Dexmedetomidine (DEX) is a highly selective α2-adrenergic agonist that is approved by the Food and Drug Administration for short-term (<24 h) sedation in adult patients in the intensive care unit. It is not approved for use in children1; however, the use of DEX in infants and children for sedation and analgesia in the pediatric intensive care unit has been reported.2–4 In addition, there are a growing number of published reports describing the administration of DEX during anesthesia in adults and children.5,6
There is concern regarding the circulatory effects of DEX, including hypertension, hypotension, and bradycardia.7 It is thought that hypertension is due to activation of peripheral α2B-adrenergic receptors, leading to vasoconstriction.8 Hypertension may be a transient, initial circulatory effect after an initial loading dose of DEX and may also be associated with continuous infusions resulting in high plasma concentrations.9 Entry into the central nervous system (CNS) leads to activation of α2A-adrenergic receptors in the locus coeruleus, causing a decrease in norepinephrine release.10,11 This CNS effect of DEX is associated with a decrease in arterial blood pressure (MAP). The decrease in heart rate (HR) associated with the administration of DEX may be caused both by a reflex response at the sinus node to peripheral vasoconstriction and the decrease in sympathetic outflow from the CNS.
At the cellular level, the interaction of DEX with α2-adrenergic receptors results in activation of G proteins.12 This leads to a decrease in adenylate cyclase activity.13 The resulting decrease in the intracellular concentration of cyclic adenosine monophosphate causes an alteration in ion channel conductance and decreased neuronal activation.14,15 This accounts for the clinical effects of DEX. It is unknown whether the cardiac effects of DEX are related strictly to interaction with α2A-adrenergic receptors in the CNS and α2B-adrenergic receptors in the peripheral vasculature, or whether direct interaction with α2-adrenergic receptors in the heart itself may play a role.
The aim of this study was to characterize the effects of DEX on cardiac conduction in children.
After IRB approval and informed consent, 12 patients were included in this study. They were 5–17 yr of age and scheduled for a cardiac electrophysiology (EP) study and ablation under anesthesia for a diagnosis of supraventricular tachycardia (SVT). Patients in whom ablation was attempted but not successful, as well as those with atrioventricular (AV) nodal dysfunction, were excluded. Antiarrhythmic medications were discontinued in all patients at least 3 days before the procedure.
Patient monitoring included electrocardiogram (ECG), noninvasive MAP, skin temperature, pulse oximetry, and capnography. Supplemental oxygen was administered via nasal cannula or facemask during spontaneous breathing. Patients were premedicated with midazolam (0.5 mg/kg up to 20 mg PO or 1–2 mg IV) as needed. Continuous infusions of propofol 75–125 μg · kg−1 · min−1 IV and ketamine 3.75–12.5 μg · kg−1 · min−1 were administered to achieve an adequate level of sedation and analgesia for catheter insertion and EP study and ablation.
Once stable anesthesia was achieved, the right femoral vein and right internal jugular vein were catheterized using standard techniques. Electrode catheters were advanced to the right atrial appendage, right ventricular apex, His Bundle location, and coronary sinus. A diagnostic EP study was then performed using a standard protocol. If SVT was not induced in the baseline state, isoproterenol (0.01–0.04 μg · kg−1 · min−1) was added and the protocol repeated. Once the arrhythmia focus was identified, radiofrequency or cryoablation was performed.
After a 30-min observation period to ensure the success of the ablation and to allow offset of the isoproterenol, baseline EP data were recorded. Baseline surface ECG intervals, including PR, QRS, QT interval corrected for rate using Bazett’s formula (QTc), and sinus cycle length, were measured. Intracardiac intervals, specifically atrial-His and His-ventricular intervals, were measured. Sinus node function was assessed by measuring corrected sinus node recovery times using standard techniques, measuring the return interval after 30 s of progressive right atrial overdrive pacing cycle lengths until the return interval did not further prolong. The maximum recovery interval was corrected by subtracting the sinus cycle length. AV nodal and atrial effective refractory periods were also measured by introducing progressively more premature atrial stimuli after eight-beat atrially-paced drive trains at a set cycle length. Ventriculoatrial block cycle length was measured with ventricular overdrive pacing. VA and ventricular effective refractory periods were assessed with placement of a ventricular extrastimulus after an eight-beat paced drive train in the ventricle.
After recording of baseline EP data, DEX 1 μg/kg IV was administered over 10 min, followed by a continuous infusion at a dose of 0.7 μg · kg−1 · h−1 for 10 min. The ECG and intracardiac electrograms were continuously recorded before and during this 20-min infusion period. The identical EP data were again recorded after the 20-min DEX infusion period in the same order as previously recorded before discontinuation of the drug. The EP study was terminated upon completion of this monitoring and data collection period. Indwelling catheters were removed, anesthetics were discontinued, and the patient was transported to the postanesthesia care unit. Continuous observation of the ECG was performed in the postanesthesia care unit until complete recovery from anesthesia (i.e., 1–2 h). Using study-specific flow sheets, nursing staff recorded vital signs every 5 min to document variations in HR and MAP. Any episodes of bradycardia and/or tachycardia (HR < or >95% confidence limits for age, respectively) were recorded. As per routine for EP studies at this institution, patients were discharged 4–6 h after completion of their procedure.
SPSS version 15.0 for Windows was used for statistical analysis. Comparisons of hemodynamic and respiratory variables were made from baseline versus 10 and 20 min after initiation of DEX infusion using one-way ANOVA with post hoc comparisons of individual means by Tukey’s HSD test. Two-sided paired Student’s t-test compared the EP variable measured in a baseline state and after the 20-min infusion of DEX. All results are expressed as mean ± sd. A P value of <0.05 was considered statistically significant.
Fifteen patients were enrolled. One patient was withdrawn due to unsuccessful ablation, and two patients were withdrawn due to unanticipated AV nodal dysfunction. Twelve patients (7 females and 5 males) with a median age of 13 yr (5–17 yr) and a median weight of 59.5 kg (20–117 kg) were studied. All patients studied underwent successful ablation. Seven of the 12 patients received isoproterenol during the EP study.
Hemodynamic and Respiratory Variables
A significant increase in MAP was seen compared with baseline (66.2 ± 9.3 mm Hg) at 10 min (78.5 ± 8.9 mm Hg, P = 0.006) but not at 20 min (71.3 ± 9.1 mm Hg) during administration of DEX (Table 1). This was accompanied by a significant decrease in HR compared with baseline (94.3 ± 19.8 bpm) at 10 min (75.9 ± 17.1 bpm, P = 0.045) but not at 20 min (80.1 ± 16.8 bpm).
Respiratory rate and end-tidal carbon dioxide (ETco2) did not change with administration of DEX.
Sinus node function was significantly depressed after administration of DEX (Table 2). Corrected sinus node recovery times increased significantly from baseline. AV nodal function also showed depression after administration of DEX. AV nodal block cycle lengths and PR intervals significantly lengthened. Neither atrial nor ventricular muscle refractoriness changed significantly, although the change in ventricular effective refractory period did approach statistical significance. QTc, a measure of ventricular repolarization that is influenced by autonomic input, also significantly increased, but no patient had an abnormally prolonged QTc (i.e., QTc >445 ms).
We found that DEX significantly depressed sinus and AV nodal function in pediatric patients. Sinus node recovery times (a measure of sinus automaticity) and baseline sinus cycle lengths, which are markers of sinus nodal function, were both lengthened with administration of DEX. AV nodal function, as evidenced by Wenckebach cycle length and AV nodal effective refractory periods, were also lengthened significantly. His-Purkinje conduction and atrial and ventricular muscle properties were not affected. These effects might be related to a decrease in sympathetic outflow from the CNS and/or reflex effects secondary to an increase in systemic vascular resistance. The concomitant decrease in HR and increase in MAP after the initial 10-min infusion of DEX, followed by the subsequent decrease in MAP and increase in HR during the next 10 min might suggest a reflex phenomenon. DEX did not have a direct effect on ventricular or atrial refractoriness, at least at the standard pacing sites chosen. No spontaneous AV nodal block was seen in these patients with normal baseline AV nodal conduction.
No patient developed clinically significant bradycardia during this study. Our patients were otherwise healthy children with SVT. The changes we observed in sinus node and AV conduction might predispose patients with selected comorbidities to significant bradycardia. Such patients might include those having undergone cardiac surgery with conduction abnormalities noted intraoperatively and/or suture lines in proximity to cardiac conduction tissue (e.g., repair of ventricular septal defect, AV canal). Patients receiving other medications that affect cardiac conduction (e.g., digoxin, β-blockers, antiarrhythmic drugs) might also be at enhanced risk of bradycardia related to DEX infusion, although further studies are needed to confirm this.
The incidence of bradycardia associated with DEX in adult patients is 9%.16 Although the bradycardia observed in clinical practice is usually mild, sinus arrest may occur. Peden et al. reported an episode of sinus arrest in a patient who was lying quietly and talking while receiving an initial loading dose of DEX (0.675 μg/kg over 15 min).17 This required treatment with two doses of atropine 0.6 mg IV and a brief period of cardiac massage. Mitigating factors, such as the effect of other drugs or the vagal stimulus of intubation, could not be implicated. Two additional patients in this study had brief, self-limited periods of sinus arrest during an initial loading dose of DEX (1 μg/kg over 15 min). These events occurred during laryngoscopy and the coadministration of propofol and alfentanil infusions. The authors of this study recommended that all patients under 40 yr of age receiving dexmedetomidine should be pretreated with an anticholinergic drug. Significant bradycardias, including sinus pauses of 3 s, related to DEX have been reported in up to 40% of adult patients in other studies.18–20 Sinus arrest has occurred in a young, healthy volunteer 3.5 h after receiving DEX.21 In a study of the effects of a single IM dose of DEX (2.5 μg/kg) for premedication before surgery, a previously healthy patient had an episode of bradycardia with a HR of 35 bpm before anesthetic induction requiring pharmacologic management.19
The incidence of bradycardia associated with the administration of DEX in infants and children is unknown. A recent article summarized the published reports of the use of DEX in more than 800 pediatric patients.22 In general, these reports highlight the favorable sedative and anxiolytic properties of the drug and the limited adverse effects on hemodynamic and respiratory function. Severe bradycardia (HR <50 bpm) was reported in an infant receiving both digoxin and DEX.7 The bradycardia was temporally related to initiation of the DEX infusion and resolved 1 h after the infusion was discontinued. Bradycardia (HR <70 bpm) has also been reported in a 2-mo-old infant receiving DEX 0.7 μg · kg−1 · h−1 after repair of a ventricular septal defect.4 The bradycardia resolved 20 min after discontinuing the infusion. This patient was part of a retrospective review of pediatric patients treated with DEX after cardiac or thoracic surgery.
The respiratory rate and ETco2 did not change during the administration of DEX. This is consistent with previous reports that DEX administration is not associated with a relevant degree of respiratory depression.
Patients in this study were receiving propofol and ketamine infusions in addition to DEX. The effects of these medications on cardiac conduction are not well described. It is possible that the effects we observed would have been different in the absence of these drugs. Because of the need to provide sedation and analgesia to our patients before obtaining baseline EP data, the administration of anesthetics was required. No changes were made in the infusion rates of propofol or ketamine proximate to the initiation of or during the administration of DEX, and the cardiac effects observed were likely primarily or completely related to DEX.
Dexmedetomidine significantly depressed sinus and AV nodal function in pediatric patients. It did not have a direct effect on ventricular or atrial refractoriness. No spontaneous AV nodal block was seen, although these patients all had normal baseline AV nodal conduction. DEX was associated with an increase in MAP commensurate with a decrease in HR. Accordingly, the conduction changes observed in this study might be related to a decrease in the CNS of sympathetic tone and/or reflex response to systemic vasoconstriction caused by DEX.
We recommend that DEX not be used to provide sedation for EP studies, as the effects we observed are likely to cause undesired and misleading measurements of cardiac conduction and might also interfere with the inducibility of some tachycardias. DEX should be used with caution in patients at risk for bradycardia and/or AV nodal dysfunction due to associated comorbidities.
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