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Fifty Percent Effective Dose of Intranasal Dexmedetomidine Sedation for Transthoracic Echocardiography in Children With Cyanotic and Acyanotic Congenital Heart Disease
ARTICLE IN PRESS Journal of Cardiothoracic and Vascular Anesthesia 000 (2019) 16
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Original Article
Fifty Percent Effective Dose of Intranasal Dexmedetomidine Sedation for Transthoracic Echocardiography in Children With Cyanotic and Acyanotic Congenital Heart Disease Fei Yang, MM*, Shangyingying Li, MM*, Yuan Shi, MD*, Lu Liu, Nurse*, Mao Ye, MD*, Jin Zhang, MM*, Hui Liu, MM*, Feng Liu, MD*, Qing Yu, MM*,y, Mang Sun, MM*,y, Qin Tian, MM* Shengfen Tu, MD*,y,1 *
Department of Anesthesiology, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders (Chongqing); China International Science and Technology Cooperation base of Child development and Critical Disorders; Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China y Chongqing Key Laboratory of Pediatrics, Children’s Hospital of Chongqing Medical University, Chongqing, China
Objectives: To determine the 50% and 95% effective dose of intranasal dexmedetomidine sedation for transthoracic echocardiography in children with cyanotic and acyanotic congenital heart disease. Design: A prospective, nonrandomized study. Setting: A tertiary care teaching hospital. Participants: Patients younger than 18 months with known or suspected congenital heart disease scheduled for transthoracic echocardiography with sedation. Interventions: Patients were divided into a cyanotic group (blood oxygen saturation <85%) or an acyanotic group (blood oxygen saturation 85%). This study used Dixon’s up-and-down method sequential allocation design. In both groups, the initial dose of intranasal dexmedetomidine was 2 mg/kg and the gradient of increase or decrease was 0.25 mg/kg. Measurements and Main Results: The 50% effective dose (95% confidence interval) of intranasal dexmedetomidine sedation for transthoracic echocardiography was 3.2 (2.78-3.55) mg/kg and 1.9 (1.69-2.06) mg/kg in the cyanotic and acyanotic groups, respectively. None of the patients experienced significant adverse events. Conclusion: The 50% (95% confidence intervals) effective doses of intranasal dexmedetomidine sedation for transthoracic echocardiography were 3.2 (2.78-3.55) mg/kg and 1.9 (1.69-2.06) mg/kg in children with cyanotic and acyanotic congenital heart disease, respectively. Ó 2019 Elsevier Inc. All rights reserved. Key Words: dexmedetomidine; sedation; transthoracic echocardiography
This work was supported by the National Key Clinical Program (grant number [2013] 544]; Natural Science Foundation of Chongqing (grant number cstc2012jjA10036), and the National Natural Science Foundation of China (grant number 31200853). 1 Address reprint requests to Shengfen Tu, Department of Anesthesiology, Children’s Hospital of Chongqing Medical University, No. 136, Second Zhongshan Road, Yuzhong District, Chongqing City, China. E-mail address: [email protected] (S. Tu). https://doi.org/10.1053/j.jvca.2019.11.037 1053-0770/Ó 2019 Elsevier Inc. All rights reserved.
ACCURATE TRANSTHORACIC ECHOCARDIOGRAPHY (TTE) is a mainstay for the diagnosis and periodic surveillance of congenital cardiac disease. Children younger than 3 years who require TTE but cannot cooperate usually require sedation. Previous studies have shown that intranasal administration is suitable for infants and children because it yields
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high bioavailability, reduced first-pass metabolism, and low gastrointestinal tract stimulation. In addition, it requires a low degree of coordination and is highly tolerated by children.1-5 Intranasal dexmedetomidine is suitable for sedation in children undergoing TTE, and many studies have analyzed the optimal dosing of intranasal dexmedetomidine for TTE or compared it with other sedation methods.6-8 According to the authors’ clinical experience, children with cyanotic congenital heart disease who have undergone successful sedation for TTE may require a larger dose of intranasal dexmedetomidine than children with acyanotic congenital heart disease. However, there are few reports about this phenomenon. Therefore, the primary aim of this research was to determine the 50% effective dose (ED50) and 95% effective dose (ED95) of intranasal dexmedetomidine sedation for TTE in children with cyanotic and acyanotic congenital heart disease. The second objective was to study the adverse events associated with these doses.
increased or decreased by 0.25 mg/kg, depending on the previous patient’s response. If the patient achieved successful sedation, the dose of dexmedetomidine for the next patient was decreased by 0.25 mg/kg. If sedation failed, the dose of dexmedetomidine for the next patient was increased by 0.25 mg/ kg. Patients were recruited until 6 crossovers (from failed sedation to successful sedation) were obtained and at least 20 to 40 patients provided stable estimates of the target dose.10 Sedation Method
The protocol was approved by the Institutional Review Board of Children’s Hospital of Chongqing Medical University, Chongqing, China (File No. 2016124-1) on September 22, 2017. The study is registered at chictr.org.cn (ChiCTROPC-17012983, registration date: October 14, 2017). Written informed consent was obtained from parents or guardians as part of the standard requirement for the procedure. The study began October 20, 2017 and ended February 2, 2018. An anesthesiologist evaluated the inclusion and exclusion criteria and decided whether children would be included in the study. The inclusion criteria were children younger than 18 months (American Society of Anesthesiologists [ASA] physical status II-III) with known or suspected congenital heart disease scheduled for TTE with sedation. The exclusion criteria were lack of consent, an allergy to dexmedetomidine, a postoperative status, an abnormal structure of the nasal cavity, renal or hepatic dysfunction, the presence of any other serious systemic diseases except heart disease, and the TTE report was normal or there were differences between the type of TTE reported and the patient’s assigned group.
One nurse prepared the sedation medicine according to the anesthesiologist’s recommendation. The undiluted dexmedetomidine was administered slowly into both nostrils by another nurse after the patient fasted for at least 1 hour. Once a satisfactory sedation effect was achieved, the patient was sent to the examination room. After the examination, the patient was sent back to the sedation center. Parents were encouraged to wake their children with gentle tactile stimulation (patting on the shoulder) or by calling their names. Patients were discharged upon attaining a Modified Aldrete Score11 of 9 or upon reaching the following states: (1) stable cardiovascular function and the respiratory tract was unobstructed; (2) awakened easily, with the protective airway reflexes intact; (3) ability to communicate with others (age-appropriate assessment); (4) able to sit up unassisted (age-appropriate assessment); (5) for very small children or children with disabilities who were unable to exhibit the usual expected responses, a return to presedation response levels or to as close to normal as possible; and (6) adequate hydration status. The criteria used for determining a response were as follows. Satisfactory sedation was defined as a Modified Observer Assessment of Alertness and Sedation Scale12 3 within 30 minutes. Successful sedation was defined as successful completion of the TTE examination and adequate diagnostic-quality images and reports; if these aims were not achieved, the sedation was defined as having failed. For children with failed sedation, a rescue dose of 1 mg/kg dexmedetomidine or 2% to 3% sevoflurane was administered continuously for 3 to 5 minutes through inhalation to complete the examination.
Dixon’s Up-and-Down Method
Data Acquisition
This nonrandomized study used Dixon’s up-and-down method sequential allocation design in a sequential allocation trial. According to their blood oxygen saturation (SpO2) level, the patients were pre-divided into a cyanotic group (SpO2 < 85%) or an acyanotic group (SpO2 85%).9 Patients were excluded from the study if their TTE results were normal or if there were differences between the type of TTE reported and the patient’s assigned blood oxygen saturation group; in that case, the same dose of dexmedetomidine was administered to the next eligible patient until TTE showed congenital heart disease and the type of heart disease reported on the TTE was the same as the patient’s assigned group. Based on the authors’ pilot experiments and a previous study, the initial dose of intranasal dexmedetomidine was 2 mg/kg, which subsequently was
After the patient’s parent signed the informed consent for sedation, the patient was monitored and the relevant data were recorded, including the patient’s sex, age, weight, ASA physical status, and any special circumstances. Heart rate (HR), SpO2, and respiratory rate were collected at baseline (before drug administration) and at 5-minute intervals after until the patient was discharged. HR and SpO2 were monitored using a portable monitor if the patient tolerated one. BP measurement was deferred if the patient resisted, and it was not performed routinely as standard practice because experience has shown that many sedated children become aroused from inflation of the cuff. Data for sedation onset time, TTE scan time, recovery time, and adverse events were collected simultaneously. Sedation
Methods
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onset time was defined as the time from drug administration to the onset of satisfactory sedation. TTE scan time was defined as the period from when the echocardiography probe first touched the patient’s skin to the end of the examination. Recovery time was defined as the time from satisfactory sedation to discharge. Adverse events were defined as the following: (1) an unexpected change in HR >20% of normal, with age-adjusted values13; (2) nausea or vomiting; (3) an SpO2 reduction to <10% of the baseline value; (4) delayed awakening; and (5) any other adverse events encountered during treatment. Delayed awakening was defined as a time from satisfactory sedation to discharge that lasted more than 2 hours. Rest and the injection of ondansetron were recommended for patients with nausea and vomiting. An injection of atropine was used if bradycardia occurred. The adoption of various postures, supplemental oxygen, and suctioning were used for patients with an SpO2 reduction to <10% of the baseline value.
were no differences in the age, sex, weight, or baseline HR of the patients. The ASA status was higher in the cyanotic group than in the acyanotic group, and the baseline SpO2 was lower in the cyanotic group than in the acyanotic group (Table 1).
Statistical Analysis
The sequences of successful and failed sedation outcomes of the 2 groups are shown in Figure 2. The ED50 (95% CI) by Dixon’s method was 3.2 (2.78-3.55) mg/kg and 1.9 (1.692.06) mg/kg in the cyanotic and acyanotic groups, respectively. Based on isotonic regression, the ED50 (95% CI) and ED95 (95% CI) of intranasal dexmedetomidine were 3.3 (2.483.53) mg/kg and 3.7 (3.44-3.73) mg/kg in the cyanotic group and 1.7 (1.00-2.03) mg/kg and 2.2 (1.96-2.23) mg/kg in the acyanotic group, respectively (Table 3). Eventually, all the patients finished their TTE examination. Twenty-five patients exhibited failed sedation with initial administration and were administered additional rescue intranasal dexmedetomidine (1 mg/kg) or inhaled sevoflurane. All patients recovered uneventfully from sedation; none of the patients required intervention, and no adverse events or delayed adverse events occurred.
SPSS for Windows, version 22.0 (IBM Corp, Armonk, NJ), was used for the statistical analysis. Descriptive statistics were calculated using counts and means § standard deviations for patient demographics and sedation procedure characteristics. The ED50 of intranasal administration was determined using Dixon’s up-and-down method, which calculated the mean of the crossover midpoints. The ED50 and ED95 values also were calculated using isotonic regression with bias-corrected 95% confidence intervals (CIs) derived by bootstrapping, and an adjusted response probability was obtained by the pooled-adjacent-violators algorithm. The CIs were estimated using R, version 3.2.5 (R Foundation for Statistical Computing [https:// www.r-project.org]), with the bootstrap approach. If the data exhibited a normal distribution, a 2-tailed Student t test was used to measure the difference between groups; otherwise, the nonparametric test was used. The chi-square test was used for other categorical data, such as sex, ASA status, and adverse events. The ED50 and ED95 values were compared using Mann-Whitney U tests. Statistical significance was defined as a p value < 0.05. Results Demographics and Sedation Characteristics A total of 55 patients with congenital heart disease received intranasal dexmedetomidine sedation for TTE, and 50 patients were enrolled in this prospective study (Fig 1). There were 27 patients in the cyanotic group and 23 patients in the acyanotic group. Most patients had more than 1 anatomic lesion, mainly including tetralogy of Fallot, single ventricle, double outlet of the right ventricle, transposition of the great arteries, pulmonary atresia, tricuspid atresia or stenosis, and total anomalous pulmonary venous connection in the cyanotic group and atrial septal defect, patent ductus arteriosus, ventricular septal defect, and patent foramen ovale in the acyanotic group. There
Time to Sedation Twenty-five patients underwent successful sedation with the initial administration. The onset and duration of sedation are shown in Table 2. For patients who finished their TTE examination with initial intranasal administration, the sedation onset time, TTE scan time, and recovery time were 13.9 § 4.7 minutes, 10.8 § 4.6 minutes, and 34.2 § 9.7 minutes in the cyanotic group and 17.5 § 3.2 minutes, 5.8 § 2.7 minutes, and 32.6 § 3.1 minutes in the acyanotic group, respectively. ED50 and ED95 Values of Intranasal Dexmedetomidine
Discussion Intranasal dexmedetomidine has been found to be safe, effective, and acceptable in children; it does not cause nasal irritation or burning4 and can be used for procedural sedation in doses ranging from 1 to 4 mg/kg.8,14-16 Studies of procedural sedation for TTE have revealed that intranasal dexmedetomidine at 2.5 to 3.0 mg/kg is the optimal dose range for satisfactory sedation of children with congenital heart disease.7,8,17 However, those investigations did not distinguish between children with cyanotic versus acyanotic congenital heart disease. For the present study, ED50 and the estimated ED95 of intranasal dexmedetomidine sedation for TTE in pediatric patients with cyanotic and acyanotic congenital heart disease were determined to provide a basis for the personalized use of intranasal dexmedetomidine for procedural sedation of children undergoing TTE. The ED50 of intranasal dexmedetomidine sedation for TTE procedures in children with cyanotic and acyanotic congenital heart disease using Dixon’s “up-and-down” methodology was evaluated, and isotonic regression was used to estimate the
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Assessed for eligibility (n=55)
Excluded (n=5) Declined to participate (n=2) Withdrew from the study (n=3)
Patients study (n=50)
acyanotic group (n=23)
cyanotic group (n=27) Received allocated intervention (n = 27)
Received allocated intervention (n =23)
Did not receive allocated intervention (n = 0)
Did not receive allocated intervention (n = 0)
Success sedation (n=12)
Failed sedation (n=15)
Success sedation (n=13)
Failed sedation (n=10)
Analysed (n = 27)
Analysed (n =23)
•Excluded from analysis (n = 0)
•Excluded from analysis (n = 0) Fig 1. Consort flow diagram.
ED95. The ED50 and ED95 of intranasal dexmedetomidine were found to be greater in the cyanotic group than in the acyanotic group. The possible reasons are as follows. First, in children with cyanotic congenital heart disease, cardiac structural Table 1 Patient Characteristics Group Age (mo) Weight (kg) Baseline heart rate (beats/ min) Baseline SpO2 (%) Sex (M/F) ASA II/III
Cyanotic Group
Acyanotic Group
7.9 § 4.9 7.0 § 2.1 127 § 21
8.6 § 5.2 7.8 § 2.0 124 § 22
68 § 8 12/15 0/27
98 § 2 9/14 21/2
p Value 0.605 0.233 0.541 < 0.001 0.704 < 0.001
NOTE. Data are presented as mean § standard deviation. Sex and American Society of Anesthesiologists physical status are expressed as numbers. Abbreviations: ASA, American Society of Anesthesiologists; SpO2, blood oxygen saturation.
deformities such as intracardiac shunts, widespread formation of collateral blood vessels,18 secondary erythrocytosis and thrombocytopenia,19 and a high level of oxidative stress20 and internal environment changes affect the metabolism and absorption of drugs, thereby influencing the depth and duration of sedation. Second, cyanotic patients necessitated a longer TTE scan time and more complex ultrasonic manipulation. Third, unrepaired cyanotic congenital heart disease decreases cerebral oxygen delivery21 and may affect brain development. Studies have reported that chronic hypoxemia may cause a delay in the myelination process22-24 and significant retardation of brainstem maturation, especially in infants younger than 1 year old.25 Therefore, the authors speculate that the poorly developed brain may be more susceptible to the external environment and stimulation and that cyanotic patients more easily awaken during the examination. The reason for this is not clear but possibly involves factors such as the blood concentration, bioavailability, pharmacokinetics, and pharmacodynamics of the drug, which requires further investigation.
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Table 2 Sedation Onset Time, TTE Scan Time, Recovery Time, and Sedation Time After Dexmedetomidine Administration Cyanotic Group (n = 12) Sedation onset time (min) TTE scan time (min) Recovery time (min)
13.9 § 4.7 10.8 § 4.6 34.2 § 9.7
Acyanotic Group (n = 13) 17.5 § 3.2 5.8 § 2.7 32.6 § 3.1
p Value
0.044 0.004 0.620
NOTE. Time intervals (minutes) are presented as mean § standard deviation. The p value was determined by the Student t test; the sedation onset time was defined as the time from drug administration to the onset of satisfactory sedation; the TTE scan time was defined as the time from when the color Doppler probe touched the patient’s skin to the end of the examination; and recovery time was defined as the time from satisfactory sedation to discharge. Abbreviation: TTE, transthoracic echocardiography.
Table 3 ED50 and ED95 of Intranasal Dexmedetomidine in the 2 Groups
ED50 (mg/kg)* ED50 (mg/kg)y ED95 (mg/kg)y
Cyanotic Group
Acyanotic Group
p Value
3.2 (2.78-3.55) 3.3 (2.48-3.53) 3.7 (3.44-3.73)
1.9 (1.69-2.06) 1.7 (1.00-2.03) 2.2 (1.96-2.23)
< 0.001 < 0.001 < 0.001
NOTE. Values are ED50 or ED95 with 95% confidence interval. The p value was determined with Mann-Whitney U tests. Abbreviations: ED50, 50% effective dose; ED95, 95% effective dose. * Determined with Dixon’s method. y Determined with isotonic regression with bias-corrected 95% confidence interval derived by bootstrapping.
In the cyanotic group, the onset time was shorter than that of the acyanotic group, but the comparison is not very accurate because the doses of dexmedetomidine used in the 2 groups were different; the dose used for the cyanotic group was significantly greater than that used for the acyanotic group. Additional research is needed to compare the onset time at the same dose of intranasal dexmedetomidine in the cyanotic and acyanotic groups. Many studies have indicated that hemodynamic changes mostly occur when dexmedetomidine is used and that no patient requires pharmacologic intervention.26-29 A large-sample cohort study evaluated the risks associated with using dexmedetomidine and suggested that HR or BP >30% of the baseline accounted for 0.93% of cases.30 Baier found that no patients presented with bradycardia (bradycardia was defined as a >20% deviation from the age-adjusted normal awake values) when intranasal dexmedetomidine 2.5 mg/kg and 3 mg/kg was used as a single agent.31 In the present study, no patients experienced an unexpected change in HR >20% of the normal age-adjusted values; the results thus echo the idea that intranasal dexmedetomidine may be safe with regard to hemodynamics. The authors have found through their experiences in daily practice that the success rate of sedation is influenced by dose of the drug, quality of sleep, sense of hunger, and temperature of the environment. Poor-quality sleep, no hunger, and an appropriate ambient temperature will increase the rate of sedation success. In contrast, adequate sleep, hunger, and
Fig 2. Dexmedetomidine dose in each patient with response of cyanotic group and acyanotic group. Success dose is denoted by a solid circle; failure dose is denoted by an open circle. Horizontal arrows represent crossover midpoints (failure to success).
an ambient temperature that is too high or too low may reduce the rate of sedation success. The most suitable fasting time and environmental temperature are unclear, and more research is needed. The present study has several limitations. First, only the effective dose of intranasal dexmedetomidine between patients with cyanotic congenital heart disease and those with acyanotic congenital heart disease was evaluated. However, whether the required effective dose of intranasal dexmedetomidine was different for various degrees of cyanosis was not clarified, and more research is needed to confirm this difference. Second, there are differences in the metabolism of drugs in patients of different ages. One study reported that the clearance of dexmedetomidine in a neonate is 42.2% of the adult value, reaching 84.5% by 1 year of age. Infants require a lower dose of dexmedetomidine than children >1 year.32,33 The present study was not grouped by age, and additional research should be conducted to clarify this issue. In conclusion, the ED50 and ED95 of intranasal dexmedetomidine sedation for TTE examination in children with cyanotic and acyanotic congenital heart disease were estimated, which will be helpful as a guide for choosing the appropriate dose for children with congenital heart disease. The results suggest that when selecting the dose of intranasal dexmedetomidine for TTE sedation, it is necessary to consider whether the child has cyanotic congenital heart disease.
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Acknowledgments The authors acknowledge the support of the staff from the Anesthesia Department and Transthoracic Echocardiography Department at the Children’s Hospital affiliated with Chongqing Medical University, Chongqing, China, for their cooperation in the study. Conflict of Interest The authors have nothing to disclose. References 1 Malinovsky JM, Populaire C, Cozian A, et al. Premedication with midazolam in children. Effect of intranasal, rectal and oral routes on plasma midazolam concentrations. Anaesthesia 1995;50:351–4. 2 Kogan A, Katz J, Efrat R, et al. Premedication with midazolam in young children: A comparison of 4 routes of administration. Paediatr Anaesth 2002;12:685–9. 3 Iirola T, Vilo S, Manner T, et al. Bioavailability of dexmedetomidine after intranasal administration. Eur J Clin Pharmacol 2011;67:825–31. 4 Sheta SA, Al-Sarheed MA, Abdelhalim AA. Intranasal dexmedetomidine vs midazolam for premedication in children undergoing complete dental rehabilitation: A double-blinded randomized controlled trial. Paediatr Anaesth 2014;24:181–9. 5 Yuen VM, Hui TW, Irwin MG, et al. Optimal timing for the administration of intranasal dexmedetomidine for premedication in children. Anaesthesia 2010;65:922–9. 6 Fett J, Hackbarth R, Boville BM, et al. Comparative effectiveness of intranasal dexmedetomidine-midazolam versus oral chloral hydrate targeting moderate sedation during pediatric transthoracic echocardiograms. J Pediatr Intensive Care 2017;6:182–7. 7 Miller J, Xue B, Hossain M, et al. Comparison of dexmedetomidine and chloral hydrate sedation for transthoracic echocardiography in infants and toddlers: A randomized clinical trial. Paediatr Anaesth 2016;26:266–72. 8 Miller JW, Divanovic AA, Hossain MM, et al. Dosing and efficacy of intranasal dexmedetomidine sedation for pediatric transthoracic echocardiography: A retrospective study. Can J Anaesth 2016;63:834–41. 9 Oc B, Akinci SB, Kanbak M, et al. The effects of sevoflurane anesthesia and cardiopulmonary bypass on renal function in cyanotic and acyanotic children undergoing cardiac surgery. Ren Fail 2012;34:135–41. 10 Pace NL, Stylianou MP. Advances in and limitations of up-and-down methodology: A precis of clinical use, study design, and dose estimation in anesthesia research. Anesthesiology 2007;107:144–52. 11 Aldrete JA. The post-anesthesia recovery score revisited. J Clin Anesth 1995;7:89–91. 12 Chernik DA, Gillings D, Laine H, et al. Validity and reliability of the Observer’s Assessment of Alertness/Sedation Scale: Study with intravenous midazolam. J Clin Psychopharmacol 1990;10:244–51. 13 Mathers LH, Frankel LR, et al. Pediatric emergencies and resuscitation. In: Kliegman RM, Behrman RE, Jenson HB, editors. Nelson textbook of pediatrics, 18th ed., Philadelphia, PA: Saunders Elsevier; 2007. p. 387–404.
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Original Article
Fifty Percent Effective Dose of Intranasal Dexmedetomidine Sedation for Transthoracic Echocardiography in Children With Cyanotic and Acyanotic Congenital Heart Disease Fei Yang, MM*, Shangyingying Li, MM*, Yuan Shi, MD*, Lu Liu, Nurse*, Mao Ye, MD*, Jin Zhang, MM*, Hui Liu, MM*, Feng Liu, MD*, Qing Yu, MM*,y, Mang Sun, MM*,y, Qin Tian, MM* Shengfen Tu, MD*,y,1 *
Department of Anesthesiology, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders (Chongqing); China International Science and Technology Cooperation base of Child development and Critical Disorders; Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China y Chongqing Key Laboratory of Pediatrics, Children’s Hospital of Chongqing Medical University, Chongqing, China
Objectives: To determine the 50% and 95% effective dose of intranasal dexmedetomidine sedation for transthoracic echocardiography in children with cyanotic and acyanotic congenital heart disease. Design: A prospective, nonrandomized study. Setting: A tertiary care teaching hospital. Participants: Patients younger than 18 months with known or suspected congenital heart disease scheduled for transthoracic echocardiography with sedation. Interventions: Patients were divided into a cyanotic group (blood oxygen saturation <85%) or an acyanotic group (blood oxygen saturation 85%). This study used Dixon’s up-and-down method sequential allocation design. In both groups, the initial dose of intranasal dexmedetomidine was 2 mg/kg and the gradient of increase or decrease was 0.25 mg/kg. Measurements and Main Results: The 50% effective dose (95% confidence interval) of intranasal dexmedetomidine sedation for transthoracic echocardiography was 3.2 (2.78-3.55) mg/kg and 1.9 (1.69-2.06) mg/kg in the cyanotic and acyanotic groups, respectively. None of the patients experienced significant adverse events. Conclusion: The 50% (95% confidence intervals) effective doses of intranasal dexmedetomidine sedation for transthoracic echocardiography were 3.2 (2.78-3.55) mg/kg and 1.9 (1.69-2.06) mg/kg in children with cyanotic and acyanotic congenital heart disease, respectively. Ó 2019 Elsevier Inc. All rights reserved. Key Words: dexmedetomidine; sedation; transthoracic echocardiography
This work was supported by the National Key Clinical Program (grant number [2013] 544]; Natural Science Foundation of Chongqing (grant number cstc2012jjA10036), and the National Natural Science Foundation of China (grant number 31200853). 1 Address reprint requests to Shengfen Tu, Department of Anesthesiology, Children’s Hospital of Chongqing Medical University, No. 136, Second Zhongshan Road, Yuzhong District, Chongqing City, China. E-mail address: [email protected] (S. Tu). https://doi.org/10.1053/j.jvca.2019.11.037 1053-0770/Ó 2019 Elsevier Inc. All rights reserved.
ACCURATE TRANSTHORACIC ECHOCARDIOGRAPHY (TTE) is a mainstay for the diagnosis and periodic surveillance of congenital cardiac disease. Children younger than 3 years who require TTE but cannot cooperate usually require sedation. Previous studies have shown that intranasal administration is suitable for infants and children because it yields
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high bioavailability, reduced first-pass metabolism, and low gastrointestinal tract stimulation. In addition, it requires a low degree of coordination and is highly tolerated by children.1-5 Intranasal dexmedetomidine is suitable for sedation in children undergoing TTE, and many studies have analyzed the optimal dosing of intranasal dexmedetomidine for TTE or compared it with other sedation methods.6-8 According to the authors’ clinical experience, children with cyanotic congenital heart disease who have undergone successful sedation for TTE may require a larger dose of intranasal dexmedetomidine than children with acyanotic congenital heart disease. However, there are few reports about this phenomenon. Therefore, the primary aim of this research was to determine the 50% effective dose (ED50) and 95% effective dose (ED95) of intranasal dexmedetomidine sedation for TTE in children with cyanotic and acyanotic congenital heart disease. The second objective was to study the adverse events associated with these doses.
increased or decreased by 0.25 mg/kg, depending on the previous patient’s response. If the patient achieved successful sedation, the dose of dexmedetomidine for the next patient was decreased by 0.25 mg/kg. If sedation failed, the dose of dexmedetomidine for the next patient was increased by 0.25 mg/ kg. Patients were recruited until 6 crossovers (from failed sedation to successful sedation) were obtained and at least 20 to 40 patients provided stable estimates of the target dose.10 Sedation Method
The protocol was approved by the Institutional Review Board of Children’s Hospital of Chongqing Medical University, Chongqing, China (File No. 2016124-1) on September 22, 2017. The study is registered at chictr.org.cn (ChiCTROPC-17012983, registration date: October 14, 2017). Written informed consent was obtained from parents or guardians as part of the standard requirement for the procedure. The study began October 20, 2017 and ended February 2, 2018. An anesthesiologist evaluated the inclusion and exclusion criteria and decided whether children would be included in the study. The inclusion criteria were children younger than 18 months (American Society of Anesthesiologists [ASA] physical status II-III) with known or suspected congenital heart disease scheduled for TTE with sedation. The exclusion criteria were lack of consent, an allergy to dexmedetomidine, a postoperative status, an abnormal structure of the nasal cavity, renal or hepatic dysfunction, the presence of any other serious systemic diseases except heart disease, and the TTE report was normal or there were differences between the type of TTE reported and the patient’s assigned group.
One nurse prepared the sedation medicine according to the anesthesiologist’s recommendation. The undiluted dexmedetomidine was administered slowly into both nostrils by another nurse after the patient fasted for at least 1 hour. Once a satisfactory sedation effect was achieved, the patient was sent to the examination room. After the examination, the patient was sent back to the sedation center. Parents were encouraged to wake their children with gentle tactile stimulation (patting on the shoulder) or by calling their names. Patients were discharged upon attaining a Modified Aldrete Score11 of 9 or upon reaching the following states: (1) stable cardiovascular function and the respiratory tract was unobstructed; (2) awakened easily, with the protective airway reflexes intact; (3) ability to communicate with others (age-appropriate assessment); (4) able to sit up unassisted (age-appropriate assessment); (5) for very small children or children with disabilities who were unable to exhibit the usual expected responses, a return to presedation response levels or to as close to normal as possible; and (6) adequate hydration status. The criteria used for determining a response were as follows. Satisfactory sedation was defined as a Modified Observer Assessment of Alertness and Sedation Scale12 3 within 30 minutes. Successful sedation was defined as successful completion of the TTE examination and adequate diagnostic-quality images and reports; if these aims were not achieved, the sedation was defined as having failed. For children with failed sedation, a rescue dose of 1 mg/kg dexmedetomidine or 2% to 3% sevoflurane was administered continuously for 3 to 5 minutes through inhalation to complete the examination.
Dixon’s Up-and-Down Method
Data Acquisition
This nonrandomized study used Dixon’s up-and-down method sequential allocation design in a sequential allocation trial. According to their blood oxygen saturation (SpO2) level, the patients were pre-divided into a cyanotic group (SpO2 < 85%) or an acyanotic group (SpO2 85%).9 Patients were excluded from the study if their TTE results were normal or if there were differences between the type of TTE reported and the patient’s assigned blood oxygen saturation group; in that case, the same dose of dexmedetomidine was administered to the next eligible patient until TTE showed congenital heart disease and the type of heart disease reported on the TTE was the same as the patient’s assigned group. Based on the authors’ pilot experiments and a previous study, the initial dose of intranasal dexmedetomidine was 2 mg/kg, which subsequently was
After the patient’s parent signed the informed consent for sedation, the patient was monitored and the relevant data were recorded, including the patient’s sex, age, weight, ASA physical status, and any special circumstances. Heart rate (HR), SpO2, and respiratory rate were collected at baseline (before drug administration) and at 5-minute intervals after until the patient was discharged. HR and SpO2 were monitored using a portable monitor if the patient tolerated one. BP measurement was deferred if the patient resisted, and it was not performed routinely as standard practice because experience has shown that many sedated children become aroused from inflation of the cuff. Data for sedation onset time, TTE scan time, recovery time, and adverse events were collected simultaneously. Sedation
Methods
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onset time was defined as the time from drug administration to the onset of satisfactory sedation. TTE scan time was defined as the period from when the echocardiography probe first touched the patient’s skin to the end of the examination. Recovery time was defined as the time from satisfactory sedation to discharge. Adverse events were defined as the following: (1) an unexpected change in HR >20% of normal, with age-adjusted values13; (2) nausea or vomiting; (3) an SpO2 reduction to <10% of the baseline value; (4) delayed awakening; and (5) any other adverse events encountered during treatment. Delayed awakening was defined as a time from satisfactory sedation to discharge that lasted more than 2 hours. Rest and the injection of ondansetron were recommended for patients with nausea and vomiting. An injection of atropine was used if bradycardia occurred. The adoption of various postures, supplemental oxygen, and suctioning were used for patients with an SpO2 reduction to <10% of the baseline value.
were no differences in the age, sex, weight, or baseline HR of the patients. The ASA status was higher in the cyanotic group than in the acyanotic group, and the baseline SpO2 was lower in the cyanotic group than in the acyanotic group (Table 1).
Statistical Analysis
The sequences of successful and failed sedation outcomes of the 2 groups are shown in Figure 2. The ED50 (95% CI) by Dixon’s method was 3.2 (2.78-3.55) mg/kg and 1.9 (1.692.06) mg/kg in the cyanotic and acyanotic groups, respectively. Based on isotonic regression, the ED50 (95% CI) and ED95 (95% CI) of intranasal dexmedetomidine were 3.3 (2.483.53) mg/kg and 3.7 (3.44-3.73) mg/kg in the cyanotic group and 1.7 (1.00-2.03) mg/kg and 2.2 (1.96-2.23) mg/kg in the acyanotic group, respectively (Table 3). Eventually, all the patients finished their TTE examination. Twenty-five patients exhibited failed sedation with initial administration and were administered additional rescue intranasal dexmedetomidine (1 mg/kg) or inhaled sevoflurane. All patients recovered uneventfully from sedation; none of the patients required intervention, and no adverse events or delayed adverse events occurred.
SPSS for Windows, version 22.0 (IBM Corp, Armonk, NJ), was used for the statistical analysis. Descriptive statistics were calculated using counts and means § standard deviations for patient demographics and sedation procedure characteristics. The ED50 of intranasal administration was determined using Dixon’s up-and-down method, which calculated the mean of the crossover midpoints. The ED50 and ED95 values also were calculated using isotonic regression with bias-corrected 95% confidence intervals (CIs) derived by bootstrapping, and an adjusted response probability was obtained by the pooled-adjacent-violators algorithm. The CIs were estimated using R, version 3.2.5 (R Foundation for Statistical Computing [https:// www.r-project.org]), with the bootstrap approach. If the data exhibited a normal distribution, a 2-tailed Student t test was used to measure the difference between groups; otherwise, the nonparametric test was used. The chi-square test was used for other categorical data, such as sex, ASA status, and adverse events. The ED50 and ED95 values were compared using Mann-Whitney U tests. Statistical significance was defined as a p value < 0.05. Results Demographics and Sedation Characteristics A total of 55 patients with congenital heart disease received intranasal dexmedetomidine sedation for TTE, and 50 patients were enrolled in this prospective study (Fig 1). There were 27 patients in the cyanotic group and 23 patients in the acyanotic group. Most patients had more than 1 anatomic lesion, mainly including tetralogy of Fallot, single ventricle, double outlet of the right ventricle, transposition of the great arteries, pulmonary atresia, tricuspid atresia or stenosis, and total anomalous pulmonary venous connection in the cyanotic group and atrial septal defect, patent ductus arteriosus, ventricular septal defect, and patent foramen ovale in the acyanotic group. There
Time to Sedation Twenty-five patients underwent successful sedation with the initial administration. The onset and duration of sedation are shown in Table 2. For patients who finished their TTE examination with initial intranasal administration, the sedation onset time, TTE scan time, and recovery time were 13.9 § 4.7 minutes, 10.8 § 4.6 minutes, and 34.2 § 9.7 minutes in the cyanotic group and 17.5 § 3.2 minutes, 5.8 § 2.7 minutes, and 32.6 § 3.1 minutes in the acyanotic group, respectively. ED50 and ED95 Values of Intranasal Dexmedetomidine
Discussion Intranasal dexmedetomidine has been found to be safe, effective, and acceptable in children; it does not cause nasal irritation or burning4 and can be used for procedural sedation in doses ranging from 1 to 4 mg/kg.8,14-16 Studies of procedural sedation for TTE have revealed that intranasal dexmedetomidine at 2.5 to 3.0 mg/kg is the optimal dose range for satisfactory sedation of children with congenital heart disease.7,8,17 However, those investigations did not distinguish between children with cyanotic versus acyanotic congenital heart disease. For the present study, ED50 and the estimated ED95 of intranasal dexmedetomidine sedation for TTE in pediatric patients with cyanotic and acyanotic congenital heart disease were determined to provide a basis for the personalized use of intranasal dexmedetomidine for procedural sedation of children undergoing TTE. The ED50 of intranasal dexmedetomidine sedation for TTE procedures in children with cyanotic and acyanotic congenital heart disease using Dixon’s “up-and-down” methodology was evaluated, and isotonic regression was used to estimate the
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Assessed for eligibility (n=55)
Excluded (n=5) Declined to participate (n=2) Withdrew from the study (n=3)
Patients study (n=50)
acyanotic group (n=23)
cyanotic group (n=27) Received allocated intervention (n = 27)
Received allocated intervention (n =23)
Did not receive allocated intervention (n = 0)
Did not receive allocated intervention (n = 0)
Success sedation (n=12)
Failed sedation (n=15)
Success sedation (n=13)
Failed sedation (n=10)
Analysed (n = 27)
Analysed (n =23)
•Excluded from analysis (n = 0)
•Excluded from analysis (n = 0) Fig 1. Consort flow diagram.
ED95. The ED50 and ED95 of intranasal dexmedetomidine were found to be greater in the cyanotic group than in the acyanotic group. The possible reasons are as follows. First, in children with cyanotic congenital heart disease, cardiac structural Table 1 Patient Characteristics Group Age (mo) Weight (kg) Baseline heart rate (beats/ min) Baseline SpO2 (%) Sex (M/F) ASA II/III
Cyanotic Group
Acyanotic Group
7.9 § 4.9 7.0 § 2.1 127 § 21
8.6 § 5.2 7.8 § 2.0 124 § 22
68 § 8 12/15 0/27
98 § 2 9/14 21/2
p Value 0.605 0.233 0.541 < 0.001 0.704 < 0.001
NOTE. Data are presented as mean § standard deviation. Sex and American Society of Anesthesiologists physical status are expressed as numbers. Abbreviations: ASA, American Society of Anesthesiologists; SpO2, blood oxygen saturation.
deformities such as intracardiac shunts, widespread formation of collateral blood vessels,18 secondary erythrocytosis and thrombocytopenia,19 and a high level of oxidative stress20 and internal environment changes affect the metabolism and absorption of drugs, thereby influencing the depth and duration of sedation. Second, cyanotic patients necessitated a longer TTE scan time and more complex ultrasonic manipulation. Third, unrepaired cyanotic congenital heart disease decreases cerebral oxygen delivery21 and may affect brain development. Studies have reported that chronic hypoxemia may cause a delay in the myelination process22-24 and significant retardation of brainstem maturation, especially in infants younger than 1 year old.25 Therefore, the authors speculate that the poorly developed brain may be more susceptible to the external environment and stimulation and that cyanotic patients more easily awaken during the examination. The reason for this is not clear but possibly involves factors such as the blood concentration, bioavailability, pharmacokinetics, and pharmacodynamics of the drug, which requires further investigation.
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Table 2 Sedation Onset Time, TTE Scan Time, Recovery Time, and Sedation Time After Dexmedetomidine Administration Cyanotic Group (n = 12) Sedation onset time (min) TTE scan time (min) Recovery time (min)
13.9 § 4.7 10.8 § 4.6 34.2 § 9.7
Acyanotic Group (n = 13) 17.5 § 3.2 5.8 § 2.7 32.6 § 3.1
p Value
0.044 0.004 0.620
NOTE. Time intervals (minutes) are presented as mean § standard deviation. The p value was determined by the Student t test; the sedation onset time was defined as the time from drug administration to the onset of satisfactory sedation; the TTE scan time was defined as the time from when the color Doppler probe touched the patient’s skin to the end of the examination; and recovery time was defined as the time from satisfactory sedation to discharge. Abbreviation: TTE, transthoracic echocardiography.
Table 3 ED50 and ED95 of Intranasal Dexmedetomidine in the 2 Groups
ED50 (mg/kg)* ED50 (mg/kg)y ED95 (mg/kg)y
Cyanotic Group
Acyanotic Group
p Value
3.2 (2.78-3.55) 3.3 (2.48-3.53) 3.7 (3.44-3.73)
1.9 (1.69-2.06) 1.7 (1.00-2.03) 2.2 (1.96-2.23)
< 0.001 < 0.001 < 0.001
NOTE. Values are ED50 or ED95 with 95% confidence interval. The p value was determined with Mann-Whitney U tests. Abbreviations: ED50, 50% effective dose; ED95, 95% effective dose. * Determined with Dixon’s method. y Determined with isotonic regression with bias-corrected 95% confidence interval derived by bootstrapping.
In the cyanotic group, the onset time was shorter than that of the acyanotic group, but the comparison is not very accurate because the doses of dexmedetomidine used in the 2 groups were different; the dose used for the cyanotic group was significantly greater than that used for the acyanotic group. Additional research is needed to compare the onset time at the same dose of intranasal dexmedetomidine in the cyanotic and acyanotic groups. Many studies have indicated that hemodynamic changes mostly occur when dexmedetomidine is used and that no patient requires pharmacologic intervention.26-29 A large-sample cohort study evaluated the risks associated with using dexmedetomidine and suggested that HR or BP >30% of the baseline accounted for 0.93% of cases.30 Baier found that no patients presented with bradycardia (bradycardia was defined as a >20% deviation from the age-adjusted normal awake values) when intranasal dexmedetomidine 2.5 mg/kg and 3 mg/kg was used as a single agent.31 In the present study, no patients experienced an unexpected change in HR >20% of the normal age-adjusted values; the results thus echo the idea that intranasal dexmedetomidine may be safe with regard to hemodynamics. The authors have found through their experiences in daily practice that the success rate of sedation is influenced by dose of the drug, quality of sleep, sense of hunger, and temperature of the environment. Poor-quality sleep, no hunger, and an appropriate ambient temperature will increase the rate of sedation success. In contrast, adequate sleep, hunger, and
Fig 2. Dexmedetomidine dose in each patient with response of cyanotic group and acyanotic group. Success dose is denoted by a solid circle; failure dose is denoted by an open circle. Horizontal arrows represent crossover midpoints (failure to success).
an ambient temperature that is too high or too low may reduce the rate of sedation success. The most suitable fasting time and environmental temperature are unclear, and more research is needed. The present study has several limitations. First, only the effective dose of intranasal dexmedetomidine between patients with cyanotic congenital heart disease and those with acyanotic congenital heart disease was evaluated. However, whether the required effective dose of intranasal dexmedetomidine was different for various degrees of cyanosis was not clarified, and more research is needed to confirm this difference. Second, there are differences in the metabolism of drugs in patients of different ages. One study reported that the clearance of dexmedetomidine in a neonate is 42.2% of the adult value, reaching 84.5% by 1 year of age. Infants require a lower dose of dexmedetomidine than children >1 year.32,33 The present study was not grouped by age, and additional research should be conducted to clarify this issue. In conclusion, the ED50 and ED95 of intranasal dexmedetomidine sedation for TTE examination in children with cyanotic and acyanotic congenital heart disease were estimated, which will be helpful as a guide for choosing the appropriate dose for children with congenital heart disease. The results suggest that when selecting the dose of intranasal dexmedetomidine for TTE sedation, it is necessary to consider whether the child has cyanotic congenital heart disease.
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Acknowledgments The authors acknowledge the support of the staff from the Anesthesia Department and Transthoracic Echocardiography Department at the Children’s Hospital affiliated with Chongqing Medical University, Chongqing, China, for their cooperation in the study. Conflict of Interest The authors have nothing to disclose. References 1 Malinovsky JM, Populaire C, Cozian A, et al. Premedication with midazolam in children. Effect of intranasal, rectal and oral routes on plasma midazolam concentrations. Anaesthesia 1995;50:351–4. 2 Kogan A, Katz J, Efrat R, et al. Premedication with midazolam in young children: A comparison of 4 routes of administration. Paediatr Anaesth 2002;12:685–9. 3 Iirola T, Vilo S, Manner T, et al. Bioavailability of dexmedetomidine after intranasal administration. Eur J Clin Pharmacol 2011;67:825–31. 4 Sheta SA, Al-Sarheed MA, Abdelhalim AA. Intranasal dexmedetomidine vs midazolam for premedication in children undergoing complete dental rehabilitation: A double-blinded randomized controlled trial. Paediatr Anaesth 2014;24:181–9. 5 Yuen VM, Hui TW, Irwin MG, et al. Optimal timing for the administration of intranasal dexmedetomidine for premedication in children. Anaesthesia 2010;65:922–9. 6 Fett J, Hackbarth R, Boville BM, et al. Comparative effectiveness of intranasal dexmedetomidine-midazolam versus oral chloral hydrate targeting moderate sedation during pediatric transthoracic echocardiograms. J Pediatr Intensive Care 2017;6:182–7. 7 Miller J, Xue B, Hossain M, et al. Comparison of dexmedetomidine and chloral hydrate sedation for transthoracic echocardiography in infants and toddlers: A randomized clinical trial. Paediatr Anaesth 2016;26:266–72. 8 Miller JW, Divanovic AA, Hossain MM, et al. Dosing and efficacy of intranasal dexmedetomidine sedation for pediatric transthoracic echocardiography: A retrospective study. Can J Anaesth 2016;63:834–41. 9 Oc B, Akinci SB, Kanbak M, et al. The effects of sevoflurane anesthesia and cardiopulmonary bypass on renal function in cyanotic and acyanotic children undergoing cardiac surgery. Ren Fail 2012;34:135–41. 10 Pace NL, Stylianou MP. Advances in and limitations of up-and-down methodology: A precis of clinical use, study design, and dose estimation in anesthesia research. Anesthesiology 2007;107:144–52. 11 Aldrete JA. The post-anesthesia recovery score revisited. J Clin Anesth 1995;7:89–91. 12 Chernik DA, Gillings D, Laine H, et al. Validity and reliability of the Observer’s Assessment of Alertness/Sedation Scale: Study with intravenous midazolam. J Clin Psychopharmacol 1990;10:244–51. 13 Mathers LH, Frankel LR, et al. Pediatric emergencies and resuscitation. In: Kliegman RM, Behrman RE, Jenson HB, editors. Nelson textbook of pediatrics, 18th ed., Philadelphia, PA: Saunders Elsevier; 2007. p. 387–404.
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