|Year : 2018 | Volume
| Issue : 2 | Page : 522-527
Prevention of emergence delirium in children – A randomized study comparing two different timings of administration of midazolam
Gerard Gonsalvez, Deepa Baskaran, Vasudeva Upadhyaya
Department of Anaesthesiology and Critical Care, St. Johns Medical College Hospital, Bengaluru, Karnataka, India
|Date of Web Publication||14-Jun-2018|
Dr. Deepa Baskaran
Department of Anaesthesia and Critical Care, St. Johns Medical College Hospital, Sarjapur Road, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Emergence delirium (ED) is a distressing side effect of sevoflurane anesthesia in children. Midazolam is a widely studied drug for the prevention of ED with conflicting results. Aim, Settings and Design: We designed this prospective randomized double-blind study to compare the effect of 0.03 mg/kg midazolam administered at induction and the same dose administered 10 min before the end of surgery in the prevention of ED in children undergoing sevoflurane anesthesia and also the effect on the time to recovery in both groups. Materials and Methods: Eighty children between 2 and 8 years belonging to patient physical status American Society of Anesthesiologist Classes 1 and 2 undergoing infra-umbilical surgeries under general anesthesia were randomly allocated to receive 0.03 mg/kg midazolam at induction (Group A) and 10 min before the end of surgery (Group B). Caudal block was administered for analgesia after induction. The primary outcome, the incidence of ED was evaluated using the Paediatric Anaesthesia Emergence Delirium Scale from the time of extubation till 30 min postsurgery. The secondary outcome measured was the time to recovery (time from discontinuation of sevoflurane to the time of extubation) and the results were statistically analyzed. Results: The incidence of ED was comparable between the groups (30%, 10%, 5%, and 2.5% at 5, 10, 15, and 20 min, respectively in Group A and 25%, 10%, 5%, and 2.5% of children at 5, 10, 15, and 20 min, respectively in Group B). Recovery was significantly prolonged in Group B (42.5% of patients in Group A recovered within 6 min of discontinuation of sevoflurane in Group A compared to only 20% of patients in Group B). Conclusion: There is no difference in the reduction of incidence of ED following sevoflurane anesthesia when midazolam is administered at induction or the end of surgery. However, the time to recovery was longer when the drug was administered at the end of the surgery.
Keywords: Caudal analgesia, emergence delirium, laryngeal mask airway, postanesthesia care
|How to cite this article:|
Gonsalvez G, Baskaran D, Upadhyaya V. Prevention of emergence delirium in children – A randomized study comparing two different timings of administration of midazolam. Anesth Essays Res 2018;12:522-7
|How to cite this URL:|
Gonsalvez G, Baskaran D, Upadhyaya V. Prevention of emergence delirium in children – A randomized study comparing two different timings of administration of midazolam. Anesth Essays Res [serial online] 2018 [cited 2020 Apr 2];12:522-7. Available from: http://www.aeronline.org/text.asp?2018/12/2/522/234430
| Introduction|| |
Delirium is defined as an acutely altered and fluctuating disturbance of consciousness with reduced ability to focus, maintain, or shift attention accompanied by perceptual disturbances. Emergence delirium (ED) was first described by Dr. Eckenhoff et al. as a dissociated state of consciousness that occurs in the first 30 min following recovery from anesthesia and is self-limiting. Emergence or postoperative delirium is shown to occur in 5%–30% of patients of all ages.
ED has been observed to be more common in pediatric population characterized by agitation, and excessive crying. Parental presence at induction and recovery, perioperative pain and use of inhalational agents influence the susceptibility to ED. Sevoflurane, the ideal induction agent in children is associated with 0%–80% incidence in ED in children. Rapid recovery from sevoflurane in conjunction with psychological immaturity in these young patients has been postulated for this emergence event.
ED not only predisposes the child to injury but also causes profound psychological trauma and unpleasantness to parents. Despite a lot of researches, neither the etiology of this phenomenon is understood nor a strategy of prevention yet developed. No single effective drug has been shown to be superior despite extensive researches. It is very difficult to compare studies as the assessment tools, type of surgical procedures, or even anesthetic techniques are different. The pharmacological adjuncts used for prevention include propofol, benzodiazepines, fentanyl, ketamine, alpha2 agonists (clonidine and dexmedetomidine), and melatonin.,,
Midazolam is a commonly used drug in pediatric population as a premedicant due to its good safety profile. The role of midazolam in forestalling the occurrence of ED has been studied by many authors with conflicting results. Researchers have studied the effect of midazolam after administering it as a premedicant (oral and rectal), at induction and the end of the surgery. Our literary search has revealed no studies comparing the effect of midazolam given at two different timings during surgery on the incidence of ED.
We designed this prospective randomized, double-blind study to compare the effect of 0.03 mg/kg of midazolam given intravenously at induction and the same dose administered 10 min before the end of surgery on the incidence of ED in children undergoing infra-umbilical surgeries.
We used a smaller dose of 0.03 mg/kg because previous studies have shown that this dose is sufficient to prevent ED and will not affect the time to recovery. Despite these inferences, we chose to study the time to recovery as a secondary objective, because our study involved short duration surgeries and we wanted to know if the residual effects of even a smaller dose influenced the time to recovery in these surgeries.
We hypothesized that midazolam administered at the end of surgery would be more effective in the prevention of ED without any significant delay in recovery.
Aims and objectives
This study aims to compare the effect of 0.03 mg/kg of midazolam administered at the time of induction and 10 min before the end of surgery in the prevention of ED in children undergoing infraumbilical surgeries under sevoflurane anesthesia.
The secondary objective was to compare the time to recovery from the discontinuation of sevoflurane anesthesia to the time of laryngeal mask airway removal in both groups.
| Materials and Methods|| |
The study was taken up after obtaining approval from the Institutional Ethics Committee (Institutional Ethics Committee, Study No Ref No. 185/17). Parents of all patients were informed about the study and a written consent for participation was obtained. This prospective randomized, double-blind study was done over a period of 12 months.
Children aged between 2 and 8 years belonging to patient physical status American Society of Anesthesiologist (ASA) Classes I and II undergoing infra-umbilical surgeries of <90 min duration were included in the study.
Children with neurological diseases, developmental delay, airway difficulty, and children of parents who refused participation were excluded from the study.
Patients were randomly allocated into two groups, Group A and Group B. Randomization was done using computer-generated numbering system after patients have consented for the study.
All children were fasted for a minimum of 6 h for solid food and 2 h for clear liquids. One parent was allowed to accompany the child to the preoperative area, to reduce the anxiety of the child. In the operating room, inhalational induction was done with 8% sevoflurane and a mixture of 50:50 concentrations of nitrous oxide and oxygen. After adequate plane was reached, an intravenous cannula was secured.
Group A received 0.03 mg/kg of midazolam intravenously after cannulation. Group B received 0.03 mg/kg of midazolam intravenously10 min before the end of the surgery.
Patients also received 10 μg/kg of glycopyrrolate, 0.15 mg/kg ondansetron, and 2 μg/kg of fentanyl intravenously. Appropriate size laryngeal mask airway (LMA) was inserted based on the patient's weight. Anesthesia was maintained with sevoflurane 2%, nitrous oxide, and oxygen, with spontaneous or assisted ventilation. Caudal block was administered to all patients with 0.75 mL/kg of 0.25% bupivacaine. Intraoperatively, patient's heart rate, oxygen saturation, end-tidal carbon dioxide were monitored. Patients showing signs of inadequate analgesia (increase in heart rate by 10% of the baseline value) at incision were excluded from the study, and intravenous fentanyl was given. At the end of the surgery, sevoflurane was discontinued, 100% oxygen was administered and the time from discontinuation of sevoflurane to the time to removal of LMA (opening eyes to commands, adequate tidal breathing, and good muscle tone) was noted in both groups by the assessor.
In the postanesthesia care unit (PACU), the patients were monitored for heart rate and pulse oxygen saturation and were cared for by one of their parents and the PACU nurses. One anesthesiologist assessed recovery and emergence behavior of the children in the PACU. He was blinded to the group assignment of the children making the study subject blinded and assessor blinded. The primary outcome variable, the emergence behavior was assessed using the Paediatric Anaesthesia Emergence Scale (PAED Scale), [Table 1]. The agitation scores were recorded from the time of extubation every 5 min till 30 min. A PAED scale score >9 was the cutoff, and if a score >9 persisted for >10 min, 0.1 μg/kg of fentanyl was administered intravenously.
|Table 1: The Paediatric Anaesthesia Emergence Delirium Scale (Devised by Sikich and Lerman)|
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Analgesia was assessed using the Facies, Legs, Activity, Cry, Consolability (FLACC) scale [Table 2]. A score >3 were considered as a sign of inadequate analgesia, and 0.1 μg/kg of fentanyl was administered intravenously.
The children were monitored for desaturation, laryngospasm, and nausea and vomiting in the PACU.
By using power analysis based on the results of the study by Chou et al., we deduced that a sample size of 40 patients per group would have a significance level of 5% (two tailed) and a power of 80% to detect a 20% difference in emergence agitation incidence among the groups.
Descriptive and inferential statistical analysis has been carried out in the present study. Results on continuous measurements are presented as mean ± standard deviation (minimum–maximum) and results on categorical measurements are presented in numbers (percentage) Significance was assessed at 5% level of significance. Student's t-test (two-tailed, independent) has been used to find the significance of study parameters on continuous scale between two groups (intergroup analysis) on metric parameters. Chi-square/Fisher's Exact test has been used to find the significance of study parameters on categorical scale between two or more groups. Nonparametric setting has been used for qualitative data analysis. The Statistical software SPSS 15.0 (SPSS Inc. Chicago, IL, USA), was used for the analysis of the data and Microsoft Word and Excel have been used to generate graphs and tables.
| Results|| |
Eighty children randomized to two groups of forty each were enrolled for the study. Mean age of children in the study was 4.9 years.
The demographic characteristics, the ASA physical status and the duration of surgery and anesthesia were comparable between the groups [Table 3].
As shown in [Figure 1], the intraoperative heart rate of the patients was comparable between the groups. No patient in either group had an increase in heart rate by 10% or more suggestive of inadequate analgesia.
As shown in [Figure 2], patients in Group A had faster recovery time compared to patients in Group B. There was a significant difference in the time of recovery time between the study groups (P = 0.003, confidence interval [CI] −3.08 to −1.2). At the end of 6 min, 17 out of 40 children (42.5%) were awake in Group A while only 8 out of 40 (20%) in Group B were awake at the end of 6 min. However, at the end of 12 min, all patients in Group A and 39 patients in Group B had recovered. Only one patient in the Group B had longer recovery time of 16 min.
The FLACC pain scale values are shown in [Table 4]. It has been observed that 39 patients in Group A and all 40 patients in Group B had a FLACC score <3 suggestive of good analgesia.
|Table 4: Comparison of Facies, Leg, Activity, Cry, Consolability Pain Scale in two groups of patients studied|
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[Table 5] analyses the PAED scale score of the patients from the time of extubation till 30 min postoperative. We observed that in Group A, 30% of children were agitated (score >9) at 5 min and 10%, 5%, and 2.5% of them were agitated at 10, 15, and 20 min, respectively. Similarly, in Group B, PAED scale score >9 was noted in 25%, 10%, 5%, and 2.5% of children at 5, 10, 15, and 20 min, respectively. As shown in [Table 5], the incidence of ED was comparable and statistically insignificant between the groups.
|Table 5: Comparison of Paediatric Anaesthesia Emergence Delirium Scale in two groups of patients studied|
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We also looked for association between FLACC and the PAED scale. Going by the 2 by 2 table [Table 6], no statistically significant association was observed. However, one patient in Group A had high FLACC score (6), and the same child had a PAED score of eleven after 20 min and was administered fentanyl.
|Table 6: Association between Facies, Leg, Activity, Cry, Consolability scale and Paediatric Anaesthesia Emergence Delirium scale|
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There were no complications such as laryngospasm, nausea, vomiting or desaturation in either group and the number of children who required rescue drug for agitation were comparable in both groups. Two patients in Group A and one in Group B received rescue fentanyl postoperatively.
| Discussion|| |
In the present study, the incidence of ED in children aged between 2 and 8 years who received midazolam 0.03 mg/kg at induction was compared to the incidence when the same dose of the drug was administered 10 min before the end of the surgery. The time to emergence after discontinuation of sevoflurane was also compared. Contrary to our hypothesis, the reduction in the incidence of ED was comparable between the two groups with a delay in recovery time in the group that received midazolam at the end of the surgery.
Sevoflurane causes ED in children. Studies have shown that the incidence of ED following sevoflurane anesthesia in children is 0%–80%. At higher concentration sevoflurane has been reported, to potentiate and at lower concentrations to block gamma-aminobutyric acid (GABAA) receptor-mediated inhibitory postsynaptic currents. Whether this biphasic effect contributes to sevoflurane-induced ED remains unclear. Midazolam with its GABA inhibitory effects could be a promising agent for improving the recovery quality after sevoflurane anesthesia.
The primary outcome measured in our study was that the incidence of ED was 30% at the end of 5 min, 10% at the end of 10 min, and 5% at the end of 15 min in children who received midazolam at induction and it was 25%, 10%, and 5%, respectively in children who received midazolam at the end of the surgery and it was comparable. As we did not have a control group, we did not know the actual incidence of ED in our cohort. Based on the results from previous studies, we inferred that midazolam irrespective of the timing of administration has been effective in decreasing the incidence of ED though it did not completely abolish agitation. We found no studies similar to ours comparing the effect of different timings of administration of midazolam on the incidence of ED.
Numerous studies have evaluated the effect of oral, rectal and intravenous premedication of midazolam on ED but the results are conflicting. Byon et al. observed in his study on 440 children that administration of 0.1 mg/kg midazolam intravenously at induction led to a small but insignificant reduction in the occurrence of ED. Lapin et al. found that preoperative oral midazolam decreased the amount of postoperative agitation in children having myringotomy surgery with sevoflurane anesthesia. These results support the observations of our study though we had used a lower dose of midazolam.
Costi et al. in their Cochrane meta-analyses of studies done on the effect of pharmacological adjuncts on the incidence of ED inferred that midazolam administered in oral or parenteral routes either as premedication or after induction did not prevent ED (relative risk 0.81; CI 0.57–1.12). Similarly, Dahmani et al. also in their met analyses found that midazolam administered at the beginning of surgery did not have a role in the prevention of ED (odds ratio 0.88; CI 0.44–1.76). However, the limitations of these analyses were that the number of studies analyzed were less and the researchers did not use a single standard assessment tool leading to conflicting results that are not fully reliable.
Premedication with midazolam either oral or rectal 30 min before surgery predisposes the patients to nightmares and suppresses rapid eye movement sleep. The amnesia leads to unawareness of the perioperative surroundings leading to agitation postoperatively which does not happen when the drug is given at induction as in our study.
In our study, administration of 0.03 mg/kg intravenous at induction resulted in PAED score of <9 in 75% of the children at the end of 10 min and 90% of them at the end of 15 min. Midazolam has a t1/2 of 1–2 h and the difference in the remaining concentration of the drug at the effector site plays an important role in postoperative anxiolysis. The effect of the drug administered at induction in our study persisted postoperatively as the duration of surgery was not >60 min, and hence was effective in preventing agitation. This may not be the case in prolonged surgeries.
With respect to the effect of midazolam administered at the end of the surgery, several studies have shown results similar to our study. Kim et al. in their study found that both propofol and midazolam effectively decreased the incidence of ED (74% in saline group had agitation compared to 42.9% in midazolam group). Cho et al. studied the effect of 0.05 mg/kg and 0.03 mg/kg of midazolam administered at the end of surgery and observed that 0.03 mg/kg of midazolam was as effective as the higher dose in controlling agitation in strabismus surgeries.
Similar results were shown in the studies of Bae et al. and Chen et al.
In the etiology of ED in children, pain is a very important predisposing factor even as studies have shown that ED can occur following pain-free procedures as well. In our study, the confounding effect of pain was abolished by administering caudal blocks in all patients. Postoperatively, 97% of patients had a FLACC score <3. Hence, successful caudal analgesia played an added role in the decrease in ED incidence in our patient cohort as supported by the study by Ozcan et al. There was one child with FLACC score >9 and the same child had higher PAED scale score also. Although the number is small, the association is noteworthy.
Researches on emergence agitation have been complicated by the use of various agitation rating systems and observational differences in defining the stages of agitation and hence the major conflicts in their observations. In our study, we have used the PAED scale. The PAED scale consists of five characteristics that are scored using a 5 point scale. The interobserver reliability of the PAED scale was 0.84 and the internal consistency was 0.89 (95% CI, 0.76–0.90). The sensitivity and specificity analyses revealed a sensitivity of 64% and a specificity of 86% making it the most valid scale of all existing scales. When a standardized assessment system is used the results of the study becomes more reliable and reproducible.
The secondary objective in our study was to evaluate the recovery time in both groups. We found that there was a small but significant delay in recovery in patients who received midazolam at the end of surgery despite a lower dose. Cho et al. in his study noted a delay in recovery when 0.05 mg/kg was administered at the end of surgery but not with lower doses. Similarly, Kim et al. and Byon et al. also showed a delay in recovery but midazolam doses were larger than our dose. The difference can be attributed to the susceptibility of the individual study group to the drugs. In our study, we found that 42.5% of patients who received midazolam in the beginning of surgery woke up within 6 min of discontinuation of sevoflurane as against 20% in the other group. Although the delay is statistically significant, it did not affect the shift out from PACU or discharge.
The limitations of our study are
- Our study is done in patients undergoing lower abdominal surgeries with caudal analgesia. The results may differ in patients undergoing other surgeries where systemic analgesics are used intraoperatively
- The surgical procedures in our study were minor lasting for about an hour, and the results cannot be extrapolated to prolonged surgeries
- We did not have a control group to know the actual incidence of ED in our patients. The results could be purely due to the caudal analgesia also.
| Conclusion|| |
We found that the incidence of ED in our study population has been reduced by the administration of midazolam. However, there is no significant difference in the incidence with respect to the time of administration.
Midazolam administered at the end of the surgery resulted in a delay in recovery though it was not clinically significant. Hence, we conclude that midazolam administered at the beginning or end of surgery was equally effective in the reduction in the incidence of ED. It may be preferable to administer the drug at induction as the time to recovery was quicker in this study group.
Approval for this study was granted by the Institutional Ethics Committee. For this, a formal written informed consent was taken from all the participants.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]