A comparison of single dose dexmedetomidine with propofol for the prevention of emergence delirium after desflurane anaesthesia in children

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1 Anaesthesia 2016, 71, Original Article doi: /anae A comparison of single dose dexmedetomidine with propofol for the prevention of emergence delirium after desflurane anaesthesia in children J. K. Makkar, 1 N. Bhatia, 2 I. Bala, 3 D. Dwivedi 4 and P. M. Singh 2 1 Associate Professor, 2 Assistant Professor, 3 Professor, 4 Senior Resident, Department of Anaesthesia and Intensive Care, Post Graduate Institute of Medical Education and Research, Chandigarh, India Summary Emergence delirium is a common problem in children recovering from general anaesthesia. We performed a study comparing emergence characteristics in 100 patients who were randomly allocated to receive either 0.3 lg.kg 1 dexmedetomidine, 1 mg.kg 1 propofol or saline 0.9% and undergoing infra-umbilical surgery. The Pediatric Anesthesia Emergence Delirium scale was used to grade emergence delirium. Emergence delirium occurred in 9.4% of children in the dexmedetomidine group compared with 13.9% in the propofol group and 40.6% in the control group (p = 0.004). In the dexmedetomidine group, sedation occurred in 62.5% of children at 10 min after transfer to the recovery area, compared with 44.4% in the propofol group and 12.5% in the control group (p = 0.010). We conclude that dexmedetomidine significantly reduced the incidence of emergence delirium but this was at the expense of a greater incidence of sedation in the recovery period.... Correspondence to: J. K. Makkar jeet1516@gmail.com Accepted: 4 August 2015 Introduction Emergence delirium (ED) is a common postoperative problem in children. It is characterised by a variety of presentations, including crying, excitation and agitation, that occur during the early stage of recovery from general anaesthesia [1]. Although not thought to be associated with long-term adverse effects, ED is one of the major causes of dissatisfaction among parents and healthcare workers, and may result in physical harm to the child [2, 3]. Drugs administered for its treatment may increase the duration of stay in the recovery area, even following short surgical procedures [3].The aetiology of ED is still largely unknown, with various anaesthetic, patient, surgical and medication-related factors playing a role [4]. The incidence of ED varies between 20% and 80% depending on the scoring system used [3, 5, 6]. Different drugs, including analgesics [7, 8], benzodiazepines [9], a 2 -adrenergic receptor agonists [10] and propofol [11] have been used, with varying success. Dexmedetomidine is a potent a 2 -adrenergic receptor agonist with an eight-times higher affinity for the a 2 -adrenergic receptor than clonidine, and is known to have sedative, analgesic and anxiolytic properties. Propofol is commonly used for conscious sedation and induction/maintenance of general anaesthesia. Several studies evaluating the effectiveness of these agents separately in reducing ED following sevoflurane anaesthesia The Association of Anaesthetists of Great Britain and Ireland

2 Makkar et al. Emergence delirium in children Anaesthesia 2016, 71, have shown positive results [2, 11 14]. However, Bong et al. recently reported that there was no significant decrease in the incidence of ED with either of these drugs in children receiving general anaesthesia with sevoflurane for magnetic resonance imaging (MRI) [15]. Use of desflurane is associated with a faster recovery than other inhalational anaesthetic agents [16 18] but there is limited data on drugs used to prevent ED following general anaesthesia with desflurane [19]. The aim of the present study was to determine whether a small dose of either intravenous dexmedetomidine or propofol, administered before the end of surgery, decreases the incidence of ED in children undergoing infra-umbilical surgery under desflurane anaesthesia. Methods Following approval by the local research ethics committee, written informed consent was obtained from the parent or carer. Children, aged between 2 and 8 years, of American Society of Anesthesiologist physical status 1 or 2 and scheduled for elective infra-umbilical surgery of less than one hours duration under general anaesthesia and single-shot caudal block were enrolled. Exclusion criteria included: developmental delay; neurological disease; recent ingestion of sedatives or analgesics; any known allergy to the study drugs; or previous general anaesthesia. No pre medication was administered. A parent or carer accompanied the child to the operating theatre. Inhalational induction was performed using 8% sevoflurane in oxygen. Standard AAGBI monitoring was applied (ECG, oxygen saturation and non-invasive blood pressure) and an intravenous cannula inserted. Adequate anaesthetic depth was obtained, the child was then turned into the left lateral position and a single shot caudal injection was performed using 0.75 ml.kg 1 bupivacaine 0.25%. Children were then turned supine and an appropriately sized laryngeal mask inserted. Anaesthesia was maintained with 4 6% desflurane in a 50:50 oxygen:nitrous oxide mixture using controlled ventilation and aiming for a target end-tidal carbon dioxide value of kpa. Surgery commenced 10 min after the caudal injection, and successful caudal block was defined as the absence of an increase in heart rate of 20% or increase in blood pressure 20% above baseline. If the caudal injection was considered unsuccessful, then 1 2 lg.kg 1 fentanyl was administered and the patient withdrawn from the study. Patients were assigned by means of a computergenerated random number table (SPSS Version 21; IBM Corp., Armonk, NY, USA) into one of three groups. Fifteen minutes before the end of surgery, patients in the dexmedetomidine group received 0.3 lg.kg 1 intravenous dexmedetomidine diluted to a total volume of 10 ml using saline 0.9% and administered over 5 min, while patients in the propofol group received 10 ml saline 0.9% and patients in the control group received 10 ml saline 0.9%. Five minutes before the end of surgery, patients in the dexmedetomidine group received saline 0.9%, patients in the propofol group received a single intravenous bolus of 1 mg.kg 1 propofol and patients in the control group received saline 0.9%. All the syringes were wrapped in foil for the purposes of blinding. After completion of surgery and resumption of adequate spontaneous breathing, the laryngeal mask was removed. Patients were transferred to the recovery area once they demonstrated a regular respiratory pattern, facial grimacing and appropriate limb movement. Subsequent data were collected by an anaesthetist not directly involved in care of the patient. One parent or carer met the child on arrival in the recovery area and the child was allowed to regain consciousness undisturbed. The Pediatric Anesthesia Emergence Delirium (PAED) scale [20] (Table 1) was used to assess emergence delirium. The score was recorded at 5 min, 10 min, 15 min, 20 min, 25 min and 30 min after the removal of the laryngeal mask. A score of 10 or more was considered a diagnosis of ED and a score 15 was defined as severe emergence delirium. Propofol 1 mg.kg 1 was given intravenously to treat severe ED if the patient was assessed to be pain-free and when the parent or carer could not console their child. The dose was repeated after 10 min if necessary. Pain was evaluated using the face, legs, activity, cry and consolability (FLACC) scale [21]. Intravenous fentanyl 1 lg.kg 1 was administered if the score was 3. Postoperative vomiting was assessed using a numerical ranking score The Association of Anaesthetists of Great Britain and Ireland 51

3 Anaesthesia 2016, 71, Makkar et al. Emergence delirium in children Table 1 The Pediatric Anesthesia Emergence Delirium (PAED) scale [20]. We defined emergence delirium as a score of 10 or more. Not at all Just a little Quite a bit Very much Behaviour Makes eye contact with caregiver Actions are purposeful Aware of surroundings Restless Inconsolable Extremely Sedation was assessed using the University of Michigan Sedation Scale [22] (Table 2) at 5 min intervals until the child was awake. A score of 2 or more was considered a state of sedation. The primary outcome was the incidence of ED. Secondary outcomes were transfer time, recovery time (defined as the time from arrival in the recovery area until spontaneous eye opening or response to verbal command) and complications. The incidence of ED in children following desflurane anaesthesia has been reported to be approximately 60%. In order to detect a 25% reduction in the incidence of ED with a power of 80% and an a error of 0.05, 33 patients were required in each group. To allow for a dropout rate of 10%, we required a total of 110 patients. Normally distributed data were analysed using Student s t-test and categorical data were analysed using the chi-squared test or Fisher s exact test. One-way ANOVA (F-test) and the Kruskal Wallis test were used to compare mean PAED score and sedation Table 2 The University of Michigan Sedation Scale [22]. We defined sedation as a score of 2 or more. 0 Awake and alert 1 Minimally sedated: tired/sleepy, appropriate response to verbal conversation and/or sound 2 Moderately sedated: somnolent/sleeping, easily aroused with light tactile stimulation or a simple verbal command 3 Deeply sedated: deep sleep, arousable only with significant physical stimulation 4 Unarousable scores between the three groups. A mixed model longitudinal analysis was performed on PAED scores with patients as random effects assuming normally distributed errors and using an unconstrained variance covariance matrix. All analyses were performed using SPSS version 32 software and a p value of < 0.05 was considered statistically significant. Results A CONSORT flow diagram for patients in our study is shown in Fig. 1. A total of 110 patients were enrolled, 10 patients were excluded and the data for 100 patients were analysed. Patient characteristics are shown in Table 3. Transfer time was significantly prolonged in the dexmedetomidine group compared with the control group (p = 0.002). The median (95% CI) time to awakening was ( ) min in the dexmedetomidine group, compared with 5.00 ( ) min in the propofol group and 0.00 ( ) min in the control group. The incidence (95% CI) of ED was 9.4% ( ) in the dexmedetomidine group, 13.9% ( ) in propofol group and 40.6% ( ) in the control group (p = 0.004). Paired comparisons between the groups revealed a significant difference between the dexmedetomidine group compared with the propofol group (p = 0.043) and the dexmedetomidine group compared with the control group (p = 0.030). Figure 2 shows the proportion of children with ED in the three study groups at 5 min intervals from 0 to 30 min after awakening. The median (IQR [range]) PAED score was significantly higher in the control group (8.5 ( [ ]) compared with the dexmedetomidine group (3.0 ( [ ]), at 10 min after awakening, p = Most episodes of ED were self-limiting and did not require any treatment. Three children in the propofol group and five in the control group had severe ED (a PAED score of > 15) and required pharmacological treatment. Table 4 shows pairwise PAED least-square mean differences from the longitudinal analysis that reflect the precision in estimating PAED score differences between groups. Figure 3 shows the median sedation scores for children in the three groups. Sedation occurred in The Association of Anaesthetists of Great Britain and Ireland

4 Makkar et al. Emergence delirium in children Anaesthesia 2016, 71, Assessed for eligibility (n =128) Enrollment Excluded (n = 18) Not meeting inclusion criteria (n = 10) Refused to participate (n = 8) Randomised (n = 110) Allocation Allocated to Dexmedetomidine group (n = 37) Received allocated intervention (n = 32) Did not receive allocated intervention (n = 5) (n= 4, deviation from methodology N=1, intraoperative laryngospasm) Allocated to Propofol group (n = 37) Received allocated intervention (n =36) Did not receive allocated intervention (n = 1; deviation from methodology) Allocated to Control group (n = 36) Received allocated intervention (n = 32) Did not receive allocated intervention (n = 4; deviation from methodology) Follow up Lost to follow up (n = 0) Lost to follow up (n = 0) Lost to follow up (n = 0) Analysis Analysed (n = 32) Analysed (n = 36) Analysed (n = 32) Figure 1 CONSORT flow diagram of patients included in the study. Table 3 Patient characteristics, anaesthesia duration, transfer and awakening times of patients included in the study. Values are median (IQR [range]) or mean (SD). Dexmedetomidine group n = 32 Propofol group n = 36 Control group n = 32 Age; years 5.00 ( [ ]) 4.75 ( [ )] 3.00 ( [ ]) Weight; kg ( [ ]) ( [ ]) ( [ )] Gender; male:female 20:12 22:14 19:13 Anaesthesia duration; min (14.83) (12.46) (9.04) Transfer time; min 6.41 (5.36) 5.56 (2.48) 3.31 (1.57) Awakening time; min (27.26) 9.83 (7.55) 5.06 (3.33) 62.5% of children in the dexmedetomidine group at 10 min after transfer to the recovery area, compared with 44.4% in the propofol group and 12.5% in the control group (p = 0.010). Twelve children had a FLACC score greater than 3 at any time and, of these, ten had a PAED score of less than 10. Two children had both a FLACC score greater than 3 and a PAED score of 10 or more and they were both in the propofol group. After removal of the laryngeal mask, coughing occurred in three children and mild laryngospasm was observed in four children. There were no episodes of oxygen desaturation. Discussion The incidence of ED following desflurane anaesthesia in children varies between 20% and 80% and in this study we found an incidence of 40.6% in our control group The Association of Anaesthetists of Great Britain and Ireland 53

5 Anaesthesia 2016, 71, Makkar et al. Emergence delirium in children Figure 2 Proportion of children with emergence delirium having received dexmedetomidine (black), propofol (grey) or saline 0.9% (white). Table 4 Pair-wise differences in least-square mean PAED scores by follow-up time since awakening in children receiving dexmedetomidine (dex), propofol or saline 0.9% (control). Values are mean (95% CI). Pair-wise differences in estimated marginal means Time after awakening; min Dex vs propofol Dex vs control Propofol vs control ( 6.72, 4.91) 1.57 ( 7.66, 4.51) 1.00 ( 4.99, 2.98) ( 7.74, 5.41) 2.29 ( 8.91, 4.34) 1.12 ( 5.46, 3.22) ( 6.05, 6.52) 1.07 ( 7.40, 0.04) 1.30 ( 6.43, 3.82) ( 4.79, 4.82) 0.96 ( 5.81, 3.88) 0.98 ( 4.15, 2.19) ( 5.33, 3.87) 0.50 ( 5.13, 4.13) 0.23 ( 2.80, 3.27) ( 5.45, 2.81) 1.25 ( 5.41, 2.91) 0.07 ( 2.66, 2.79) ( 4.64, 2.84) 1.14 ( 4.91, 2.63) 0.24 ( 2.71, 2.23) A significant decrease was found when dexmedetomidine was administered. Several studies have reported a decrease in the incidence of ED following administration of dexmedetomidine or propofol in children undergoing surgery under sevoflurane anaesthesia [2, 11, 13, 23]. Aouad et al. [11] reported a decrease in the incidence when intravenous propofol 1 mg.kg 1 was given at the end of squint surgery, whereas Ali and Abdellatif [13] found a significant decrease in the incidence with both propofol and dexmedetomidine in children undergoing adenotonsillectomy. In another study, Abu Shahwan observed a significant decrease in the incidence and severity of ED following the administration of sub-hypnotic doses of propofol at the end of sevoflurane general anaesthesia in children undergoing MRI [24]. Isik et al. [25] reported ED in 48% of children undergoing MRI under sevoflurane anaesthesia and that the administration of 1 lg.kg 1 intravenous dexmedetomidine following induction of anaesthesia significantly reduced its incidence. However, in a recent study, Bong et al. [15] did not find any benefit from a single dose of either The Association of Anaesthetists of Great Britain and Ireland

6 Makkar et al. Emergence delirium in children Anaesthesia 2016, 71, Median seda on score Time (min) Figure 3 Median sedation scores in the recovery period in patients having received dexmedetomidine (black), propofol (grey) or saline 0.9% (white). dexmedetomidine or propofol in children undergoing MRI under sevoflurane general anaesthesia. This observation may be attributed to several factors. The effects of dexmedetomidine start in < 5 min and its peak effect occurs within 15 min of intravenous administration. Bong et al. administered dexmedetomidine at the time of induction of anaesthesia and the median time to removal of the laryngeal mask after completion of the procedure was 70 min. Therefore, it is not surprising that they found no decrease in the incidence of ED with dexmedetomidine [26]. Furthermore, ED usually occurs within the first 30 min after the termination of anaesthesia, with the highest incidence in the first 5 15 min [27, 28]. The authors, however, found a relatively high incidence (39%) at 20 min after the end of anaesthesia. It is possible that the presence of an oral airway at the time of awakening in Bong et al. s study, might have resulted in a peak incidence of ED at that time. Mean awakening times reported with the use of short acting inhalational agents vary between 8 min and 10 min [29]. Bong et al. reported a mean (SD) awakening time of 20 (9) min in their control group. This is unexpected as no pre-medication was given and children did not receive any intra-operative opioids. Residual sedation can affect the PAED scores so it is important to evaluate sedation when the PAED scale is used to diagnose emergence delirium. Only a limited number of studies have reported sedation scores when dexmedetomidine or propofol were administered [24, 30]. We found that a significantly greater number of children were sedated in the dexmedetomidine group and time to awakening was significantly prolonged in this group. Bong et al. did not use any sedation scores to grade sedation. A blinded observer is likely to assign a higher score in a sedated or sleeping child when using the PAED scale [31]. Thus, a PAED score of 10 or more may be assigned to a child who is asleep, or sedated, rather than suffering from ED and this could be another reason for the apparent lack of efficacy of dexmedetomidine in the study by Bong et al. Postoperative pain is thought to be one of the major causes of ED, although the absence of pain does not guarantee calm emergence from sevoflurane anaesthesia [32]. In a recent meta-analysis, no negative correlation was seen between the incidence of ED and administration of analgesic agents [33]. On the other hand, the co-existing sedative properties of some agents might explain their preventative effect on the incidence of ED [34]. Transfer and emergence times were significantly greater in both the dexmedetomidine and propofol groups compared with the control group in our study and are consistent with previous studies [11, 13, 24] which showed that time to awakening is inversely related to emergence delirium. A limited number of studies have assessed the effect of various drugs on ED following the use of 2015 The Association of Anaesthetists of Great Britain and Ireland 55

7 Anaesthesia 2016, 71, Makkar et al. Emergence delirium in children desflurane. Fentanyl 2.5 lg.kg 1 has been shown to reduce the incidence of severe ED without a delay in emergence [35, 36]. Kim et al. reported a decrease in the incidence of ED with a continuous infusion of low-dose dexmedetomidine [0.2 lg.kg 1.h 1 ] following desflurane anaesthesia [19]. However, neither propofol nor midazolam were effective in patients undergoing adenotonsillectomy under desflurane anaesthesia [8]. We found a significant decrease in the incidence of ED with dexmedetomidine administered in a dose of 0.3 lg.kg 1, although propofol was not effective. A limitation of our study is that we did not record discharge time. All procedures were performed as day cases and no patients required an overnight stay. In conclusion, we have demonstrated that intravenous dexmedetomidine administered in a dose of 0.3 lg.kg 1 over 5 min, 15 min before the end of surgery, significantly reduced the incidence of ED in children following desflurane anaesthesia but this was at the expense of an increase in sedation. Acknowledgements We thank the patients, parents and carers for their help with the study. Competing interests No external funding and no competing interests declared. References 1. Yamashita M. Postanaesthetic excitation and agitation. Pediatric Anesthesia 2003; 13: Ibacache ME, Munoz HR, Brandes V, Morales AL. Single-dose dexmedetomidine reduces agitation after sevoflurane anesthesia in children. Anesthesia and Analgesia 2004; 98: Voepel-Lewis T, Malviya S, Tait AR. A prospective cohort study of emergence agitation in the pediatric postanesthesia care unit. Anesthesia and Analgesia 2003; 96: Na HS, Song IA, Hwang JW, Do SH, Oh AY. 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