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Pediatric Anesthesiology: Research Report

To Pretreat or Not to Pretreat

Prophylactic Anticholinergic Administration Before Dexmedetomidine in Pediatric Imaging

Subramanyam, Rajeev MBBS, DNB, MNAMS, MD, MS*; Cudilo, Elizabeth Maria MD*; Hossain, Mohamed Monir PhD; McAuliffe, John MD, MBA*; Wu, Junzheng MD*; Patino, Mario MD*; Gunter, Joel MD*; Mahmoud, Mohamed MD*

Author Information
doi: 10.1213/ANE.0000000000000765

Dexmedetomidine (Dex) is a α2-adrenergic agonist that produces anxiolysis, amnesia, sedation, potentiation of opioid analgesia, and sympatholysis. In contrast to other sedatives, it converges on sleep pathways within the brainstem and is associated with changes in neuronal activity similar to those seen in deeper stages of non-rapid eye movement sleep, without significant respiratory depression.1,2 To date, there are no US Food and Drug Administration–approved indications for its use in the pediatric population. Because of its sedative and anxiolytic properties, there has been recent increased interest in its use for imaging in pediatric patients, especially those with obstructive sleep apnea.3–12

When Dex is used as a sole sedative, large doses are required to initiate and maintain adequate level of sedation required during pediatric imaging in children.3–11 The biphasic hemodynamic effects of Dex are dose-dependent and occur mainly during administration of the loading/bolus dose. The initial hypertensive response is because of peripheral postsynaptic α2-B stimulation with vasoconstriction, where stimulation of the central presynaptic α2-A receptors will result in decreased norepinephrine release, leading to hypotension and bradycardia. Bradycardia is a concern with Dex, especially in young children. Hence, some anesthesiologists routinely use a prophylactic anticholinergic to prevent bradycardia and/or hypotension. Thus far, there is no clinical evidence to indicate whether Dex-sedated patients should be pretreated with an anticholinergic to prevent bradycardia and hypotension. These effects are most evident in children who have comorbid cardiac disease, in patients with enhanced vagal tone, or when Dex is administered with other medications that have negative chronotropic effects.13

Current evidence suggests that caution should be exercised when administering an anticholinergic to treat Dex-induced bradycardia in children. An exaggerated hypertensive response after IV glycopyrrolate administration used for the treatment of intraoperative bradycardia has been reported.14 The aim of this study was to demonstrate the changes in heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) after Dex sedation for MRI in children receiving or not receiving an anticholinergic pretreatment. The hypothesis was that patients who received a prophylactic anticholinergic would have clinically and statistically significant increases in HR and blood pressure ([BP] in comparison with patients who did not receive anticholinergic pretreatment). A subgroup analysis was performed in children with Down syndrome (DS).

METHODS

After IRB approval, the medical records of 163 consecutive children receiving Dex anesthesia for MRI as outpatients at Cincinnati Children’s Hospital Medical Center between July 2006 and March 2012 were reviewed retrospectively. The study start and end dates were determined based on the feasibility of data extraction. Strengthening of Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed to report this study.15 The hemodynamic data of some of the patients in this study have been published previously in 2 prospective studies examining the effect of Dex on upper airway morphology in patients with normal airway and patients with the history of obstructive sleep apnea where anticholinergic agents were administered as a part of the study design.4,5 An IV catheter was inserted after inhaled induction with sevoflurane and/or nitrous oxide. After an IV cannula was placed, sevoflurane and nitrous oxide were promptly discontinued. At the discretion of the anesthesiologist, patients then received or did not receive an anticholinergic (weight-based atropine or glycopyrrolate) before their initial loading dose of Dex. After the loading dose was administered over 10 minutes, sedation was maintained by a Dex infusion. Once an adequate level of sedation was achieved, nasal cannula with a sample port for end-tidal carbon dioxide analysis was applied. The children were positioned supine and permitted spontaneous ventilation. With the exception of temperature, standard physiologic variables (electrocardiogram, oxygen saturation (SpO2), capnography, and noninvasive BP) were monitored during the scan and recorded at 5-minute intervals on the anesthetic record. If patients moved during the study, an additional bolus dose of Dex was administered; infusion rates were adjusted at the discretion of the attending anesthesiologist based on patient’s response. Data were obtained from 75 handwritten and 88 electronic anesthesia records. Study data were captured with an automated electronic monitor. HR was monitored continuously and recorded every minute. BP was monitored and recorded at 5-minute intervals throughout imaging. At the completion of imaging, the Dex infusion was discontinued and patients were transferred to the recovery room. Patients were discharged after meeting standard postanesthesia care unit (PACU) discharge criteria, including level of consciousness (awake or easily arousable with verbal commands), core temperature 36°C, ability to swallow (taking oral fluids), adequacy of muscle strength (strong and close to baseline movements of extremities and head), and condition consistent with the patient’s preoperative status.

Data extracted included age, weight, gender, ethnicity, American Society of Anesthesiology class, presence of DS, and other comorbidities. Dex bolus dose and infusion rates were noted. The data on administration of anticholinergic (atropine or glycopyrrolate) were collected. Hemodynamic data included HR, SBP, DBP, SpO2, and respiratory rate. These data were extracted at baseline (i.e., before the start of anesthesia), during the scan, and in the recovery room after arrival to the PACU.

Statistical Analysis

Continuous data were compared with the Welch 2-sample t test, proportions with χ2 test, and pairwise comparisons between groups were done with paired t test. Demographic data are summarized in Table 1.

Table 1
Table 1:
Demographic Data

For the analysis of the percentage change for HR, we first calculated for each patient the percentage change between the baseline HR and the minimum HR over 7 time points (until PACU), and the percentage change between baseline HR and the PACU HR. Similar computations were also conducted for the SBP and DBP. A t test was applied to each of these measures to find if there was any significant treatment difference between the 2 groups (i.e., no anticholinergic versus anticholinergic). These results are reported in Table 2. Table 3 provides results from a similar analysis performed on the subgroup of patients with DS.

Table 2
Table 2:
Percentage Change of Hemodynamics for All Patients
Table 3
Table 3:
Percentage Change of Hemodynamics for Patients with Down Syndrome

Generalized linear mixed models, specifically, normal regression models with subject-specific random effect, were used to produce the least squares mean estimates for various time points and treatment groups. In each of these models, 3 main effects for the covariates age, time points only and treatment groups, and an interaction effect for the time points and treatment group were included. Results from all the patients and the DS subgroup are reported in Figures 1, 2 and 3. The figures also include the P values for the significance of time points and treatment group interaction effect. Least squares means, their standard errors, and Bonferroni-adjusted P value for testing the equality of least squares means for the treatment groups are provided in the Supplementary Digital Content 1 (http://links.lww.com/AA/B120). Probability plots and histograms of the residuals of the mixed-effects models are provided in the Supplementary Digital Content 2 (http://links.lww.com/AA/B121). The statistical significance was defined if the P ≤ 0.05. A Bonferroni adjustment for multiple comparisons was then performed on the P values.

Figure 1
Figure 1:
The heart rate between the patients receiving an anticholinergic and not receiving an anticholinergic at baseline, during the scan period, and in the postanesthesia care unit (PACU) is shown and compared. The x-axis represents the heart rate at baseline (before the start of the scan), during the scan at 5-minute intervals (5 minutes through 35 minutes), and in the PACU. The y-axis indicates the least squares estimates of time and treatment interaction mean effect. There was a significant reduction in the heart rates during scan period when an anticholinergic was not used compared with using a prophylactic anticholinergic in all patients (P < 0.0001) and in patients with Down syndrome (DS) (P = 0.0052). The solid line and the broken line with the round dot indicate the heart rate for all patients. The solid line and the broken line with the diamond dot indicate the heart rate for patients with DS. The standard error for each of the least squares mean estimates is provided in the Supplementary Digital Content 1 (http://links.lww.com/AA/B120).
Figure 2
Figure 2:
The systolic blood pressure between the patients receiving an anticholinergic and not receiving an anticholinergic at baseline, during the scan period, and in the postanesthesia care unit (PACU) is shown and compared. The x-axis represents the systolic blood pressure at baseline (before the start of the scan), during the scan at 5-minute intervals (5 minutes through 35 minutes), and in the PACU. The y-axis indicates the least squares estimates of time and treatment interaction mean effect. There was a significant reduction in systolic blood pressure during scan period when an anticholinergic was not used compared with when a prophylactic anticholinergic was used in all patients (P = 0.0153) and in patients with Down syndrome (DS) (P < 0.0001). The solid line and the broken line with the round dot indicate the systolic blood pressure for all patients. The solid line and the broken line with the diamond dot indicate the systolic blood pressure for patients with DS. The standard error for each of the least squares mean estimates is provided in the Supplementary Digital Content 1 (http://links.lww.com/AA/B120).
Figure 3
Figure 3:
The diastolic blood pressure between the patients receiving and not receiving an anticholinergic at baseline, during the scan period, and in the postanesthesia care unit (PACU) is shown and compared. The x-axis represents the diastolic blood pressure at baseline (before the start of the scan), during the scan at 5-minute intervals (5 minutes through 35 minutes), and in the PACU. The y-axis indicates the least squares estimates of time and treatment interaction mean effect. There were no significant differences in diastolic blood pressure during scan period when an anticholinergic was not used compared with when a prophylactic anticholinergic was used in all patients (P = 0.0649) and in patients with Down syndrome (DS) (P < 0.0824). The solid line and the broken line with the round dot indicate the diastolic blood pressure for all patients. The solid line and the broken line with the diamond dot indicate the diastolic blood pressure for patients with DS. The standard error for each of the least squares mean estimates is provided in the Supplementary Digital Content 1 (http://links.lww.com/AA/B120).

RESULTS

Data were obtained and analyzed from 163 children. The mean age of children was 94.5 months, and the mean weight was 32.1 kg (Table 1). The loading dose of Dex was 1 to 2 μg/kg administered over 10 minutes, and the infusion dose was 1 to 3 μg/kg/h. The doses of the anticholinergics were 10 μg/kg for both atropine and glycopyrrolate.

Comparison of Hemodynamics Between Groups in All Patients

Generalized linear mixed-effects regression model showed significant reduction in HR (P < 0.0001; Fig. 1) and SBP (P = 0.0153; Fig. 2) when no prophylactic anticholinergic was administered compared with administering prophylactic anticholinergic. There was no significant change with DBP (P = 0.0649; Fig. 3) when prophylactic anticholinergic was not used compared with using it. The percentage changes of the hemodynamics during the scan and in the PACU compared with baseline are presented in Table 2. During the scan period, the HR of the no-anticholinergic group decreased 26.6%, whereas the HR of the anticholinergic group decreased only 16.7% from baseline (P < 0.01). The maximal SBP increased significantly, compared with baseline, in the anticholinergic group when compared with the no-anticholinergic group (20.2% vs 10.4%, respectively, P = 0.02; Table 2). Although, the percentage changes in HR between groups remained statistically significant in the PACU (P < 0.01), the difference is unlikely to have hemodynamic significance, because the changes from baseline SBP (P = 0.75) and DBP (P = 0.48) were not significant in the PACU.

Comparison of Hemodynamics Between Groups in Patients with DS

DS was present in 52 (32%) children. Generalized linear mixed-effects regression model showed similar results in DS as above: significant reduction in HR (P = 0.0052; Fig. 1) and SBP (P < 0.0001; Fig. 2) when no prophylactic anticholinergic was administered compared with administering a prophylactic anticholinergic. The percentage change in the hemodynamics during the scan and in the PACU compared with baseline in patients with DS is presented in Table 3. During the scan period, we may have observed a trend for decreasing HR, with the mean percentage reduction in HR from baseline to the minimum of 25.3% when no anticholinergic was administered compared with 15.1% when anticholinergic was administered (P = 0.07; Table 3). The difference in the maximal SBP change during the scan period was exaggerated in the DS group with a percentage increase that was 36 times larger in the anticholinergic group compared with the no-anticholinergic group (22% vs −0.6%, respectively; P < 0.01; Table 3). There was no significant change with DBP (P = 0.13; Fig. 3) when a prophylactic anticholinergic was not used compared with when it was used. In DS, the percentage changes in HR, SBP, and DBP compared with baseline and PACU between both groups were not significantly different (P = 0.11, 0.14, and 0.15, respectively; Table 3).

DISCUSSION

Sedation with Dex was associated with a significant reduction in HR and SBP when no prophylactic anticholinergic was administered compared with when a prophylactic anticholinergic was administered. However, in all patients, the percentage change in minimal SBP from baseline during scans was not significantly different when a prophylactic anticholinergic was not used compared with when it was used, and, more importantly, the maximal SBP increased by a significantly greater percentage, compared with baseline, in the anticholinergic group when compared with the no-anticholinergic group. In the subset of patients with DS, the percentage change in minimal SBP from baseline during scans was significantly different when a prophylactic anticholinergic was not used compared with when it was used, but administration of a prophylactic anticholinergic was associated with an exaggerated percentage increase in maximal SBP during scans. Although the percentage changes of HR were significantly different between the baseline and the PACU, it was clinically not relevant, because the percentage changes of SBP and DBP were not significantly different.

Understanding the expected hemodynamic variations associated with the use of high doses of Dex is essential. The extent of these variations is related to the dose and the rate of drug titration, as well as the concomitant sources of hemodynamic instability, such as hypovolemia and increased vagal tone. To achieve an adequate level of sedation when Dex is used as the sole anesthetic, a high bolus (2–3 μg/kg) and an infusion rate of 2 to 3 μg/kg/h are required. Although hypotension, hypertension, and bradycardia are expected side effects of Dex when used in this dose range, overall, significant hemodynamic instability is rare.13,16,17 Transient hypertension, thought to be due to activation of the peripheral α2-adrenoceptors that mediate vasoconstriction, appears earlier than the activation of α2-adrenoceptors in the central nervous system that mediate decreased sympathetic outflow. This transient increase in systemic vascular resistance is observed less often in pediatric patients and is postulated to be attenuated by the inhaled anesthetics.18 This attenuation is lost when patients are pretreated with anticholinergics, as seen by an increase in BP as observed in our study.

Bradycardia is a well-known side effect of Dex.3–5,16 Large doses of Dex (2–3 μg/kg followed by a continuous infusion of 2 μg/kg/h) produce a 16% incidence of bradycardia, with HRs as low as 30 beats per minute. Of note, the degree of bradycardia is inversely related to age—with younger children experiencing more pronounced bradycardia than older children.19 Previous studies have shown that hypotension and bradycardia are more common in patients with preexisting cardiac disease and intact baroreflexes, when given large bolus doses of Dex and concomitant negative chronotropics.13

Children with DS often present for imaging studies and pose special challenges. The incidence of bradycardia and hypotension during inhaled induction with sevoflurane in children with DS is high (57%) in comparison with that in healthy children for all ages (12%).20 In comparison with the control group, significantly more patients with DS received anticholinergic drugs after induction (0% vs 24%; P < 0.001), with 14%, 5%, and 5% receiving IV atropine, IM atropine, and IV glycopyrrolate, respectively.20 Although there is a significantly higher prevalence and degree of bradycardia reported in DS with a sevoflurane induction, this is corrected by decreasing the inhaled concentration of sevoflurane and airway manipulation.21 Dex has been used successfully for pediatric imaging in children with DS.3,4,22 Patients with DS pose a special risk for procedures, because they are predisposed to bradycardia either with or without heart disease.20,22 In children with known heart disease, Dex depresses the sinus and atrioventricular node function and poses an increased risk for children already prone to bradycardia.23 Bradycardia during induction in children with DS can be associated with profound hypotension because in some of these patients cardiac output is rate-dependent. Hence, more anesthesiologists tend to administer a prophylactic anticholinergic to these patients before or after an inhaled induction.20

There is no evidence to support the choice between atropine or glycopyrrolate as the preferred anticholinergic in patients receiving Dex, because both drugs have been shown to induce inconsistent hemodynamic effects.14,24–26 A study in dogs combining 0.02 mg/kg IM atropine with 10 μg/kg IM Dex found that decreases in HR and BP were reversed by atropine; however, atrioventricular blocks, ventricular premature contractions, and ventricular bigeminy were also observed. Therefore, these authors caution about the concomitant use of atropine with Dex in dogs.25 In contrast to this animal study, atropine has been used successfully to resuscitate an adult human patient with Dex-induced bradycardia progressing to pulseless electrical activity.26 A recent report showed that IV glycopyrrolate (5 μg/kg) reversed the Dex-induced bradycardia but produced exaggerated systemic hypertension,14 a finding similar to the one observed in this present study in children. The exact mechanism of the exaggerated response remains unclear. Perhaps this can be attributed to the initial peripheral vasoconstriction (a biphasic response of immediate increase in SBP followed by stabilization) that occurs with Dex.27

Our study has limitations. It is a retrospective, observational analysis of existing data. The administration of the anticholinergic drugs was not randomized based on preset criteria but was based on the judgment of the anesthesiologist in charge of the case. It is also not possible to distinguish between patients who received treatment of sevoflurane-induced bradycardia versus pretreatment from the Dex administration. Age-related hemodynamic assessment analysis could not be performed because of a relatively small sample in the subgroups. The data were extracted from a mix of electronic and manually recorded records. Nonetheless, our results offer some guidance for the use of anticholinergics in children receiving Dex for imaging studies.

In conclusion, administration of a prophylactic anticholinergic with Dex does not offer any hemodynamic benefit and, at worst, causes morbidity in animal studies; hence, we believe it is not indicated, based on our study results. Bradycardia associated with significant hypotension requires intervention by stopping Dex administration and administrating an anticholinergic and/or β-agonists and/or inotropes based on pediatric advanced life support guidelines.13

DISCLOSURES

Name: Rajeev Subramanyam, MBBS, DNB, MNAMS, MD, MS.

Contribution: This author helped with study design, data collection, data analysis, and manuscript preparation.

Attestation: Rajeev Subramanyam approved the final manuscript and also attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Elizabeth Maria Cudilo, MD.

Contribution: This author helped with study design and manuscript preparation.

Attestation: Elizabeth Maria Cudilo approved the final manuscript and attests to the analysis reported in this manuscript.

Name: Mohamed Monir Hossain, PhD.

Contribution: This author helped with data analysis and manuscript preparation.

Attestation: Mohamed Monir Hossain approved the final manuscript and also attests to the integrity of the original data and the analysis reported in this manuscript.

Name: John McAuliffe, MD, MBA.

Contribution: This author helped with data analysis and manuscript preparation.

Attestation: John McAuliffe approved the final manuscript and also attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Junzheng Wu, MD.

Contribution: This author helped with conduct of the study, data collection, and manuscript preparation.

Attestation: Junzheng Wu approved the final manuscript and also attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Mario Patino, MD.

Contribution: This author helped with manuscript preparation.

Attestation: Mario Patino approved the final manuscript and also attests to the analysis reported in this manuscript.

Name: Joel Gunter, MD.

Contribution: This author helped with study design, data analysis, and manuscript preparation.

Attestation: Joel Gunter approved the final manuscript and also attests to the analysis reported in this manuscript.

Name: Mohamed Mahmoud, MD.

Contribution: This author helped with study design, conduct of the study, data collection, data analysis, and manuscript preparation.

Attestation: Mohamed Mahmoud approved the final manuscript, attests to the integrity of the original data and the analysis reported in this manuscript, and is the archival author.

This manuscript was handled by: James A. DiNardo, MD.

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