Children with congenital heart disease undergo transthoracic echocardiography (TTE) procedures repeatedly during the course of their treatment. Some children undergoing TTE require sedation to allay their anxiety and prevent motion artefacts. Various drugs, such as chloral hydrate, midazolam (dormicum, Roche Ilaç Sanayi A.S. Turkey), propofol (propofol-lipuro 1%, B. Braun Melsungen AG, Germany) or ketamine, alone or in combination, have been used to induce sedation for TTE.1–3 However, these drugs have well known disadvantages, including a long half-life, respiratory depression, and delayed resedation or their route of administration (oral, intravenous, intramuscular) is difficult.
Dexmedetomidine (DEX) (Aibeining; Hengru Medicine co., Ltd., Jiangsu, China) is a highly selective α2-adrenergic receptor agonist that provides sedation without respiratory depression. Previous studies have reported that DEX is suitable for premedication,4 as an adjunct for elective surgery, or as a sedative for MRI and TTE.5,6 Intranasal DEX is reportedly more effective and safer than midazolam.7–9 According to our clinical experience, compared with normal children with no cardiac pathology, postcardiac surgery children require a larger dose of intranasal DEX to achieve satisfactory sedation for a TTE procedure. However, there are few data in the literature about this.
Hence, the primary aim of this study was to compare the median effective dose of intranasal DEX for TTE sedation in postcardiac surgery children with that of children with no congenital heart disease. The second objective was to study the haemodynamic stability and adverse events with these doses. We hypothesised that postcardiac surgery children would require a larger dose of DEX for TTE than normal children.
The registry Uniform Resource Locator of this study is chictr.org.cn (ChiCTR-OOC-16009846, registration date: 14 October 2016). Ethical approval for this study (File NO. 2016124) was provided by Institutional Review Board of Children's Hospital Affiliated Chongqing Medical University, Chongqing, China (Chairperson Professor Lu Zhongyi) on 25 October 2016. The study started on 25 October 2016 and ended on 30 November 2016. Written informed consent was taken from all parents or legal guardians.
The inclusion criteria were children under the age of 3 years (American Society of Anesthesiologists physical status I to II) undergoing a follow-up TTE 1 month after open heart surgery (postcardiac surgery group) or children having TTE for suspected congenital heart disease. Of these latter children, only those whose TTE was subsequently found to be normal had their data analysed and they formed the normal group. The exclusion criteria were lack of consent, allergy to DEX, nasal discharge, renal or hepatic dysfunction, any serious systemic diseases, history of preterm birth, trisomy 21 and recent administration of digoxin (Digaoxin; Shanghai Xinyi Pharmaceutical Co., Ltd. Shanghai, China) or β-blockers.
When a child had fasted for at least 2 h after liquids, intranasal DEX was administered by an anaesthetist who was not involved in the data collection. With the child lying in the supine position, undiluted DEX was dripped into both nostrils using a 1-ml syringe. All the children were encouraged to stay in the supine position for 1 to 2 min to maximise drug absorption, gently rubbing the allae of the nose to ensure the drug was absorbed better.
Sedation was assessed by the Modified Observer Assessment of Alertness and Sedation Scale (MOAA/S)10,11 (Table 1) by a blinded anaesthesiologist before, and every 5 min after the administration of DEX. Successful sedation was defined as MOAA/S 3 or less within 30 min of the initial DEX administration and subsequently adequate diagnostic-quality images were obtained. Failed sedation was defined as MOAA/S more than 3 or if, despite apparently successful sedation, adequate diagnostic-quality images could not be acquired because of physical resistance during the TTE procedures. Additional ‘rescue’ DEX (1 μg kg−1) was administered intranasally to the children whose initial sedation failed and, if required, this was followed by sevoflurane inhalation to allow completion of the TTE examination.
We used the Dixon and Massey up-and-down method12 to determine the median effective dose of DEX. Based on a previous study13 and our pilot experiments, the starting dose of DEX was 2 μg kg−1 (Aibeining; Jiangsu Hengru Medicine co., Ltd., Jiangsu, China). If sedation was successful, the DEX dose for the next patient was decreased by 0.5 μg kg−1 in the postcardiac surgery group and 0.25 μg kg−1 in the normal group. If sedation was not successful, the DEX dose for the next patient was increased by 0.5 μg kg−1 in the postcardiac surgery group and 0.25 μg kg−1 in the normal group.
Using a portable noninvasive monitor, the anaesthetist collected the following data from before the drug administration (baseline), and every 5 min after drug administration until discharge: heart rate, blood pressure, oxygen saturation and respiratory rate. Time to sedation was defined as the time from drug administration to the onset of satisfactory sedation. The wake-up time was defined as the time from successful sedation to the time to wake-up. As soon as the echocardiograph examination was completed, parents were encouraged to wake up their children with gentle tactile stimulation (patting on shoulder) or by calling their name. Children were discharged from the hospital when they attained a modified Aldrete score (Table 2) of 9.14 Each patient was followed up the next day, by telephone, to note any adverse event such as regurgitation, vomiting or respiratory depression. Hypotension or bradycardia was defined as a reduction in blood pressure and heart rate of more than 20% from baseline. Significant oxyhaemoglobin desaturation was defined as an oxygen saturation less than 90%. All observations and data collection were performed by an anaesthesiologist who was blinded to the drug doses.
The sample size of the two groups was determined according to the Dixon and Massey up-and-down method12 and patients were enrolled until six pairs (from failed sedation to successful sedation) were obtained. The response of each patient with the dose used was plotted on a figure, with the dosage in μg kg−1 on the Y axis and the patient number on the X axis. The median effective dose was calculated as the average of the crossover midpoints15 and by probit regression. The effective dose in 95% of the population (ED95) was also estimated from probit regression.
Statistical analysis was performed using SPSS 17.0 for windows (SPSS Inc.,Chicago, IL, USA). Clinical data were expressed as mean ± SD. Statistical analysis for differences between the groups was undertaken using the two-tailed Student's t-test when normality (and homogeneity of variance) assumptions were satisfied, otherwise the nonparametric test (Mann–Whitney U) was used. For categorical data, a χ2 test was used. A value of P less than 0.05 was considered as statistically significant.
Twenty consecutive children who had previously undergone corrective open heart surgery and 19 consecutive normal children with a clinically suspected congenital heart disease but normal TTE were enrolled in this prospective study (Fig. 1). In the postcardiac surgery group, five children with cyanotic congential heart disease (tetralogy of Fallot, total anomalous pulmonary venous drainage, double outlet right ventricle) and 15 children with noncyanotic congential heart disease (ventricular septal defect, atrial septal defect, patent ductus arteriosus) had undergone corrective surgery. There were no significant differences between the groups in demographic variables (P > 0.05, Table 3).
For those patients who had successful sedation with the estimated dose of DEX (nine postcardiac surgery group, 10 normal group), there were no differences in sedation induction time, TTE examination time or wake-up time between the groups (P > 0.05, Table 4). A 2-year-old girl did not have satisfactory sedation after 30 min, possibly because of a prolonged fasting time, as she fell asleep after 20 ml of milk. All patients with failed sedation received an additional rescue dose of intranasal dexmetomidine (1 μg kg−1) and subsequently two patients in the postcardiac surgery group and one in the normal group required sevoflurane inhalation to complete the examination.
The sequences of successful and failed sedation outcomes of the two groups are shown in Fig. 2. The median effective dose and ED95 (95% confidence interval) values of intranasal DEX for sedation were 3.3 (2.7 to 3.8) and 4.4 (3.8 to 12.7) μg kg−1 in the postcardiac surgery group, 1.8 (1.7 to 2.0) and 2.1 (1.9 to 3.9) μg kg−1 in the normal group (P < 0.05, Table 5). The median effective dose of intranasal DEX for TTE sedation in postcardiac surgery children was higher than in normal children (P < 0.05).
Adverse events such as regurgitation, vomiting and apnoea were not observed in either group. None of the children had oxyhaemoglobin desaturation of less than 90% during the observation period. Haemodynamic variables were stable (within 20% of the baseline) during the procedure in both groups.
In the current study, by using Dixon and Massey's ‘up-and-down’ methodology and probit regression, we found that the doses of DEX to achieve adequate sedation were almost doubled in postcardiac surgery children compared with normal children. Drug tolerance and posttraumatic stress may be important factors underlying this need for an increased dose.
Postoperative sedation is an essential component during a patient's recovery after cardiac surgery. Sedation reduces the discomfort and anxiety caused by surgery, intubation, mechanical ventilation, suction, physiotherapy and so on. DEX, midazolam, propofol and opioids are commonly used for sedation in the ICU and tolerance to their clinical effects occurs. Pharmacological studies also show that continuous administration of DEX produces drug tolerance.16
The dose of intranasal DEX for successful sedation in children is not uniform.17–19 This may be partly because of the type of noninvasive procedure being performed, as well as child-related factors (e.g. the age of the child, the degree of sleep deprivation before sedation, fasting time) and environmental factors such as air temperature. Lower doses of intranasal DEX increase the failure rate for successful sedation but, whereas higher doses of intranasal DEX increase the rate of successful sedation, they extend wake-up times,20 and may also result in cardiovascular complications.21–24 When considering the optimal dose of intranasal DEX for TTE sedation, one must take into consideration previous cardiac surgery as our results clearly demonstrate that to attain the same degree of sedation for TTE such children require higher doses of DEX than normal children. The time to wake up, we observed, was consistent with previous reports25 and the children had no adverse events such as regurgitation, vomiting, respiratory depression or undesirable haemodynamic changes requiring intervention. These results are helpful for daily clinical practice in enabling better selection of the optimal dose of intranasal DEX for TTE sedation.
The main limitation of this study is that the dose of DEX has been calculated by the Dixon and Massey up-and-down method, using the minimum number of crossover points (6), and thus the results are obtained from a small sample size. The lack of haemodynamic effects and adverse events needs to be validated with a larger sample size. The second limitation of this study is that some factors might have modified the degree of sedation; these would include age,26,27 fasting time, the quality of the child's sleep the night before sedation and the type of congenital heart disease. There are also considerable changes in DEX clearance depending on a child's age and weight.28,29 Our results may have been more precise if the study had been designed to include stratification according to age. In addition, there was no standard fasting time in our study. Longer fasting times may result in younger children being distressed by hunger hypoglycaemia and dehydration and these could antagonise sedation. Shorter fasting time increases the incidence of regurgitation and vomiting. In our study, one 2-year-old girl did not have a satisfactory sedative effect after 30 min because of a long fasting time: she immediately fell asleep after drinking 20 ml of milk, without any additional DEX.
In conclusion, the median effective dose of intranasal DEX required for TTE sedation is increased in children 1 month after cardiac surgery. The history of such surgery must be taken into account when choosing the dose of intranasal DEX for TTE sedation.
Acknowledgements relating to this article
Assistance with the study: we express our gratitude to Dr Peng Bin, Department of Health Statistics, Chongqing Medical University, China, for his assistance with the statistical analysis. We would like to acknowledge the support of the staff from the Anaesthesia Department and Ultrasound Department at the Children's Hospital affiliated to Chongqing Medical University, China for their cooperation in the study.
Financial support and sponsorship: financial support was provided from the National Key Clinical Program [(2013) 544], Health and Family Planning Commission of Chongqing, China (2015HBRC007), Natural Science Foundation of Chongqing (cstc2012jjA10036).
Conflicts of interest: none.
1. Heistein LC, Ramaciotti C, Scott WA, et al. Chloral hydrate sedation for pediatric echocardiography: physiologic responses, adverse events, and risk factors. Pediatrics
2. Toman H, Erkilinc A, Kocak T, et al. Sedation for transesophageal echocardiography: comparison of propofol, midazolam andmidazolam-alfentanil combination. Med Glas (Zenica)
3. Jha AK, Gharde P, Chauhan S, et al. Echocardiographic assessment of the alterations in pulmonary blood flow associated with ketamine and etomidate administration in children with tetralogy of Fallot. Echocardiography
4. Peng K, Wu SR, Ji FH, et al. Premedication with dexmedetomidine in pediatric patients: a systematic review and meta-analysis. Clinics (Sao Paulo)
5. Ambi US, Joshi C, Ganeshnavar A, et al. Intranasal dexmedetomidine for paediatric sedation for diagnostic magnetic resonance imaging studies. Indian J Anaesth
6. Miller JW, Divanovic AA, Hossain MM, et al. Dosing and efficacy of intranasal dexmedetomidine sedation for pediatric transthoracic echocardiography: a retrospective study. Can J Anesth
7. Ghali AM, Mahfouz AK, Al-Bahrani M. Preanesthetic medication in children: a comparison of intranasal dexmedetomidine versus oral midazolam. Saudi J Anaesth
8. Kumar L, Kumar A, Panikkaveetil R, et al. Efficacy of intranasal dexmedetomidine versus oral midazolam for paediatric premedication. Indian J Anaesth
9. Sheta SA, Alsarheed MA, Abdelhalim AA. Intranasal dexmedetomidine vs midazolam for premedication in children undergoing complete dental rehabilitation: a double-blinded randomized controlled trial. Paediatr Anaesth
10. Yuen VM, Irwin MG, Hui TW, et al. A double-blind, crossover assessment of the sedative and analgesic effects of intranasal dexmedetomidine. Anesth Analg
11. 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
12. Pace NL, Stylianou MP. Advances in and limitations of up-and-down methodology: a précis of clinical use, study design, and dose estimation in anesthesia research. Anesthesiology
13. 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
14. Li BL, Yuen VM, Song XR, et al. Intranasal dexmedetomidine following failed chloral hydrate sedation in children. Anaesthesia
15. Burlacu CL, Gaskin P, Fernandes A, et al. A comparison of the insertion characteristics of the laryngeal tube and the laryngeal mask airway: a study of the ED50 propofol requirements. Anaesthesia
16. Reid K, Guo TZ, Davies MF, et al. Nifedipine, an L-type calcium channel blocker, restores the hypnotic response in rats made tolerant to the alpha-2 adrenergic agonist dexmedetomidine. J Pharmacol Exp Ther
17. Baier NM, Mendez SS, Kimm D, et al. Intranasal dexmedetomidine: an effective sedative agent for electroencephalogram and auditory brain response testing. Paediatr Anaesth
18. Li BL, Ni J, Huang JX, et al. Intranasal dexmedetomidine for sedation in children undergoing transthoracic echocardiography study: a prospective observational study. Paediatr Anaesth
19. Yuen VM, Hui TW, Irwin MG, et al. A randomised comparison of two intranasal dexmedetomidine doses for premedication in children. Anaesthesia
20. Zhang W, Wang Z, Song X, et al. Comparison of rescue techniques for failed chloral hydrate sedation for magnetic resonanceimaging scans: additional choral hydrate vs intranasal dexmedetomidine. Paediatr Anaesth
21. Shuplock JM, Smith AH, Owen J, et al. Association between perioperative dexmedetomidine and arrhythmias after surgery for congenital heart disease. Circ Arrhythm Electrophysiol
22. Tobias JD, Chrysostomou C. Dexmedetomidine: antiarrhythmic effects in the pediatric cardiac patient. Pediatr Cardiol
23. Ezzati M, Broad K, Kawano G, et al. Pharmacokinetics of dexmedetomidine combined with therapeutic hypothermia in a piglet asphyxia model. Acta Anaesthesiol Scand
24. Tug A, Hanci A, Turk HS, et al. Comparison of two different intranasal doses of DEX in children for magnetic resonance imaging sedation. Paediatr Drugs
25. Li BL, Zhang N, Huang JX, et al. A comparison of intranasal dexmedetomidine for sedation in children administered either by atomiser or by drops. Anaesthesia
26. Vilo S, Rautiainen P, Kaisti K, et al. Pharmacokinetics of intravenous dexmedetomidine in children under 11 yr of age. Br J Anaesth
27. Zhang WH, Fan YT, Zhao TY, et al. Median effective dose of intranasal dexmedetomidine for rescue sedation in pediatric patients undergoing magnetic resonance imaging. Anesthesiology
28. Potts AL, Anderson BJ, Warman GR, et al. Dexmedetomidine pharmacokinetics in pediatric intensive care: a pooled analysis. Pediatr Anesth
© 2018 European Society of Anaesthesiology
29. Su F, Nicolson SC, Gastonguay MR, et al. Population pharmacokinetics of dexmedetomidine in infants after open heart surgery. Anesth Analg