TITLE: 
Prevention of sevoflurane related emergence agitation in children undergoing adenotonsillectomy: A comparison of dexmedetomidine and propofol



ABSTRACT.BACKGROUND:
Emergence agitation (EA) in children is increased after sevoflurane anesthesia. Propofol and dexmedetomidine have been used for prophylactic treatment with controversial results. The aim of the present study was to compare the effect of a single dose of propofol or dexmedetomidine prior to termination of sevoflurane-based anesthesia on the incidence and severity of EA in children.

ABSTRACT.METHODS:
One hundred and twenty children, American Society of Anesthesiologists I-II, 2-6 years old undergoing adenotonsillectomy under sevoflurane based anesthesia were enrolled in the study. Children were randomly allocated to one of the three equal groups: (Group C) received 10 ml saline 0.9%, (Group P) received propofol 1 mg/kg or (group D) received dexmedetomidine 0.3 ug/kg-1. The study drugs were administered 5 min before the end of surgery. In post anesthesia care unit (PACU), the incidence of EA was assessed with Aonos four point scale and the severity of EA was assessed with pediatric anesthesia emergence delirium scale upon admission (T0), after 5 min (T5), 15 min (T15) and 30 min (T30). Extubation time, emergence time, duration of PACU stay and pain were assessed.

ABSTRACT.RESULTS:
The incidence and severity of EA were lower in group P and group D compared to group C at T0, T5 and T15. The incidence and severity of EA in group P were significantly higher than group D at the same times. The incidence and severity of EA decreased significantly over time in all groups. The modified Children's Hospital of Eastern Ontario Pain Scale was significantly lower in group D compared to group C and group P.

ABSTRACT.CONCLUSIONS:
Dexmedetomidine 0.3 ug/kg1 was more effective than propofol 1 mg/kg in decreasing the incidence and severity of EA, when administered 5 min before the end of surgery in children undergoing adenotonsillectomy under sevoflurane anesthesia.

BODY.INTRODUCTION:
The occurrence of emergence agitation (EA) in children after sevoflurane anesthesia is common, with a reported incidence up to 80%.[1] EA is characterized by a period of restlessness, agitation, inconsolable crying, disorientation, delusion, hallucination and cognitive changes plus memory impairment.[2] EA in children is generally short-lived with no after-effect, however, it is a troublesome phenomenon, because it can result in injury to the patient or damage to the surgical site, leads to dissatisfaction and anxiety for the parents, and requires extra nursing care with associated costs.[3]
Different drugs such as propofol, α2-adrenoreceptor agonists, midazolam, and ketamine have been used to allow a smooth emergence from sevoflurane anesthesia.[4] However, their efficacy remains the subject of debate. Propofol is a short-acting sedative and hypnotic agent. Generally, propofol is used in children for its sedative action as well as for induction and maintenance of general anesthesia.[5] Based on previous studies,[67] propofol seems to be effective in preventing EA and is dependent on the timing of administration.[4]
Dexmedetomidine, is a more highly specific α2-adrenoreceptor agonist (α2/α1=1620/1) than clonidine (α2/α1=220/1), has sedative and analgesic properties without significant respiratory depression at clinical dosages.[89] Dexmedetomidine is reported to significantly reduce EA frequency after sevoflurane anesthesia in pediatric surgery and non-surgical procedures in inpatient[1011] and outpatient settings.[1213]
This double-blinded randomized prospective study was conducted to compare the effect of administration of a single dose of propofol or dexmedetomidine prior to the termination of sevoflurane-based anesthesia on the incidence and severity of EA as well as emergence and discharge time in children undergoing adenotonsillectomy.

BODY.METHODS:
After institutional review board (Menoufiya University hospital, Menoufiya City, Egypt) approval and written informed consent from parents, 120 healthy children aged 2-6 years, with American Society of Anesthesiologists (ASA) physical status I or II, scheduled to undergo adenotonsillectomy were prospectively enrolled in this double blind, randomized prospective controlled study. The patients were then randomized to one of three equal groups using a computer generated randomization table. The control group (Group C), propofol group (Group P) and dexmedetomidine group (Group D). Exclusion criteria included mental disease, neurologic disease, and treatment with sedatives, full stomach, or indication for rapid sequence induction.
Children fasted for 8 h and received 0.5 mg/kg1 oral midazolam approximately 30 min before separation from the parents. The number of children who were agitated or combative during induction of anesthesia despite premedication with midazolam was recorded in each group. An electrocardiogram, pulse oximeter and noninvasive arterial blood pressure monitor were attached. General anesthesia was induced with 8% sevoflurane in 70% nitrous oxide in oxygen, via a facemask. After establishing a venous access, rocuronium 0.6 mg/kg1 was given. Orotracheal intubation was performed and anesthesia was maintained with 60% nitrous oxide in oxygen, supplemented by an end-tidal concentration of 2-3% sevoflurane with controlled ventilation, to maintain an end-tidal CO2 of 4.6±0.5 kPa (35±4 mmHg). All patients received 15 mg/kg1 i.v. paracetamol (Perfalgan; UPSA Laboratories, Agen, France) for the control of postoperative pain and 1 mg/kg1 i.v. dexamethasone (maximum 16 mg) for the control of postoperative pain, nausea, and vomiting. About 5 min before the end of surgery, patients in (Group C) received 10 ml NaCI 0.9%, patients in (Group P) received propofol 1 mg/kg1 and patients in (Group D) received dexmedetomidine 0.3 ug/kg1 diluted in 10 ml NaCI 0.9%. Experimental drugs were administered intravenously over 5 min. At the conclusion of the procedure, following the discontinuation of sevoflurane and nitrous oxide, residual muscle relaxation was reversed with neostigmine 0.05 mg/kg1 and atropine 0.02 mg/kg1 i.v. Extubation was performed when the patients’ gag reflex was restored and they showed facial grimaces or purposeful appearing motor movements, and the rate of train of four (TOF) was higher than 0.8 by a nerve stimulator (TOF-Watch®, Organon, Ireland). Children were transferred to the post anesthesia care unit (PACU). Upon arrival to the PACU, all children were received by one of their parents, who stayed with them until discharge.
The incidence of EA was evaluated using Aonos four point scale;[14] 1=calm; 2=not calm but could be easily consoled; 3=moderately agitated or restless and not easily calmed; 4=combative, excited, or disoriented, thrashing around. Scores of one and two were considered as absence of EA, and scores of three and four were analyzed as presence of EA. The severity of EA was evaluated using pediatric anesthesia emergence delirium (PAED) scale devised by Sikich et al.[2] [Table 1], a five-point rating scale with five grades for each item. The incidence and severity of EA were measured upon admission to the PACU (T0) and in the PACU at 5 min (T5), at 15 min (T15) and at 30 min (T30). Children were considered severely agitated if they had a PAED scale of 15/20 or higher.
Table 1Pediatric anesthesia emergence delirium scale
Postoperative pain was assessed using the modified Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) in the PACU at (T0), (T5), (T15) and (T30). Vomiting was treated with metoclopramide 0.15 mg/kg1 i.v. and the incidence of vomiting was recorded. Nausea was not recorded as it was difficult to assess in children. The incidence of adverse events such as hypotension, bradycardia, laryngospasm, bronchospasm and oxygen desaturation, were noted.
The following time intervals were recorded: The duration of surgery (from the time of mouth opening to the completion of the procedure), duration of sevoflurane anesthesia (from mask induction to the discontinuation of the inhaled anesthetic), duration of extubation (from the discontinuation of sevoflurane to the removal of endotracheal tube), time of emergence (from discontinuation of sevoflurane to the first response to a simple verbal command), and duration of PACU stay (from arrival to the PACU until discharge). Children were discharged from the PACU to a ward when the modified aldrete score was more than nine without agitation and vomiting.
Two anesthesiologists were involved in the study. All above i.v. agents were prepared and hidden behind drapes and administered by the first anesthesiologist according to the group to which the patient was randomized. The recordings of all variables were collected by the second anesthesiologist who was blinded to the group to which the patient was assigned.
BODY.STATISTICAL ANALYSIS:
Distribution of baseline variables was assessed by the Shapiro-Wilk W tests. Assuming an incidence of postoperative agitation of 30% or more after sevoflurane anesthesia was previously reported,[1516] and a 50% reduction in EA was considered to be clinically significant, we calculated that 40 patients were required in each group (for a level of significance of 0.05 and a power of 0.80). By using Statistical program for social science (SPSS) software for Windows, version 11(SPSS Inc, Chicago, IL, USA), arithmetic mean and standard deviation values for different variables were calculated and statistical analyses were performed for each group. Independent sample t-test was used to compare continuous variables exhibiting normal distribution, and Chi-squared or Fisher exact test for non-continuous variables. Serial measurements such as Aonos four point scale, PAED scale and modified CHEOPS were analyzed by repeated measures analysis of variance. P<0.05 is considered significant.


BODY.RESULTS:
There were no significant differences among the three studied groups in patient characteristics, incidence of agitation before induction of anesthesia as well as the different durations of anesthesia and surgery [Table 2].
Table 2Patients’ criteria and anesthetic details
The incidence and severity of EA were significantly lower in group P and group D compared to group C at T0, T5, T15 but not at T30. Compared to group D, the incidence and severity of EA in group P were significantly higher at T0, T5, and T15 but not at T30. The number of patients who developed severe EA (PAED >15) was significantly lower in group D and group P compared to group C. Compared to group D, group P showed no statistically significant difference. Modified CHEOPS was significantly lower in group D compared to group P and group C at T0 and T5 but not at T15 and T30. There was no significant difference between group P and group C at any time of measurement. Aonos four point scale, PAED scale and modified CHEOPS decreased significantly over time in each group. Regarding the incidence of vomiting, there was no statistically significant difference among the studied groups. Times to emergence and extubation in group P were significantly longer compared to group C and group D. Time to discharge from the PACU was not significantly different among the studied groups [Table 3].
Table 3Incidence of emergence agitation, pediatric anesthesia emergence delirium scale, modified children's hospital of eastern ontario pain scale and recovery characteristics
No adverse events such as laryngospasm, bronchospasm, hypotension, bradycardia and oxygen desaturation episodes were recorded in any of the children.

BODY.DISCUSSION:
The etiology of EA in children is not fully understood but possible risk factors are intrinsic characteristics of an anesthetic, rapid emergence from anesthesia, postoperative pain, preschool age, otolaryngologic surgical procedures, preoperative anxiety, and child temperament.[1] Meta-analysis of 23 randomized controlled trials revealed that EA occurred more frequently with sevoflurane than halothane.[17] Rapid awakening after sevoflurane anesthesia has been assumed to be a cause for the phenomenon. However, it is currently thought that rapid emergence is not the only cause of EA, because recovery from propofol anesthesia, which also has rapid emergence properties, is associated with low incidence of EA.[18]
In our study, the incidence and severity of EA were significantly lower in group D compared to group P and group C. Previous studies[101319] showed that dexmedetomidine reduces the incidence of EA after sevoflurane anesthesia in children because of their sedative and analgesic effects. In a study by Guler et al.[11] 1.5-2% sevoflurane in 60% N2 O in Oxygen and muscle relaxants were used in children undergoing adenotonsillectomy. They reported that dexmedetomidine given 5 min before the end of surgery, was effective in reducing the agitation with prolongation of extubation and emergence times. Ibacache et al.[10] found patients undergoing lower abdominal surgery anesthetized with 1-3% sevoflurane in 50% N2O in oxygen and a single i.v. dose of dexmedetomidine after induction, resulted in a reduction of postoperative agitation from 37% in the control group to 17% and 10% with 0.15 and 0.3 μg/kg1, respectively.
Recovery from propofol anesthesia is smooth and delayed, so propofol anesthesia is associated with a lower incidence of EA compared to sevoflurane.[20] The decreased incidence of EA could be accounted for the residual sedative effect and euphoric effect of propofol in the early recovery period.[21] Due to rapid pharmacokinetics of propofol, a bolus of 1 mg/kg1 given at the end of the procedure or continuous infusion used during maintenance of anesthesia results in increased concentrations during emergence and decreased incidence of EA.[4] Abu-Shahwan's study[6] showed that the administration of sub-hypnotic doses of propofol at the end of sevoflurane general anesthesia was effective in decreasing the incidence and severity of EA in children undergoing magnetic resonance imaging (MRI). Aouad et al.[7] reported that the administration of a single dose of propofol 1 mg/kg1 after discontinuation of sevoflurane at the end of surgery in children undergoing strabismus surgery significantly decreased the incidence of EA and improved patient satisfaction. On the other hand, Lee et al.[22] reported that administration of a single dose of 1 mg/kg1 propofol at the end of surgery in children undergoing adenotonsillectomy under sevoflurane anesthesia did not decrease the incidence and severity of EA.
The presence of pain is thought to be one of the major causes of EA, but painless treatment does not guarantee calm emergence from sevoflurane anesthesia.[1] Isik et al.[12] reported that EA was seen in 48% of pediatric patients after sevoflurane anesthesia for MRI. A recent meta-analysis shows no correlation of the efficacy of ketamine, α2-agonists, or fentanyl in postoperative pain relief and EA reduction.[4] These results suggest that the analgesic properties alone of these compounds are unlikely to be involved in their preventive effects for EA. Nevertheless, the properties to induce emergence sedation could explain their preventive effect.
The modified CHEOPS was significantly lower in group D compared to group P and group C at T0 and T5. Modified CHEOPS in each group decreased significantly over time. Modified CHEOPS was not influenced by propofol because propofol is not an analgesic agent. Kim et al.[23] reported that propofol 1 mg/kg1 at the strabismus surgery under sevoflurane anesthesia did not reduce EA in children, and they emphasized the importance of pain control.
Many studies have shown that EA is self-limited and is resolved without pharmacologic intervention over time.[124] Our data also demonstrated that the incidence and severity of EA and pain intensity are improved over time without analgesic or sedative drugs. Our study allowed children to stay with one of parents in the PACU and this seemed to help them to acclimate themselves to a strange and naive environment.
Time of extubation and emergence time were significantly longer in group P compared to group C. This is consistent with previous studies[67] showing that the time to awakening correlates negatively with EA scores. The statistically significant difference between group P and group D is of small magnitude and is not clinically significant. The delayed extubation time and emergence from anesthesia in group P did not delay discharge; children in all groups had comparable durations of PACU stay.
Dexmedetomidine produces dose-dependent HR and BP decrease.[925] Ibacache et al.[10] and Guler et al.[11] reported no hemodynamic effects at a 0.3-0.5 ug/kg1 bolus dose. Similarly, there was no significant hemodynamic effect in our study. Administering dexmedetomidine before extubation may contribute to hemodynamic stability.
Despite the fact that adenotonsillectomy surgery is well known to be associated with a high incidence of postoperative nausea and vomiting[26] the incidence of vomiting in our study is lower than previous studies.[26] This finding may be explained by the following facts: Only paracetamol, a nonopioid analgesic was administered, in addition to dexamethasone that possesses both analgesic[27] and antiemetic properties. Also, children stayed for approximately half an hour in the PACU. Discharge from the PACU coincided with the end of the study period. Therefore, the occurrence of delayed vomiting may have not been recorded by the investigators.
In our study dexmedetomidine 0.3 ug/kg1 was more effective than propofol 1 mg/kg1 in decreasing the incidence and severity of EA, when they administered 5 min. before the end of surgery in children undergoing adenotonsillectomy under sevoflurane anesthesia. Dexmedetomidine decreased postoperative pain, extubation time and emergence time compared to propofol without affecting the length of stay in PACU.

Question: Compared to 10 ml saline 0.9% or dexmedetomidine 0.3 ug/kg-1 what was the result of propofol 1 mg/kg  on Times to emergence and extubation?
Evidence:  details
The incidence and severity of EA were significantly lower in group P and group D compared to group C at T0, T5, T15 but not at T30
Answer: significantly increased