discharged home to follow-up with her cardiologist the next day.
3. Discussion Dexmedetomidine recently has been advocated as a suitable alternative to propofol, ketamine, and general anesthesia/endotracheal intubation during pediatric cardiac catheterization [3]. The drug requires dilution for pediatric administration, and is dosed in mcg/kg/hr, not mcg/kg/ min. Unfamiliarity with the drug as well as dosing and dilution requirements are major factors that constitute risks for drug errors. Accidental dexmedetomidine overdoses have been reported in three adults [5] and a child [6]. Hemodynamic effects consisted of moderate bradycardia and hypertension, consistent with previous reports of overdose [5,6]. Bradycardia is felt to be due to dexmedetomidine's central sympatholytic activity and it responds to atropine [4]. Dexmedetomidine can affect BP in at least two ways: hypotension caused by central sympatholysis, and hypertension caused by vasoconstriction via direct peripheral α2receptor stimulation [4]. While hypotension is most frequently observed during therapeutic infusion in children, it appears that vasoconstriction predominates at higher doses, such as during loading or an overdose [9]. Development of hypertension during a dexmedetomidine infusion should prompt suspicion for a dosage or delivery miscalculation. Hypoglycemia has not been reported to occur with therapeutic or supratherapeutic doses of dexmedetomidine. This is a striking finding, in particular, as α2-agonists cause hypoinsulinemia and hyperglycemia due to their effect on α2-adrenoreceptors on pancreatic beta cells [10,11]. Interestingly, significant hypoglycemia has been shown in children who received clonidine after overnight fasting for growth hormone testing [12]. These authors proposed that in a fasting child, clonidine may blunt regulatory responses to hypoglycemia. Furthermore, central α-agonist related sedation and drowsiness may lead to poor intake, with subsequent further substrate deficiency [12]. It is conceivable that large decreases in circulating norepinephrine consistent with an overdose of dexmedetomidine might also inhibit beta-adrenergic stimulation, thereby causing hypoglycemia. The significant hypoglycemia in our patient likely was due to substrate deficiency, with a possible dexmedetomidine effect. Many strategies could have been employed to alter this patient scenario. Customarily, isotonic fluids are adminis-
P.A. Bernard et al. tered while children undergo sedation. The maintenance fluids could have contained glucose to add substrate after a long fast such as described above. It is still debated whether patients should have routine dosing of glycopyrrolate [13,14]. In this patient, glycopyrrolate might have attenuated the bradycardia. Strategies that have been successful in preventing this type of error with unfamiliar medications include preprogrammed drug libraries on syringe pumps, standardized concentrations of medications, as well as double-checking medication doses with other providers [15]. Dexmedetomidine has the potential to be a suitable sedative agent for pediatric cardiac catheterization. As with any new and relatively unfamiliar drug, great care must be taken to avoid accidental dosing errors. The dosing in mcg/kg/hr rather than mcg/kg/min constitutes a possible cause for confusion. High-dose dexmedetomidine overdose in children causes prolonged sedation. Respiratory depression in this patient who received 36 mcg/kg of dexmedetomidine was not observed. Hypoglycemia needs to be ruled out, especially in the child who underwent pre-procedure fasting.
References [1] Verghese ST, Martin GR. Heavy sedation versus general anesthesia for pediatric invasive cardiology: a grayer shade of blue versus a pinker shade of pale? Pediatr Cardiol 2003;24:193-4. [2] Bernath MA, Sekarski N. Management of paediatric patients undergoing diagnostic and invasive cardiology procedures. Curr Opin Anaesthesiol 2001;14:441-6. [3] Munro HM, Tirotta CF, Felix DE, et al. Initial experience with dexmedetomidine for diagnostic and interventional cardiac catheterization in children. Paediatr Anaesth 2007;17: 109-12. [4] Jorden VS, Tung A. Dexmedetomidine: clinical update. Semin Anesth Perioper Med Pain 2002;21:265-74. [5] Jorden VS, Pousman RM, Sanford MM, Thorborg PA, Hutchens MP. Dexmedetomidine overdose in the perioperative setting. Ann Pharmacother 2004;38:803-7. [6] Rosen DA, Daume JT. Short duration large dose dexmedetomidine in a pediatric patient during procedural sedation. Anesth Analg 2006;103: 68-9. [7] Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974;2(5920): 656-9. [8] McCallum JB, Boban N, Hogan Q, Schmeling WT, Kampine JP, Bosnjak ZJ. The mechanism of alpha2-adrenergic inhibition of sympathetic ganglionic transmission. Anesth Analg 1998;87: 503-10. [9] Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology 2000;93:382-94. [10] Angel I, Bidet S, Langer SZ. Pharmacological characterization of the hyperglycemia induced by alpha-2 adrenoceptor agonists. J Pharmacol Exp Ther 1988;246:1098-103. [11] García-Barrado MJ, Sancho C, Palomero J, Moratinos J. Role of alpha2-adrenoceptors on the hyperglycaemic and insulin secretory effects derived from alpha1- and beta-adrenoceptor stimulation in the rabbit. J Auton Pharmacol 1998;18:287-95.
Hypoglycemia from dexmedetomidine overdose? [12] Huang C, Banerjee K, Sochett E, Perlman K, Wherrett D, Daneman D. Hypoglycemia associated with clonidine testing for growth hormone deficiency. J Pediatr 2001;139:323-4. [13] Annila P, Rorarius M, Reinikainen P, Oikkonen M, Baer G. Effect of pre-treatment with intravenous atropine or glycopyrrolate on cardiac arrhythmias during halothane anaesthesia for adenoidectomy in children. Br J Anaesth 1998;80:756-60.
53 [14] Reyntjens K, Foubert L, De Wolf D, Vanlerberghe G, Mortier E. Glycopyrrolate during sevoflurane-remifentanil-based anaesthesia for cardiac catheterization of children with congenital heart disease. Br J Anaesth 2005;95:680-4. [15] Selbst SM, Levine S, Mull C, Bradford K, Friedman M. Preventing medical errors in pediatric emergency medicine. Pediatr Emerg Care 2004;20:702-9.
Case report
Hypoglycemia associated with dexmedetomidine overdose in a child? Philip A. Bernard MD (Assistant Professor of Pediatrics)⁎, Carrie E. Makin RN (Research Nurse), Heinrich A. Werner MD, FCCM (Professor) Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, USA Department of Pediatrics, Kentucky Children's Hospital, Lexington, KY 40536, USA Received 6 September 2007; revised 2 June 2008; accepted 9 June 2008
Keywords: Anesthesia, pediatric; Children; Conscious sedation; Dexmedetomidine, overdose; Hypoglycemia
Abstract The case of an asymptomatic 20 month-old, 10.7-kg girl, scheduled for interventional cardiac catheterization to close a patent ductus arteriosus, who suffered significant hypoglycemia possibly related in part to an overdose of dexmedetomidine, is reported. An infusion of dexmedetomidine was started using a programmable syringe pump at the intended administration rate of one mcg/kg/hr, but was actually incorrectly programmed at the rate of one mcg/kg/min. The infusion continued for 36 minutes until a total of 380 mcg (36 mcg/kg) had been given, and was stopped when the error was discovered. A peripheral blood sugar level was found to be 26 mg/dL. The significant hypoglycemia likely was due to substrate deficiency, with a possible dexmedetomidine effect. © 2009 Elsevier Inc. All rights reserved.
1. Introduction Sedation or general anesthesia is required during cardiac catheterization of children in order to provide safe and efficient conditions for the procedure [1]. Any major, sedation-related cardiorespiratory alteration impacts hemodynamic measurements and should be avoided [2]. Recently dexmedetomidine was reported to be a suitable drug for sedation in spontaneously breathing children undergoing cardiac catheterization [3]. Dexmedetomidine, which is chemically related to clonidine, is a selective α2-adrenergic receptor agonist that
⁎ Corresponding author. Medical Transport Service, Kentucky Children's Hospital, Lexington, KY 40536, USA. Tel.: +1 859 323 1496. E-mail address: [email protected] (P.A. Bernard). 0952-8180/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jclinane.2008.06.025
provides centrally mediated sympatholytic, sedative, and anxiolytic effects [4]. In a recent case series of 20 pediatric catheterizations, dexmedetomidine (one mcg/kg load over 10 min, followed by infusion at average dose of 1.15 mcg/kg/hr) did not cause airway obstruction or respiratory depression, and was associated with only mild hypotension and bradycardia [3]. Dexmedetomidine overdose has been reported in adults [5] and in a child [6].
2. Case report The patient was an asymptomatic, 20-month old, 10.7 kg girl who was scheduled for interventional cardiac catheterization to close a patent ductus arteriosus. Her last oral intake was 10 hours prior to the catheterization. The child had a routine preoperative evaluation. Physical examination was normal except for a murmur.
Hypoglycemia from dexmedetomidine overdose? The patient received 0.5 mg/kg midazalom orally, which provided appropriate anxiolysis. After peripheral intravenous (IV) catheter placement, she was given two mg/kg of propofol, followed by two mcg/kg of fentanyl, and femoral vascular access was established. Dexmedetomidine IV solution (100 mcg/mL) was diluted to a 4 mcg/mL solution. An infusion was started at the intended administration rate of one mcg/kg/hr, but was actually being administered at the rate of one mcg/kg/min. The infusion continued for 36 minutes until a total of 380 mcg (36 mcg/kg) had been given, and was stopped when the error was discovered. During this period, vital signs were recorded every 5 minutes (Fig. 1). The patient's heart rate (HR), which had been 126 beats per minute (bpm) prior to the procedure, decreased to 95 bpm during the dexmedetomidine infusion, and reached a minimum of 84 bpm 90 minutes after the end of the infusion. There was an immediate and sustained increase in HR with a dose of atropine (0.02 mg/kg). Hypertension developed during the high-dose dexmedetomidine infusion (blood pressure [BP] was 109/64 mmHg at baseline, and peaked at 152/85 mmHg 20 min into the infusion), and slowly resolved over the subsequent 90
Fig. 1
51 minutes. Respiratory rate (RR) remained unchanged, and no airway obstruction was observed. The child's end-tidal carbon dioxide (ETCO2) increased during the propofol induction but quickly returned to a normal range. The patient remained on room air with normal pulse oximetry saturation levels throughout the sedation. The patient remained deeply sedated with normal ETCO2 while breathing spontaneously throughout the procedure (Ramsay scale of 6) [7]. The child was transferred to the recovery room for close monitoring. During the initial recovery room monitoring, BPs returned to normal range, RR was unremarkable, and the patient remained sedated (Fig. 1). Three hours after the patient's dexmedetomidine infusion had been discontinued, the nurse observed two brief episodes of shaking. A peripheral blood sugar level was found to be 26 mg/dL. The patient was given a three mL/kg bolus of 10% glucose, and the blood sugar was then checked every 30 minutes. Following the glucose bolus, she had a blood sugar of 89 mg/ dL. An infusion of D50.25 NS was started at 40 mL/hr; subsequent blood sugar was 55 mg/dL; and the patient's infusion was changed to D100.25 NS. The remaining blood sugar, while asleep, was above 60 mg/dL.
Record of vital signs taken every 5 minutes.
52 At 4 hours after the end of the infusion, the child was responsive to painful stimuli with localization, withdrawal, and moaning. At 7 hours, the patient awakened and recognized her parents. She was monitored in the pediatric intensive care unit overnight, without any further events. She was at her baseline neurological status the following morning, and was discharged home to follow-up with her cardiologist the next day.
3. Discussion Dexmedetomidine recently has been advocated as a suitable alternative to propofol, ketamine, and general anesthesia/endotracheal intubation during pediatric cardiac catheterization [3]. The drug requires dilution for pediatric administration, and is dosed in mcg/kg/hr, not mcg/kg/ min. Unfamiliarity with the drug as well as dosing and dilution requirements are major factors that constitute risks for drug errors. Accidental dexmedetomidine overdoses have been reported in three adults [5] and a child [6]. Hemodynamic effects consisted of moderate bradycardia and hypertension, consistent with previous reports of overdose [5,6]. Bradycardia is felt to be due to dexmedetomidine's central sympatholytic activity and it responds to atropine [4]. Dexmedetomidine can affect BP in at least two ways: hypotension caused by central sympatholysis, and hypertension caused by vasoconstriction via direct peripheral α2receptor stimulation [4]. While hypotension is most frequently observed during therapeutic infusion in children, it appears that vasoconstriction predominates at higher doses, such as during loading or an overdose [9]. Development of hypertension during a dexmedetomidine infusion should prompt suspicion for a dosage or delivery miscalculation. Hypoglycemia has not been reported to occur with therapeutic or supratherapeutic doses of dexmedetomidine. This is a striking finding, in particular, as α2-agonists cause hypoinsulinemia and hyperglycemia due to their effect on α2-adrenoreceptors on pancreatic beta cells [10,11]. Interestingly, significant hypoglycemia has been shown in children who received clonidine after overnight fasting for growth hormone testing [12]. These authors proposed that in a fasting child, clonidine may blunt regulatory responses to hypoglycemia. Furthermore, central α-agonist related sedation and drowsiness may lead to poor intake, with subsequent further substrate deficiency [12]. It is conceivable that large decreases in circulating norepinephrine consistent with an overdose of dexmedetomidine might also inhibit beta-adrenergic stimulation, thereby causing hypoglycemia. The significant hypoglycemia in our patient likely was due to substrate deficiency, with a possible dexmedetomidine effect. Many strategies could have been employed to alter this patient scenario. Customarily, isotonic fluids are adminis-
P.A. Bernard et al. tered while children undergo sedation. The maintenance fluids could have contained glucose to add substrate after a long fast such as described above. It is still debated whether patients should have routine dosing of glycopyrrolate [13,14]. In this patient, glycopyrrolate might have attenuated the bradycardia. Strategies that have been successful in preventing this type of error with unfamiliar medications include preprogrammed drug libraries on syringe pumps, standardized concentrations of medications, as well as double-checking medication doses with other providers [15]. Dexmedetomidine has the potential to be a suitable sedative agent for pediatric cardiac catheterization. As with any new and relatively unfamiliar drug, great care must be taken to avoid accidental dosing errors. The dosing in mcg/kg/hr rather than mcg/kg/min constitutes a possible cause for confusion. High-dose dexmedetomidine overdose in children causes prolonged sedation. Respiratory depression in this patient who received 36 mcg/kg of dexmedetomidine was not observed. Hypoglycemia needs to be ruled out, especially in the child who underwent pre-procedure fasting.
References [1] Verghese ST, Martin GR. Heavy sedation versus general anesthesia for pediatric invasive cardiology: a grayer shade of blue versus a pinker shade of pale? Pediatr Cardiol 2003;24:193-4. [2] Bernath MA, Sekarski N. Management of paediatric patients undergoing diagnostic and invasive cardiology procedures. Curr Opin Anaesthesiol 2001;14:441-6. [3] Munro HM, Tirotta CF, Felix DE, et al. Initial experience with dexmedetomidine for diagnostic and interventional cardiac catheterization in children. Paediatr Anaesth 2007;17: 109-12. [4] Jorden VS, Tung A. Dexmedetomidine: clinical update. Semin Anesth Perioper Med Pain 2002;21:265-74. [5] Jorden VS, Pousman RM, Sanford MM, Thorborg PA, Hutchens MP. Dexmedetomidine overdose in the perioperative setting. Ann Pharmacother 2004;38:803-7. [6] Rosen DA, Daume JT. Short duration large dose dexmedetomidine in a pediatric patient during procedural sedation. Anesth Analg 2006;103: 68-9. [7] Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974;2(5920): 656-9. [8] McCallum JB, Boban N, Hogan Q, Schmeling WT, Kampine JP, Bosnjak ZJ. The mechanism of alpha2-adrenergic inhibition of sympathetic ganglionic transmission. Anesth Analg 1998;87: 503-10. [9] Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology 2000;93:382-94. [10] Angel I, Bidet S, Langer SZ. Pharmacological characterization of the hyperglycemia induced by alpha-2 adrenoceptor agonists. J Pharmacol Exp Ther 1988;246:1098-103. [11] García-Barrado MJ, Sancho C, Palomero J, Moratinos J. Role of alpha2-adrenoceptors on the hyperglycaemic and insulin secretory effects derived from alpha1- and beta-adrenoceptor stimulation in the rabbit. J Auton Pharmacol 1998;18:287-95.
Hypoglycemia from dexmedetomidine overdose? [12] Huang C, Banerjee K, Sochett E, Perlman K, Wherrett D, Daneman D. Hypoglycemia associated with clonidine testing for growth hormone deficiency. J Pediatr 2001;139:323-4. [13] Annila P, Rorarius M, Reinikainen P, Oikkonen M, Baer G. Effect of pre-treatment with intravenous atropine or glycopyrrolate on cardiac arrhythmias during halothane anaesthesia for adenoidectomy in children. Br J Anaesth 1998;80:756-60.
53 [14] Reyntjens K, Foubert L, De Wolf D, Vanlerberghe G, Mortier E. Glycopyrrolate during sevoflurane-remifentanil-based anaesthesia for cardiac catheterization of children with congenital heart disease. Br J Anaesth 2005;95:680-4. [15] Selbst SM, Levine S, Mull C, Bradford K, Friedman M. Preventing medical errors in pediatric emergency medicine. Pediatr Emerg Care 2004;20:702-9.