Journal http://jcn.sagepub.com/ of Child Neurology
Comparison of Effects of Different Dexmedetomidine and Chloral Hydrate Doses Used in Sedation on Electroencephalography in Pediatric Patients Hakan Gumus, Ayse Kacar Bayram, Hatice Gamze Poyrazoglu, Dilek Gunay Canpolat, Huseyin Per, Mehmet Canpolat, Karamehmet Yildiz and Sefer Kumandas J Child Neurol published online 22 September 2014 DOI: 10.1177/0883073814549582 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2014/09/17/0883073814549582
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Original Article
Comparison of Effects of Different Dexmedetomidine and Chloral Hydrate Doses Used in Sedation on Electroencephalography in Pediatric Patients
Journal of Child Neurology 1-6 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814549582 jcn.sagepub.com
Hakan Gumus, MD1, Ays¸ e Kacar Bayram1, Hatice Gamze Poyrazoglu, MD1, Dilek Gunay Canpolat2, Huseyin Per, MD1, Mehmet Canpolat, MD1, Karamehmet Yildiz, MD2, and Sefer Kumandas, MD1
Abstract The aim of this study was to compare the efficacy and safety of different oral chloral hydrate and dexmedetomidine doses used for sedation during electroencephalography (EEG) in children. One hundred sixty children aged 1 to 9 years with American Society of Anesthesiologists physical status I-II who were uncooperative during EEG recording or who were referred to our electrodiagnostic unit for sleep EEG were included to the study. The patients were randomly assigned into 4 groups. In groups D1 and D2, patients received oral dexmedetomidine doses of 2 and 3 mg/kg, respectively. In group C1 and C2, patients received oral chloral hydrate doses of 50 and 100 mg/kg, respectively. The induction time was significantly shorter in group C2 compared with other groups (P ¼ .000). The rate of adverse effects was significantly higher in group C2 compared with the dexmedetomidine groups (D1 and D2; P ¼ .004). In conclusion, dexmedetomidine can be used safely for sedation during EEG in children. Keywords chloral hydrate, dexmedetomidine, electroencephalography Received May 09, 2014. Received revised July 01, 2014. Accepted for publication August 02, 2014.
Electroencephalography (EEG) is a useful diagnostic tool in the diagnosis of seizures and differentiating them from seizurelike attacks. EEG procedure requires cooperation and immobility of patients and children. However, it may not be possible to achieve spontaneous sleep in some patients, especially in the children. Thus, sedation should be used to induce sleep. Sedation is usually required to perform EEG recordings in such patients.1 Several sedative agents can be used in the children to induce sedation during EEG monitoring. Chloral hydrate is a sedative-hypnotic agent that is widely used for sedation in pediatric patients during EEG monitoring. However, it has many disadvantages, such as longer time of action, paradoxical reaction, vomiting, respiratory depression, oxygen desaturation, inconsistent sedative effects, and potential for carcinogenicity.1,2 Dexmedetomidine is a more selective alpha-2 adrenergic agonist, which induces sedation and analgesia via stimulation of a2-receptors. Dexmedetomidine has relatively shorter half-life and hepatic metabolism. Its use in children has gained popularity because of its ability to provide adequate procedural sedation with relatively low risk of respiratory depression and fewer cardiovascular
effects.3-5 Dexmedetomidine is considered to be useful in EEG recording, as it has minimal effect on EEG peak frequency and amplitude.6,7 Other sedative agents such as benzodiazepines, barbiturates, and propofol can also be used in children to induce sedation during EEG recordings.8 Recently, hydroxyzine, promethazine, melatonin, and clonidine have been used in children to induce sedation during EEG recordings.9-12 In the present study, we aimed to compare the efficacy and safety of oral chloral hydrate and dexmedetomidine in achieving adequate sedation for sleep EEG recordings in children.
1
Division of Pediatric Neurology, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey 2 Department of Anaesthesiology, Erciyes University, Kayseri, Turkey Corresponding Author: Hakan Gumus, MD, Division of Pediatric Neurology, Department of Pediatrics, Faculty of Medicine, Erciyes University, Melikgazi, Kayseri, 38039, Turkey. Email: [email protected]
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Journal of Child Neurology
Methods The study was approved by the Local Ethics Committee of Erciyes University. Informed consent was obtained from all parents or legal guardians of the children included. This randomized, prospective study included 160 patients who were uncooperative during EEG recording or who were referred to our electrodiagnostic unit for sleep EEG recording. All patients were classified as American Society of Anesthesiologists class I (a normal healthy patient) or class II (a patient with mild systemic disease).13 All children were referred to the EEG unit by a pediatric neurologist on the basis of the indications after a clinical assessment for the differential diagnosis including suspected epilepsy, epilepsy, febrile seizure, and other diseases. Informed consent was obtained from the patients’ parents. Exclusion criteria included presence of allergy or hypersensitive reaction to dexmedetomidine or chloral hydrate, and any other serious systemic diseases such as neurologic, cardiac, respiratory, metabolic, and gastrointestinal diseases. The patients were randomly allocated to 1 of the 4 groups by a computer-generated drawing lot. The patients were not allowed to sleep within 12 hours prior to procedure. In all patients, a 24-G cannula was placed for intravenous access before procedure. All patients received single doses of dexmedetomidine or chloral hydrate via oral route before the procedure. Sedative agents were prepared and administered by a trained nurse under the supervision of the attending pediatric neurologist in all patients. In groups D1 and D2, corresponding amounts of dexmedetomidine (Precedex 100 mg/mL; Abbott Laboratories, IL) in 3 mL normal saline were given to patients via the oral route. In the D1 and D2 groups, patients received oral dexmedetomidine doses of 2 and 3 mg/kg, respectively. In groups C1 and C2, corresponding amounts of chloral hydrate (100 mg/mL) in freshly prepared, cherry-flavored liquids were given to patients in a single dose orally. In these groups (C1 and C2), patients received oral chloral hydrate doses of 50 and 100 mg/kg, respectively. After drug administration, the patients were placed in a quiet and dark room with their parents until they fell asleep. During this time, the patients were assessed by using Ramsay sedation score.14 The patients were assessed before and at every 5 minutes after ingestion of the sedative agent. A Ramsay sedation score between 4 and 6 was considered for rescue sedation. Subsequently, the patients were transferred to the electrodiagnostic room. Standard monitoring including blood pressure, peripheral oxygen saturation, and heart rate was performed and all parameters were recorded by 5-minute intervals throughout the sedation. Induction time was defined as the time from ingestion of sedative drugs to adequate sedation (Ramsay sedation score 4). If adequate sedation (Ramsay sedation score 25% decrease in mean
Figure 1. Procedure process and parts of total sedation time. arterial blood pressure from baseline), bradycardia, and nausea and vomiting were recorded. The primary aim of the study was to evaluate the efficacy of sedation induction for successful recording of sleep EEG. Secondary outcome measures included times of sedation and adverse effects of different dexmedetomidine and chloral hydrate doses. All statistical analyses were performed by using SPSS for Windows version 22.0 (SPSS, Inc, Chicago, IL). Continuous variables were presented as mean + standard deviation. The Pearson chi-square test was used to assess qualitative variables. Normal distribution was evaluated by using the Kolmogorov-Smirnov test. Homogeneity of variances was tested by using Levene’s test. For parametric statistics, data with normal distribution were analyzed by using a 1-way analysis of variance. When a significant result was obtained, the Tukey test was used for post hoc comparisons. For nonparametric statistics, data with skewed distribution were analyzed by using a Kruskal-Wallis test. When a significant result was obtained, Mann-Whitney U test with Bonferroni correction was used for post hoc comparisons. A P value less than .05 was considered as statistically significant.
Results Overall, 160 patients (85 male and 75 female) were included in this study. The mean age was 44 + 19.6 months (age range: 1-9 years) and mean weight was 13.8 + 3.7 kg. All patients were randomly divided into 4 groups as follows: group D1 (n ¼ 42; 26%), group D2 (n ¼ 42; 26%), group C1 (n ¼ 36; 23%), and group C2 (n ¼ 40; 25%). There were no significant differences in demographic characteristics between the children who received dexmedetomidine (D1 or D2) and those who received chloral hydrate (C1 or C2). Demographic characteristics, clinical diagnoses, and sedative agent–related variables are summarized in Table 1. The indications for EEG recording were suspected epilepsy in 38.1%, epilepsy in 21.3%, febrile seizure in 21.9%, and other causes in 18.7% of the patients. In group D1, reasons for referral to EEG recording were suspected epilepsy in 19 patients (45%), epilepsy in 9 patients (21%), febrile seizure in 10 patients (24%), and other causes in 4 patients (10%), whereas it was suspected epilepsy in 14 patients (33%), epilepsy in 11 patients (26%), febrile seizure in 9 patients (22%), and other causes in 8 patients (19%) in group D2. In group C1, reasons for referral to EEG recording were suspected epilepsy in 13 patients (36%), epilepsy in 8 patients (22%), febrile seizure in 7 patients (20%), and other causes in 8 patients (22%), whereas it was suspected epilepsy in 15 patients (37%),
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Gumus et al
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Table 1. The Demographic Characteristics, Clinical Diagnoses, and Sedative Drug-Related Variables.a D1 group (n ¼ 42)
D2 group (n ¼ 42)
C1 group (n ¼ 36)
C2 group (n ¼ 40)
P value
44.6 + 20.7 14.1 + 3.6
45.1 + 22.3 14.1 + 4.4
47 + 21.9 14.1 + 4.2
39.4 + 11.2 13.0 + 1.8
0.354c 0.446c 0.971d
23 (54.8) 19 (45.2)
23 (54.8) 19 (45.2)
18 (50.0) 18 (50.0)
21 (52.5) 19 (47.5)
Age (mo)b Weight (kg)b Sex Male Female Disease Epilepsy? Epilepsy Febrile seizure Other ASA ASA I ASA II
0.813d 19 (45.2) 9 (21.5) 10 (23.8) 4 (9.5)
14 (33.3) 11 (26.2) 9 (21.4) 8 (19.1)
13 (36.1) 8 (22.2) 7 (19.5) 8 (22.2)
15 (37.5) 6 (15.0) 9 (22.5) 10 (25.0) 0.965d
32 (76.2) 10 (23.8)
33 (78.6) 9 (21.4)
29 (80.6) 7 (19.4)
32 (80.0) 8 (20.0)
Abbreviations: ASA, American Society of Anesthesiologists; C, chloral hydrate; D, dexmedetomidine; Epilepsy?, suspected epilepsy. a In groups D1 and D2, patients received oral dexmedetomidine doses of 2 and 3 mg/kg, respectively. In groups C1 and C2, patients received oral chloral hydrate doses of 50 and 100 mg/kg, respectively. Values within parentheses are percentages. Level of significance: P < .05. b Variables are expressed as mean + standard deviation. c Analysis of variance. d Pearson w2 test.
Table 2. Sedation Times, Outcome, and Adverse Effects.a Total (n ¼ 160) b
Induction time (min) EEG time (min)b Recovery time (min)b Total sedation time (min)b Sedation failure Adverse effects Oxygen desaturation Hypotension Bradycardia Agitation Vomiting, nausea
33.2 + 4.8 31.7 + 6.0 53.3 + 25.6 118.2 + 25.5 20 (12.5) 16 (10.0) 2 (1.2) 1 (0.6) 1 (0.6) 2 (1.3) 10 (6.3)
D1 group (n ¼ 42) 35.9 32.0 41.7 109.6 7 0 0 1 0 0
+ 3.5 + 6.0 + 23.4 + 24.3 (16.7) (0) (0) (2.4) (0) (0)
D2 group (n ¼ 42)
C1 group (n ¼ 36)
34.5 + 4.0 31.8 + 6.4 48.3 + 28.6 114.6 + 30.7 3 (7.1)
34.0 + 4.6 31.6 + 5.6 52.2 + 24.2 117.8 + 23.4 8 (22.2)
0 (0) 1 (2.4) 0 (0) 0 (0) 0 (0)
1 (2.8) 0 (0) 0 (0) 0 (0) 3 (8.3)
C2 group (n ¼ 40) 28.9 31.4 70.0 130.3 2 1 0 0 2 7
+ 4.0 + 6.1 + 15.8 + 17.4 (5)
P value 0.000c 0.983c 0.000c 0.003c 0.074d 0.004d
(2.5) (0) (0) (5.0) (17.5)
Abbreviations: C, chloral hydrate; D, dexmedetomidine; EEG, electroencephalography. a In groups D1 and D2, patients received oral dexmedetomidine doses of 2 and 3 mg/kg, respectively. In groups C1 and C2, patients received oral chloral hydrate doses of 50 and 100 mg/kg, respectively. Values within parentheses are percentages. Level of significance: P < .05. b Variables are expressed as mean + standard deviation. c Analysis of variance. d Pearson w2 test.
epilepsy in 6 patients (15%), febrile seizure in 9 patients (23%), and other causes in 10 patients (25%) in group C2. No significant difference was detected in reasons for referral to EEG recording between groups. Referral etiology for EEG recording was not significantly different among groups (Table 1). The mean induction time was found as 35.9 + 3.5 minutes in group D1, 34.5 + 4.0 minutes in group D2, 34.0 + 4.6 minutes in group C1, and 28.9 + 4.0 minutes in group C2. The induction time was significantly shorter in group C2 compared with other groups (P ¼ .000). The mean EEG recording time was 31.7 + 6.0 minutes, with no significant difference among groups (P ¼ .983). Mean recovery time was 41.7 + 23.4 minutes in group D1, 48.3 + 28.6 minutes in group D2, 52.2 + 24.2 minutes in group C1, and 70.0 + 15.8 minutes in group C2. The recovery time was significantly longer in group C2
compared with other groups (P ¼ .000). The mean total sedation time was 109.6 + 24.3 minutes in group D1, 114.6 + 30.7 minutes in group D2, 117.8 + 23.4 minutes in group C1, and 130.3 + 17.4 minutes in group C2. The total sedation time was significantly longer in group C2 compared with groups D1 and D2 (P ¼ .003) (Table 2). The overall sedation failure rate was 16.7% in group D1, 7.1% in group D2, 22.2% in group C1, and 5% in group C2. There was no statistically significant difference in rates of sedation failure among groups (P ¼ .074) (Table 2). After the procedure, hypoxia developed in 1 patient (2.8%) in group C1 and 1 patient (2.5%) in group C2. Both patients were treated with supplemental oxygen (3-4 L/min) without need for airway management. Agitation was seen in 2 patients (5%) in group C2. Hypotension developed in 1 patient (2.4%)
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Journal of Child Neurology
Figure 2. Comparison of successful sedation and adverse effects of drugs between groups of patients who were sedated with dexmedetomidine and chloral hydrate.
in group D1, whereas bradycardia occurred in 1 patient (2.4%) in group D2. Vomiting or nausea developed in 3 patients (8.3%) in group C1 and 7 patients 17.5%) in group C2 (Table 2). The overall adverse drug effect rate was 2.4% in group D1, 2.4% in group D2, 11.1% in group C1, and 25% in group C2. Adverse drug effect rate was significantly higher in group C2 compared with the dexmedetomidine groups (D1 and D2) (P ¼ .004). Successful sedation rates and adverse drug effects in the groups are shown in Figure 2.
Discussion Chloral hydrate has 2 active metabolites, namely, trichloroethanol and trichloroacetic acid. Chloral hydrate is rapidly absorbed from the gastrointestinal tract after oral use. Its sedative and hypnotic effects occur within 20-60 minutes after administration and last for 60 to 120 minutes. Its half-life is of a few minutes but it is longer for active metabolites, being 8 to 12 hours for trichloroethanol and 67 hours for trichloroacetic acid. Trichloroethanol probably exerts its effect on the central nervous system through an unknown mechanism.16 The literature on sedation with different doses of chloral hydrate is characterized by a wide range of failure rates and adverse effects. The dosages of chloral hydrate used in this study were derived from assessments of clinical literature and practice.11,17-19 Recently, Bektas et al9 described their recent experience in low-dose chloral hydrate (26.38 + 14.73 mg/ kg) for sedation in pediatric EEG recording. The authors reported an overall success rate of 89% without adverse effects. Hijazi et al18 found that effective sedation was achieved in 79% of patients with an average dose of 56.1 + 9.3 mg and in 94% with an average dose of 71.6 + 13.4 mg. The authors reported an overall adverse effect rate of 2.7%. However, Avlonitou et al17 reported 1591 children who received sedation with chloral hydrate for auditory brain stem response testing. The authors reported a success rate of 99.7% and an adverse effect rate of 20.6% by using chloral hydrate at doses of 40 to 80 mg/
kg (maximum total dose: 1.0 g) via the oral route or a nasogastric tube. However, in a recent study, 3 cases of pediatric chloral hydrate poisoning were described. In all cases, poisoning occurred following procedural sedation in outpatient settings. All patients presented to the emergency department and required resuscitation. Of these, 1 patient died despite all interventions.20 Dexmedetomidine has a rapid distribution phase with a distribution half-life of 6 minutes, and distribution from the central to peripheral compartments requires roughly 30 to 45 minutes. However, steady-state concentrations continue for approximately 14 hours in dexmedetomidine. It is metabolized to inactive metabolites in the liver by glucuronidation and cytochrome P450. The elimination half-life of dexmedetomidine is 2 hours. Approximately 95% of dexmedetomidine and its metabolites are excreted into urine, whereas 4% are excreted into feces.3,4 Although there are several reports on intranasal, intramuscular, or intravenous use of dexmedetomidine for sedation in children, a limited number of studies were conducted with oral dexmedetomidine without a loading dose for pediatric sedation. One different aspect of the current study was the use of oral dexmedetomidine without a second dose. Lubisch et al21 found a higher success rate of 99.3% and shorter recovery times with dexmedetomidine compared to pentobarbital. The authors did not report any adverse effect. Aksu et al7 reported that dexmedetomidine provided adequate sedation by 100% for pediatric EEG recording without adverse effects. The authors reported that there was less change in EEG baseline rhythm quantitative values after dexmedetomidine compared to those after midazolam. Ray et al22 reported that dexmedetomidine provided 100% success rate and safe sedation for EEG recording in children with autism, seizure disorders, and pervasive developmental disorders. Zub et al23 reported use of oral dexmedetomidine with a mean dose of 2.6 + 0.83 mg/kg in 13 children aged 4–14 years. The authors reported adequate sedation in 84.6% of study participants without complications. They concluded that satisfaction with the sedation experiences was high in oral administration of dexmedetomidine. In a recent study, Chrysostomou et al24 investigated the safety, efficacy, and pharmacokinetic profile of dexmedetomidine in preterm and full-term neonates. The authors reported that dexmedetomidine was effective for sedation in preterm and full-term neonates, and that it was well-tolerated without significant adverse effects. However, preterm neonates had decreased plasma clearance and longer elimination half-life. To our knowledge, there is no study in the literature comparing oral chloral hydrate and oral dexmedetomidine for recording sleep EEGs in pediatric patients. In our study, the doses of oral dexmedetomidine were 2.0 mg/kg in group D1 and 3.0 mg/kg in group D2, whereas the doses of oral chloral hydrate were 50 mg/kg in group C1 and 100 mg/kg in group C2. Our study showed that the mean induction time was significantly shorter in group C2 compared with other groups (P ¼ .000). Moreover, total sedation time was significantly longer in group C2 compared with dexmedetomidine groups (D1 and
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D2) (P ¼ .003). The longer sedation period and slower return of arousal were disadvantages in C2 group for sleep EEG recording in the pediatric population. In the present study, we found that the rates of adequate sedation in the D2 and C2 groups were higher than other groups but the difference did not reach statistical significance (P ¼ .074). However, we observed that the adverse effect rate was significantly higher in group C2 compared with the dexmedetomidine groups (D1 and D2) (P ¼ .004). The most common complications included vomiting and nausea. These complications were observed in groups C1 and C2 with rates of 8.3% and 17.5%, respectively. There was no complication requiring airway management or resuscitation. One limitation of our study is small sample size. Another limitation was a shorter follow-up period. Therefore, delayed adverse event following discharge was not documented. It was concluded that further studies with larger sample sizes and longer follow-up periods as well as different doses of dexmedetomidine and chloral hydrate are needed. From our results, it appears that oral dexmedetomidine is a safe and effective drug for sleep EEG recording in the pediatric population. We observed that dexmedetomidine was effective at a dose of 2 mg/kg in 83.3%, whereas a dose of 3 mg/kg was effective in 92.9% of the patients, respectively. Furthermore, there was no significant difference in adverse effects between the 2 doses of dexmedetomidine. On the other hand, we found that 77.8% of children were sedated effectively with 50 mg/kg of chloral hydrate whereas 95.0% of children were sedated effectively with 100 mg/kg of chloral hydrate, respectively. The adverse effects of chloral hydrate were more commonly seen in the patients who were sedated with 100-mg/kg doses. In addition, total sedation time was significantly longer compared to the group receiving dexmedetomidine. In conclusion, according to our experiences in this study, considering the adverse effects and long sedative time of chloral hydrate, 3 mg/kg dexmedetomidine seems to be an appropriate sedative option for EEG recordings in children. In order to use dexmedetomidine, one should achieve a proper indication and with peace of mind in children for sleep EEG recording. Larger, randomized, prospective studies are needed. Acknowledgment All authors thank all the patients and family members for their participation in this study.
Author Contributions GH and PHG conceived the study. GH, KBA, PHG, GCD, YK, and KS reviewed the literature. HG, PHG, PH, CM, and KS were involved in patient care, including process of procedure and routine clinical follow-up. GH and KBA wrote the manuscript. KBA also performed the statistical analysis. PH, YK, GCD and KS also made helpful suggestions to improve the manuscript.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval Informed consent was obtained from all parents or legal guardians of the children included. This study was approval by the Local Ethics Committee of Erciyes University (2014/384).
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17. Avlonitou E, Balatsouras DG, Margaritis E, et al. Use of chloral hydrate as a sedative for auditory brainstem response testing in a pediatric population. Int J Pediatr Otorhinolaryngol. 2011; 75(6):760-763. 18. Hijazi OM, Haidar NA, Al-Eissa YA. Chloral hydrate. An effective agent for sedation in children with age and weight dependent response. Saudi Med J. 2005;26(5):746-749. 19. Marti-Bonmati L, Ronchera-Oms CL, Casillas C, et al. Randomized double blind clinical trial of intermediate- versus high-dose chloral hydrate for neuroimaging of children. Neuroradiology. 1995;37(8): 687-691. 20. Nordt SP, Rangan C, Hardmaslani M, et al. Pediatric chloral hydrate poisonings and death following outpatient procedural sedation. J Med Toxicol. Epub ahead of print Feb 15, 2014.
21. Lubisch N, Roskos R, Sattler SM. Improving outcomes in pediatric procedural sedation. Jt Comm J Qual Patient Saf. 2008;34(4): 192-195. 22. Ray T, Tobias JD. Dexmedetomidine for sedation during electroencephalographic analysis in children with autism, pervasive developmental disorders, and seizure disorders. J Clin Anesth. 2008;20(5):364-368. 23. Zub D, Berkenbosch JW, Tobias JD. Preliminary experience with oral dexmedetomidine for procedural and anesthetic premedication. Pediatr Anesth. 2005;15(11):932-938. 24. Chrysostomou C, Schulman SR, Herrera Castellanos M, et al. A phase II/III, multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates. J Pediatr. 2014;164(2):276-82
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Comparison of Effects of Different Dexmedetomidine and Chloral Hydrate Doses Used in Sedation on Electroencephalography in Pediatric Patients Hakan Gumus, Ayse Kacar Bayram, Hatice Gamze Poyrazoglu, Dilek Gunay Canpolat, Huseyin Per, Mehmet Canpolat, Karamehmet Yildiz and Sefer Kumandas J Child Neurol published online 22 September 2014 DOI: 10.1177/0883073814549582 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2014/09/17/0883073814549582
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>> OnlineFirst Version of Record - Sep 22, 2014 What is This?
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Original Article
Comparison of Effects of Different Dexmedetomidine and Chloral Hydrate Doses Used in Sedation on Electroencephalography in Pediatric Patients
Journal of Child Neurology 1-6 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814549582 jcn.sagepub.com
Hakan Gumus, MD1, Ays¸ e Kacar Bayram1, Hatice Gamze Poyrazoglu, MD1, Dilek Gunay Canpolat2, Huseyin Per, MD1, Mehmet Canpolat, MD1, Karamehmet Yildiz, MD2, and Sefer Kumandas, MD1
Abstract The aim of this study was to compare the efficacy and safety of different oral chloral hydrate and dexmedetomidine doses used for sedation during electroencephalography (EEG) in children. One hundred sixty children aged 1 to 9 years with American Society of Anesthesiologists physical status I-II who were uncooperative during EEG recording or who were referred to our electrodiagnostic unit for sleep EEG were included to the study. The patients were randomly assigned into 4 groups. In groups D1 and D2, patients received oral dexmedetomidine doses of 2 and 3 mg/kg, respectively. In group C1 and C2, patients received oral chloral hydrate doses of 50 and 100 mg/kg, respectively. The induction time was significantly shorter in group C2 compared with other groups (P ¼ .000). The rate of adverse effects was significantly higher in group C2 compared with the dexmedetomidine groups (D1 and D2; P ¼ .004). In conclusion, dexmedetomidine can be used safely for sedation during EEG in children. Keywords chloral hydrate, dexmedetomidine, electroencephalography Received May 09, 2014. Received revised July 01, 2014. Accepted for publication August 02, 2014.
Electroencephalography (EEG) is a useful diagnostic tool in the diagnosis of seizures and differentiating them from seizurelike attacks. EEG procedure requires cooperation and immobility of patients and children. However, it may not be possible to achieve spontaneous sleep in some patients, especially in the children. Thus, sedation should be used to induce sleep. Sedation is usually required to perform EEG recordings in such patients.1 Several sedative agents can be used in the children to induce sedation during EEG monitoring. Chloral hydrate is a sedative-hypnotic agent that is widely used for sedation in pediatric patients during EEG monitoring. However, it has many disadvantages, such as longer time of action, paradoxical reaction, vomiting, respiratory depression, oxygen desaturation, inconsistent sedative effects, and potential for carcinogenicity.1,2 Dexmedetomidine is a more selective alpha-2 adrenergic agonist, which induces sedation and analgesia via stimulation of a2-receptors. Dexmedetomidine has relatively shorter half-life and hepatic metabolism. Its use in children has gained popularity because of its ability to provide adequate procedural sedation with relatively low risk of respiratory depression and fewer cardiovascular
effects.3-5 Dexmedetomidine is considered to be useful in EEG recording, as it has minimal effect on EEG peak frequency and amplitude.6,7 Other sedative agents such as benzodiazepines, barbiturates, and propofol can also be used in children to induce sedation during EEG recordings.8 Recently, hydroxyzine, promethazine, melatonin, and clonidine have been used in children to induce sedation during EEG recordings.9-12 In the present study, we aimed to compare the efficacy and safety of oral chloral hydrate and dexmedetomidine in achieving adequate sedation for sleep EEG recordings in children.
1
Division of Pediatric Neurology, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey 2 Department of Anaesthesiology, Erciyes University, Kayseri, Turkey Corresponding Author: Hakan Gumus, MD, Division of Pediatric Neurology, Department of Pediatrics, Faculty of Medicine, Erciyes University, Melikgazi, Kayseri, 38039, Turkey. Email: [email protected]
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Methods The study was approved by the Local Ethics Committee of Erciyes University. Informed consent was obtained from all parents or legal guardians of the children included. This randomized, prospective study included 160 patients who were uncooperative during EEG recording or who were referred to our electrodiagnostic unit for sleep EEG recording. All patients were classified as American Society of Anesthesiologists class I (a normal healthy patient) or class II (a patient with mild systemic disease).13 All children were referred to the EEG unit by a pediatric neurologist on the basis of the indications after a clinical assessment for the differential diagnosis including suspected epilepsy, epilepsy, febrile seizure, and other diseases. Informed consent was obtained from the patients’ parents. Exclusion criteria included presence of allergy or hypersensitive reaction to dexmedetomidine or chloral hydrate, and any other serious systemic diseases such as neurologic, cardiac, respiratory, metabolic, and gastrointestinal diseases. The patients were randomly allocated to 1 of the 4 groups by a computer-generated drawing lot. The patients were not allowed to sleep within 12 hours prior to procedure. In all patients, a 24-G cannula was placed for intravenous access before procedure. All patients received single doses of dexmedetomidine or chloral hydrate via oral route before the procedure. Sedative agents were prepared and administered by a trained nurse under the supervision of the attending pediatric neurologist in all patients. In groups D1 and D2, corresponding amounts of dexmedetomidine (Precedex 100 mg/mL; Abbott Laboratories, IL) in 3 mL normal saline were given to patients via the oral route. In the D1 and D2 groups, patients received oral dexmedetomidine doses of 2 and 3 mg/kg, respectively. In groups C1 and C2, corresponding amounts of chloral hydrate (100 mg/mL) in freshly prepared, cherry-flavored liquids were given to patients in a single dose orally. In these groups (C1 and C2), patients received oral chloral hydrate doses of 50 and 100 mg/kg, respectively. After drug administration, the patients were placed in a quiet and dark room with their parents until they fell asleep. During this time, the patients were assessed by using Ramsay sedation score.14 The patients were assessed before and at every 5 minutes after ingestion of the sedative agent. A Ramsay sedation score between 4 and 6 was considered for rescue sedation. Subsequently, the patients were transferred to the electrodiagnostic room. Standard monitoring including blood pressure, peripheral oxygen saturation, and heart rate was performed and all parameters were recorded by 5-minute intervals throughout the sedation. Induction time was defined as the time from ingestion of sedative drugs to adequate sedation (Ramsay sedation score 4). If adequate sedation (Ramsay sedation score 25% decrease in mean
Figure 1. Procedure process and parts of total sedation time. arterial blood pressure from baseline), bradycardia, and nausea and vomiting were recorded. The primary aim of the study was to evaluate the efficacy of sedation induction for successful recording of sleep EEG. Secondary outcome measures included times of sedation and adverse effects of different dexmedetomidine and chloral hydrate doses. All statistical analyses were performed by using SPSS for Windows version 22.0 (SPSS, Inc, Chicago, IL). Continuous variables were presented as mean + standard deviation. The Pearson chi-square test was used to assess qualitative variables. Normal distribution was evaluated by using the Kolmogorov-Smirnov test. Homogeneity of variances was tested by using Levene’s test. For parametric statistics, data with normal distribution were analyzed by using a 1-way analysis of variance. When a significant result was obtained, the Tukey test was used for post hoc comparisons. For nonparametric statistics, data with skewed distribution were analyzed by using a Kruskal-Wallis test. When a significant result was obtained, Mann-Whitney U test with Bonferroni correction was used for post hoc comparisons. A P value less than .05 was considered as statistically significant.
Results Overall, 160 patients (85 male and 75 female) were included in this study. The mean age was 44 + 19.6 months (age range: 1-9 years) and mean weight was 13.8 + 3.7 kg. All patients were randomly divided into 4 groups as follows: group D1 (n ¼ 42; 26%), group D2 (n ¼ 42; 26%), group C1 (n ¼ 36; 23%), and group C2 (n ¼ 40; 25%). There were no significant differences in demographic characteristics between the children who received dexmedetomidine (D1 or D2) and those who received chloral hydrate (C1 or C2). Demographic characteristics, clinical diagnoses, and sedative agent–related variables are summarized in Table 1. The indications for EEG recording were suspected epilepsy in 38.1%, epilepsy in 21.3%, febrile seizure in 21.9%, and other causes in 18.7% of the patients. In group D1, reasons for referral to EEG recording were suspected epilepsy in 19 patients (45%), epilepsy in 9 patients (21%), febrile seizure in 10 patients (24%), and other causes in 4 patients (10%), whereas it was suspected epilepsy in 14 patients (33%), epilepsy in 11 patients (26%), febrile seizure in 9 patients (22%), and other causes in 8 patients (19%) in group D2. In group C1, reasons for referral to EEG recording were suspected epilepsy in 13 patients (36%), epilepsy in 8 patients (22%), febrile seizure in 7 patients (20%), and other causes in 8 patients (22%), whereas it was suspected epilepsy in 15 patients (37%),
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Table 1. The Demographic Characteristics, Clinical Diagnoses, and Sedative Drug-Related Variables.a D1 group (n ¼ 42)
D2 group (n ¼ 42)
C1 group (n ¼ 36)
C2 group (n ¼ 40)
P value
44.6 + 20.7 14.1 + 3.6
45.1 + 22.3 14.1 + 4.4
47 + 21.9 14.1 + 4.2
39.4 + 11.2 13.0 + 1.8
0.354c 0.446c 0.971d
23 (54.8) 19 (45.2)
23 (54.8) 19 (45.2)
18 (50.0) 18 (50.0)
21 (52.5) 19 (47.5)
Age (mo)b Weight (kg)b Sex Male Female Disease Epilepsy? Epilepsy Febrile seizure Other ASA ASA I ASA II
0.813d 19 (45.2) 9 (21.5) 10 (23.8) 4 (9.5)
14 (33.3) 11 (26.2) 9 (21.4) 8 (19.1)
13 (36.1) 8 (22.2) 7 (19.5) 8 (22.2)
15 (37.5) 6 (15.0) 9 (22.5) 10 (25.0) 0.965d
32 (76.2) 10 (23.8)
33 (78.6) 9 (21.4)
29 (80.6) 7 (19.4)
32 (80.0) 8 (20.0)
Abbreviations: ASA, American Society of Anesthesiologists; C, chloral hydrate; D, dexmedetomidine; Epilepsy?, suspected epilepsy. a In groups D1 and D2, patients received oral dexmedetomidine doses of 2 and 3 mg/kg, respectively. In groups C1 and C2, patients received oral chloral hydrate doses of 50 and 100 mg/kg, respectively. Values within parentheses are percentages. Level of significance: P < .05. b Variables are expressed as mean + standard deviation. c Analysis of variance. d Pearson w2 test.
Table 2. Sedation Times, Outcome, and Adverse Effects.a Total (n ¼ 160) b
Induction time (min) EEG time (min)b Recovery time (min)b Total sedation time (min)b Sedation failure Adverse effects Oxygen desaturation Hypotension Bradycardia Agitation Vomiting, nausea
33.2 + 4.8 31.7 + 6.0 53.3 + 25.6 118.2 + 25.5 20 (12.5) 16 (10.0) 2 (1.2) 1 (0.6) 1 (0.6) 2 (1.3) 10 (6.3)
D1 group (n ¼ 42) 35.9 32.0 41.7 109.6 7 0 0 1 0 0
+ 3.5 + 6.0 + 23.4 + 24.3 (16.7) (0) (0) (2.4) (0) (0)
D2 group (n ¼ 42)
C1 group (n ¼ 36)
34.5 + 4.0 31.8 + 6.4 48.3 + 28.6 114.6 + 30.7 3 (7.1)
34.0 + 4.6 31.6 + 5.6 52.2 + 24.2 117.8 + 23.4 8 (22.2)
0 (0) 1 (2.4) 0 (0) 0 (0) 0 (0)
1 (2.8) 0 (0) 0 (0) 0 (0) 3 (8.3)
C2 group (n ¼ 40) 28.9 31.4 70.0 130.3 2 1 0 0 2 7
+ 4.0 + 6.1 + 15.8 + 17.4 (5)
P value 0.000c 0.983c 0.000c 0.003c 0.074d 0.004d
(2.5) (0) (0) (5.0) (17.5)
Abbreviations: C, chloral hydrate; D, dexmedetomidine; EEG, electroencephalography. a In groups D1 and D2, patients received oral dexmedetomidine doses of 2 and 3 mg/kg, respectively. In groups C1 and C2, patients received oral chloral hydrate doses of 50 and 100 mg/kg, respectively. Values within parentheses are percentages. Level of significance: P < .05. b Variables are expressed as mean + standard deviation. c Analysis of variance. d Pearson w2 test.
epilepsy in 6 patients (15%), febrile seizure in 9 patients (23%), and other causes in 10 patients (25%) in group C2. No significant difference was detected in reasons for referral to EEG recording between groups. Referral etiology for EEG recording was not significantly different among groups (Table 1). The mean induction time was found as 35.9 + 3.5 minutes in group D1, 34.5 + 4.0 minutes in group D2, 34.0 + 4.6 minutes in group C1, and 28.9 + 4.0 minutes in group C2. The induction time was significantly shorter in group C2 compared with other groups (P ¼ .000). The mean EEG recording time was 31.7 + 6.0 minutes, with no significant difference among groups (P ¼ .983). Mean recovery time was 41.7 + 23.4 minutes in group D1, 48.3 + 28.6 minutes in group D2, 52.2 + 24.2 minutes in group C1, and 70.0 + 15.8 minutes in group C2. The recovery time was significantly longer in group C2
compared with other groups (P ¼ .000). The mean total sedation time was 109.6 + 24.3 minutes in group D1, 114.6 + 30.7 minutes in group D2, 117.8 + 23.4 minutes in group C1, and 130.3 + 17.4 minutes in group C2. The total sedation time was significantly longer in group C2 compared with groups D1 and D2 (P ¼ .003) (Table 2). The overall sedation failure rate was 16.7% in group D1, 7.1% in group D2, 22.2% in group C1, and 5% in group C2. There was no statistically significant difference in rates of sedation failure among groups (P ¼ .074) (Table 2). After the procedure, hypoxia developed in 1 patient (2.8%) in group C1 and 1 patient (2.5%) in group C2. Both patients were treated with supplemental oxygen (3-4 L/min) without need for airway management. Agitation was seen in 2 patients (5%) in group C2. Hypotension developed in 1 patient (2.4%)
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Figure 2. Comparison of successful sedation and adverse effects of drugs between groups of patients who were sedated with dexmedetomidine and chloral hydrate.
in group D1, whereas bradycardia occurred in 1 patient (2.4%) in group D2. Vomiting or nausea developed in 3 patients (8.3%) in group C1 and 7 patients 17.5%) in group C2 (Table 2). The overall adverse drug effect rate was 2.4% in group D1, 2.4% in group D2, 11.1% in group C1, and 25% in group C2. Adverse drug effect rate was significantly higher in group C2 compared with the dexmedetomidine groups (D1 and D2) (P ¼ .004). Successful sedation rates and adverse drug effects in the groups are shown in Figure 2.
Discussion Chloral hydrate has 2 active metabolites, namely, trichloroethanol and trichloroacetic acid. Chloral hydrate is rapidly absorbed from the gastrointestinal tract after oral use. Its sedative and hypnotic effects occur within 20-60 minutes after administration and last for 60 to 120 minutes. Its half-life is of a few minutes but it is longer for active metabolites, being 8 to 12 hours for trichloroethanol and 67 hours for trichloroacetic acid. Trichloroethanol probably exerts its effect on the central nervous system through an unknown mechanism.16 The literature on sedation with different doses of chloral hydrate is characterized by a wide range of failure rates and adverse effects. The dosages of chloral hydrate used in this study were derived from assessments of clinical literature and practice.11,17-19 Recently, Bektas et al9 described their recent experience in low-dose chloral hydrate (26.38 + 14.73 mg/ kg) for sedation in pediatric EEG recording. The authors reported an overall success rate of 89% without adverse effects. Hijazi et al18 found that effective sedation was achieved in 79% of patients with an average dose of 56.1 + 9.3 mg and in 94% with an average dose of 71.6 + 13.4 mg. The authors reported an overall adverse effect rate of 2.7%. However, Avlonitou et al17 reported 1591 children who received sedation with chloral hydrate for auditory brain stem response testing. The authors reported a success rate of 99.7% and an adverse effect rate of 20.6% by using chloral hydrate at doses of 40 to 80 mg/
kg (maximum total dose: 1.0 g) via the oral route or a nasogastric tube. However, in a recent study, 3 cases of pediatric chloral hydrate poisoning were described. In all cases, poisoning occurred following procedural sedation in outpatient settings. All patients presented to the emergency department and required resuscitation. Of these, 1 patient died despite all interventions.20 Dexmedetomidine has a rapid distribution phase with a distribution half-life of 6 minutes, and distribution from the central to peripheral compartments requires roughly 30 to 45 minutes. However, steady-state concentrations continue for approximately 14 hours in dexmedetomidine. It is metabolized to inactive metabolites in the liver by glucuronidation and cytochrome P450. The elimination half-life of dexmedetomidine is 2 hours. Approximately 95% of dexmedetomidine and its metabolites are excreted into urine, whereas 4% are excreted into feces.3,4 Although there are several reports on intranasal, intramuscular, or intravenous use of dexmedetomidine for sedation in children, a limited number of studies were conducted with oral dexmedetomidine without a loading dose for pediatric sedation. One different aspect of the current study was the use of oral dexmedetomidine without a second dose. Lubisch et al21 found a higher success rate of 99.3% and shorter recovery times with dexmedetomidine compared to pentobarbital. The authors did not report any adverse effect. Aksu et al7 reported that dexmedetomidine provided adequate sedation by 100% for pediatric EEG recording without adverse effects. The authors reported that there was less change in EEG baseline rhythm quantitative values after dexmedetomidine compared to those after midazolam. Ray et al22 reported that dexmedetomidine provided 100% success rate and safe sedation for EEG recording in children with autism, seizure disorders, and pervasive developmental disorders. Zub et al23 reported use of oral dexmedetomidine with a mean dose of 2.6 + 0.83 mg/kg in 13 children aged 4–14 years. The authors reported adequate sedation in 84.6% of study participants without complications. They concluded that satisfaction with the sedation experiences was high in oral administration of dexmedetomidine. In a recent study, Chrysostomou et al24 investigated the safety, efficacy, and pharmacokinetic profile of dexmedetomidine in preterm and full-term neonates. The authors reported that dexmedetomidine was effective for sedation in preterm and full-term neonates, and that it was well-tolerated without significant adverse effects. However, preterm neonates had decreased plasma clearance and longer elimination half-life. To our knowledge, there is no study in the literature comparing oral chloral hydrate and oral dexmedetomidine for recording sleep EEGs in pediatric patients. In our study, the doses of oral dexmedetomidine were 2.0 mg/kg in group D1 and 3.0 mg/kg in group D2, whereas the doses of oral chloral hydrate were 50 mg/kg in group C1 and 100 mg/kg in group C2. Our study showed that the mean induction time was significantly shorter in group C2 compared with other groups (P ¼ .000). Moreover, total sedation time was significantly longer in group C2 compared with dexmedetomidine groups (D1 and
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D2) (P ¼ .003). The longer sedation period and slower return of arousal were disadvantages in C2 group for sleep EEG recording in the pediatric population. In the present study, we found that the rates of adequate sedation in the D2 and C2 groups were higher than other groups but the difference did not reach statistical significance (P ¼ .074). However, we observed that the adverse effect rate was significantly higher in group C2 compared with the dexmedetomidine groups (D1 and D2) (P ¼ .004). The most common complications included vomiting and nausea. These complications were observed in groups C1 and C2 with rates of 8.3% and 17.5%, respectively. There was no complication requiring airway management or resuscitation. One limitation of our study is small sample size. Another limitation was a shorter follow-up period. Therefore, delayed adverse event following discharge was not documented. It was concluded that further studies with larger sample sizes and longer follow-up periods as well as different doses of dexmedetomidine and chloral hydrate are needed. From our results, it appears that oral dexmedetomidine is a safe and effective drug for sleep EEG recording in the pediatric population. We observed that dexmedetomidine was effective at a dose of 2 mg/kg in 83.3%, whereas a dose of 3 mg/kg was effective in 92.9% of the patients, respectively. Furthermore, there was no significant difference in adverse effects between the 2 doses of dexmedetomidine. On the other hand, we found that 77.8% of children were sedated effectively with 50 mg/kg of chloral hydrate whereas 95.0% of children were sedated effectively with 100 mg/kg of chloral hydrate, respectively. The adverse effects of chloral hydrate were more commonly seen in the patients who were sedated with 100-mg/kg doses. In addition, total sedation time was significantly longer compared to the group receiving dexmedetomidine. In conclusion, according to our experiences in this study, considering the adverse effects and long sedative time of chloral hydrate, 3 mg/kg dexmedetomidine seems to be an appropriate sedative option for EEG recordings in children. In order to use dexmedetomidine, one should achieve a proper indication and with peace of mind in children for sleep EEG recording. Larger, randomized, prospective studies are needed. Acknowledgment All authors thank all the patients and family members for their participation in this study.
Author Contributions GH and PHG conceived the study. GH, KBA, PHG, GCD, YK, and KS reviewed the literature. HG, PHG, PH, CM, and KS were involved in patient care, including process of procedure and routine clinical follow-up. GH and KBA wrote the manuscript. KBA also performed the statistical analysis. PH, YK, GCD and KS also made helpful suggestions to improve the manuscript.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval Informed consent was obtained from all parents or legal guardians of the children included. This study was approval by the Local Ethics Committee of Erciyes University (2014/384).
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