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07 September 2012 No. 30 Emergence delirium in children K Allopi Commentator: S Roberts Moderator: C Kampik Department of Anaesthetics CONTENTS INTRODUCTION ................................................................................................... 3 DEFINITION .......................................................................................................... 3 ASSESSMENT TOOLS OF EMERGENCE DELIRIUM......................................... 3 DIFFERENTIAL DIAGNOSIS ............................................................................... 5 RISK FACTORS FOR EMERGENCE DELIRIUM ................................................. 5 Age ..................................................................................................................... 5 Preoperative anxiety ......................................................................................... 6 Parental factors ................................................................................................. 6 Temperament of the child ................................................................................. 7 Type of surgical procedure............................................................................... 8 Pain..................................................................................................................... 8 PHARMACOLOGY ............................................................................................... 8 Inhalation anaesthetics .................................................................................... 8 Intravenous anaesthetics............................................................................... 10 Premedication................................................................................................. 11 Opioids ............................................................................................................ 13 5HT3 antagonist ............................................................................................. 15 RELATIONSHIP BETWEEN EMERGENCE DELIRIUM AND LONG-TERM POSTOPERATIVE MALADAPTIVE BEHAVIOURS ........................................... 16 PREVENTION AND MANAGEMENT ................................................................. 18 CONCLUSION .................................................................................................... 19 REFERENCES.................................................................................................... 20 Page 2 of 22 INTRODUCTION Emergence delirium (ED) has been identified as a significant problem in children recovering from anaesthesia with a reported incidence ranging between 10-80%. [1] Agitated behaviour associated with ED places the patient at risk for harming themselves or others, requires greater postoperative nursing resources, and decreases parent and caregiver satisfaction with the health care experience. In addition, this behaviour can dislodge cannulae, dressings, drains and catheters. Eckenhoff et al first described this phenomenon in the early 1960's.[2] Children anaesthetised with ether, cyclopropane, or ketamine undergoing tonsillectomy, thyroidectomy and circumcision experienced crying, thrashing and disorientation during emergence from anaesthesia. [2] With the popularity of the newer inhalation agents desflurane and sevoflurane, numerous clinical studies have been published questioning the association of these anaesthetics with an increased incidence of emergence delirium. DEFINITION The term “emergence agitation” has been used interchangeably with “emergence delirium” in the literature but there are differences in definitions and clinical presentations. Agitation, which is described as excessive motor activity, is a nonspecific symptom that incorporates discomfort, pain and anxiety. Delirium on the other hand, is an acute state of confusion accompanied by cognitive impairment including perceptual disturbances and hallucinations. Cognitive impairment is difficult to diagnose in children and thus the terms are used interchangeably. ED occurs within the first 30 minutes of recovery from anaesthesia, is usually self-limited but can last up to 2 days.[5] It is often missed by the attending anaesthetist as he/she begins the next case in theatre. Currently there is no clear measurement tool to assess this phenomenon. ASSESSMENT TOOLS OF EMERGENCE DELIRIUM Sixteen rating scales and two visual analogue scales have been used to measure ED in children. These scales are deficient in respects of scale content, psychometric evaluation and included behaviours that are not specific to ED. Furthermore, there is a lack of consensus on what level of behavioural disturbance and for what period constitutes ED. [3] The PAED scale, a four-point scale described by Watcha and Cravero’s five-point scale are the most commonly used scales to assess ED. [6] Page 3 of 22 The PAED scale is shown in Table 1 and has five items scored from 0 to 4 (with reverse scoring where applicable). The scores are summed to obtain a total score with a range of 0–20. The PAED scale is reported to have the advantage of being validated and better reflects the presence of ED rather than pain. The PAED scale’s first item, “The child makes eye contact with the caregiver,” and third item, “The child is aware of his/her surroundings,” reflects disturbances in the child’s consciousness during an ED reaction. The second item on the PAED scale, “The child’s actions are purposeful,” addresses changes in the child’s cognition during an ED reaction. The inclusion of items that reflect disturbances in consciousness and cognition may be pivotal in differentiating ED from pain. The authors of the PAED scale have described a sensitivity of 0.64 and a specificity of 0.86 with a PAED score of >=10. [4] However the PAED scale is cumbersome in clinical practice. The Watcha scale is a four-point scale as shown in Table 2 and defines ED at a level of 3 or 4 at any time. The Watcha scale has a higher correlation than Cravero with respect to the PAED scale. Page 4 of 22 The Cravero scale shown in Table 3 is a five-point scale. The definition for ED in this scale is reached if level 4 or 5 was evident and present for at least 3 minutes. The Cravero scale has the advantage of simplicity. Subjective assessment of ED is highly likely to score positive on all three scales. Although all three scales have their limitations, they appear to be reasonably reliable in detecting ED in clinical practice. The Watcha scale and the PAED scale when >12 give the highest sensitivity in detecting ED. However, no scale appears to match the discriminating ability of an experienced observer. DIFFERENTIAL DIAGNOSIS Agitation on emergence may relate to many sources of distress for a child – pain, hunger, parental separation, cold and continuation of preoperative distress. It is important to remember that several life threatening conditions e.g. hypoxia, severe hypercapnia, hypotension, hypoglycaemia, increased intracranial pressure may also result in disorientation and altered mental status. These entities must be diagnosed and treated promptly. Bladder distension may also yield a similar clinical picture. RISK FACTORS FOR EMERGENCE DELIRIUM Although there is ample published literature regarding emergence delirium, little is known about the pathophysiology, causal factors and appropriate remedy for this phenomenon. Emergence delirium appears to be a multifactorial syndrome resulting from an interplay of patient characteristics, age, anaesthetic factors, surgical factors, family and environmental attributes. Age Preschool boys aged 2-6 years have higher rates of ED compared to school boys.[5] Authors attributed this to rapid awakening and psychological immaturity. Page 5 of 22 There is a role of brain maturation and physiologic development to the susceptibility of the young age group to delirium. Preschool children may share some of the vulnerabilities to delirium experienced by geriatric patients. For older adults, aging decreases brain volume and weight with a concomitant decline in brain blood flow and neuron loss in the neocortex and hippocampus. The locus caeruleus and the substantia nigra can lose as much as 35% of their neurons in a normal aging process, decreasing levels of norepinephrine, acetylcholine, dopamine, and γ-aminobutyric acid. The paediatric brain is almost a mirror image of this process. The maturation of the hippocampus and later the prefrontal regions allow for the expression of semantic and episodic memory. Subcortical cholinergic nuclei provide input to the cortex and hippocampus. The development of cholinergic function and the hippocampus may, therefore, be clues to the relative susceptibility of younger children to delirium. Preoperative anxiety Preoperative anxiety has been associated with increased postoperative agitation as demonstrated by Aono et al. [7] Table 4 Twenty of 27 boys (74.1%) in the anxious group showed problematic behaviour during emergence, compared with 5 of 79 boys (6.3%) in the calm group (P<0.0001). The incidence of problematic behaviour during emergence from halothane anaesthesia was significantly greater in boys showing anxiety during induction, compared with boys not showing signs of anxiety during that period. Parental factors Fortier et al have shown that parental anxiety is a risk factor for high levels of child anxiety across the perioperative setting, from the preoperative holding area, up to two weeks postoperatively and therefore could be a contributing factor to ED. [8] Page 6 of 22 Table 5 [8] The EASI is a widely used parent-report measure of a child’s temperament with regard to emotionality (e.g. child is easily upset ⁄ frightened), activity (e.g. child fidgets or cannot sit still long), sociability (e.g. child makes friends easily), and impulsivity (e.g. child has difficulty with self-control) that has good validity and test–retest reliability. The state-trait anxiety inventory (STAI) is a self-report measure of parental situational (state) and general (trait) anxiety that has been well validated. There is a positive effect of parental presence in most studies and many hospitals today welcome early parental presence in the recovery room. Temperament of the child Voepel-Lewis et al found that low adaptability in children is associated with increased incidence of EA. [9] Table 6 Kain et al have also shown that ED was higher among children who are more emotional, more impulsive and less sociable [19] . Voepel-Lewis et al also showed that children with attention deficit hyperactivity disorder are more likely to have emergence delirium. Page 7 of 22 Type of surgical procedure Surgical procedures involving the ears, eyes, tonsils, thyroid and urological surgeries have been associated with higher rates of ED. When Eckenhoff et al first described ED in 1961, he attributed the increased incidence among otolaryngologic procedures to the “sense of suffocation”.[2] Voepel-Lewis has shown in a prospective cohort study that the otolaryngologic procedures are an independent risk factor for ED.[9] Forty-two (26%) and 23 (28%) children who underwent otorhinolaryngologic and ophthalmologic procedures, respectively, experienced ED, compared with urologic (15%), orthopaedic (15%), general surgical (12%), and other (6%) procedures (P=0.02). Pain Pain has been the most confounding variable that poses a diagnostic dilemma when assessing a child’s behaviour upon emergence because of the overlapping clinical picture with ED, especially in pre-verbal children. Pain has been acknowledged as a major risk factor for ED. Although it is a risk factor, studies have shown ED to occur when there is adequate pain control from caudal blocks [10] , non-painful procedures such as MRI scans and in the presence of no surgery [11] . This suggests the presence of ED despite adequate pain control and thus pain cannot be pointed out as the sole contributing factor to ED. Several studies have been done in order to study the causal effect of pain and ED and to decrease the incidence of ED by treating pain with different modalities.[5] PHARMACOLOGY Inhalation anaesthetics Emergence agitation was reported as a problem in general anaesthesia recovery before the development of the modern inhalational agents (sevoflurane and desflurane), and ED has been shown to occur with the use of all anaesthetic gases. Page 8 of 22 The increased use of sevoflurane and desflurane in recent years has been associated with a higher incidence of ED compared with isoflurane and halothane. (Table 7) [12] This phenomenon is thought to be due to the low blood-gas solubility and rapid recovery characteristics of sevoflurane and desflurane. ED has been attributed to shorter duration surgeries that allowed for rapid washout of anaesthetics from the body, causing rapid emergence before analgesics had time to act and reach their peak effect. In a comparative evaluation of the incidence of emergence agitation and post-operative recovery profile in paediatric patients after isoflurane, sevoflurane and desflurane anaesthesia, Singh et al found a higher number of patients in the sevoflurane group were agitated in the recovery period and required rescue medications compared with desflurane and isoflurane. [1] Table 7 Although the rapid emergence following sevoflurane has been speculated to be the cause of ED, Cohen et al compared emergence from sevoflurane and propofol, which allows a fast recovery. [13] They found that rapid emergence from propofol was smooth and pleasant compared to sevoflurane and concluded that ED was not related to the speed of recovery. In fact, delaying emergence by stepwise decrease of sevoflurane did not reduce the incidence of ED as shown by Oh et al. [14] Similarly, Grundmann et al have shown that in children, TIVA with remifentanil and propofol is a well-tolerated anaesthetic method, with a lower perioperative heart rate and less postoperative agitation compared with a desflurane-N2O based anaesthesia. [15] Therefore, ED is not related to the rapid recovery but could be related to the intrinsic property of inhalation anaesthetics. Adding nitrous oxide to anaesthesia with sevoflurane reduces the minimum alveolar concentration (MAC) of sevoflurane, meaning that lower concentrations of the anaesthetic can be used, thereby reducing the incidence of emergence delirium. [43] Page 9 of 22 Intravenous anaesthetics Propofol Ibrahim et al showed that the addition of propofol 1 mg/kg at the end of sevoflurane general anaesthesia can significantly decrease the incidence of ED in children undergoing magnetic resonance imaging (MRI). [16] An extensive literature review was performed by Logan Key et al that evaluated three categories of anaesthesia techniques: sevoflurane inhalational general anaesthetic, propofol as an adjunct to sevoflurane general anaesthetic, and propofol total intravenous anaesthesia (TIVA) techniques.[12] Table 8 They concluded that there is an advantage to either propofol TIVA or adjunctive propofol with sevoflurane (compared with sevoflurane alone) and that the use of propofol is associated with a reduction in the incidence of emergence agitation. The limitations to a TIVA approach in our setting are that it is expensive and the child will usually require an initial gas induction before inserting the intravenous line. Table 8 Page 10 of 22 Ketamine Ketamine has been established as a safe and effective sedative for painful paediatric procedures. This dissociative agent can induce dreaming and hallucinations during recovery, and occasional unpleasant reactions and nightmares have traditionally limited its use in adults. Children 15 years old and younger, however, are much less prone to such unpleasant recovery reactions and display milder reactions when they occur.[26] In a randomized double blinded study involving 85 premedicated children undergoing dental repair, Ibrahim et al concluded that the addition of ketamine 0.25 mg/kg 10 min before the end of surgery, significantly decreased the incidence of emergence agitation in children after sevoflurane general anaesthesia. There was no statistically significant difference in pain scores, time to eye opening or recovery room discharge time between the placebo (saline) and ketamine groups.[27] Table 9 Table 9 Kararmaz et al found that 6 mg/kg oral ketamine given to children 30 minutes before adenotonsillectomy under desflurane anaesthesia reduced ED incidence from 56% to 18% without delaying recovery. [28] Dalens et al showed a reduced incidence of ED in children given 0.25 mg/kg of ketamine administered intravenously at the end of MRI procedures while under sevoflurane anaesthesia (12% vs 36% in the control group). [29] In our setting, ketamine may be the answer for a child at risk for emergence delirium as it is relatively cheap, easy to administer and lacks respiratory depressive effects. Premedication Benzodiazepines Although benzodiazepines do reduce anxiety their effect on ED is uncertain. The influence of midazolam on emergence behaviour seems to be somewhat controversial. Few studies have shown that midazolam premedication decreases agitation postoperatively following sevoflurane [19] while others have shown no Page 11 of 22 effect [17,18]. Christian el al compared premedication of 1 mg/kg midazolam with 0.5 mg/kg and found no statistically significant difference in emergence behaviour but negative behavioural changes occurred more frequently in children younger than 3 years of age. The amnesia surrounding induction after midazolam premedication might increase postoperative anxiety [17]. Therefore upon awakening, premedicated children could be disorientated and agitated in the belief that surgery was not over. Naturally this would more readily occur in younger children who often do not yet understand their surroundings, especially when not fully alert. Phenothiazines Trimeprazine (Vallergan) has powerful antihistaminic, anti-emetic, antipruritic and sedative actions. Patel et al randomly assigned 90 children to one of three groups for premedication with oral midazolam 0.5 mg.kg-1, diazepam 0.25 mg.kg-1 with droperidol 0.25 mg.kg-1, or trimeprazine 2 mg.kg-1. On arrival at the anaesthetic room, anxiolysis was satisfactory in 26 out of 29 (90%) children who received midazolam compared with 23 out of 29 (79%) who received diazepam-droperidol and 18 out of 29 (62%) who received trimeprazine (P < 0.05).[42] Dexmedetomidine and clonidine Dexmedetomidine, a selective alpha 2-agonist has sedative, analgesic and anxiolytic effects after IV administration. Shukry et al conducted a double-blinded randomized prospective study that showed that the perioperative infusion of 0.2 µg/kg/hr dexmedetomidine decreases the incidence and frequency of ED in children after sevoflurane-based GA without prolonging the time to extubate or discharge. [30] Table 10, The incidence of ED was statistically significantly different between the two groups, 26% in the dexmedetomidine group (Group D) vs 60.8% in the saline group (Group S) (P = 0.036). Table 10 A decreased ED incidence was also seen in a study by Berrin et al after a dose of 1µg/kg dexmedetomidine post sevoflurane gas induction in children undergoing MRI. The incidence of emergence agitation was 47.6% in the placebo group, and 4.8% in the dexmedetomidine group (P = 0.002). [11] Page 12 of 22 Dexmedetomidine has also been studied as a premedication against midazolam. [31] Subjects received 4 µg/kg of oral dexmedetomidine or 0.5 mg/kg of midazolam orally prior to anaesthesia induction. Subjects’ anxiety over parental separation, acceptance of anaesthesia masks, and presence and severity of ED were evaluated. There were no statistically significant differences in parental separation anxiety, mask acceptance and ED occurrence between the 2 groups. In this study, dexmedetomidine produced no common side effects (blood pressure and heart rate fluctuation), which may indicate that oral administration with a 16% bioavailability versus 82% in buccal preparations results in fewer side effects but requires higher dosing to gain therapeutic effects. Dexmedetomidine reduces norepinephrine release and sympathetic activity, which could explain its role in achieving superior sedation and preventing ED. Intravenous clonidine 3ug/kg reduced the incidence of post sevoflurane ED from 39% in the control group to 5% in the clonidine group with no delay in fitness to discharge [32]. Moreover, intraoperative administration of 2 µg/kg i.v. clonidine decreased the incidence of ED from 80% in the control group to 10% in the clonidine group [33]. Oral clonidine 4 µg/kg given thirty minutes prior to sevoflurane anaesthesia induction in preschool children is associated with a significant reduction in ED compared to midazolam 0.5 mg/kg (25% vs. 60%).[34] Opioids Fentanyl Fentanyl is a potent opioid, which can decrease ED following sevoflurane and desflurane anaesthesia. Cravero et al have shown that fentanyl 1 µg/kg IV given 10 minutes before the discontinuation of the sevoflurane anaesthetic in patients undergoing magnetic resonance imaging decreased the incidence of ED from 56% to 12% (P=0.02). [20] Inomata et al studied the effect of fentanyl infusion on the intubating conditions as well as emergence agitation in children anesthetized with sevoflurane. They recommended a bolus of 2 µg/kg followed by an infusion of 1 µg/kg/hr for a smooth emergence.[21] Intranasal fentanyl 2 µg/kg after induction with sevoflurane resulted in therapeutic serum levels of fentanyl and decreased agitation after ear tube placement.[22] In a randomized controlled trial, patients were treated with either with a placebo or a 1- to 1.5-ug/kg dose of fentanyl before inserting a laryngeal mask airway. Between the two treatments, there was a significant difference in the frequency of emergence agitation (P = 0.04) but no postoperative adverse effects such as postoperative nausea and vomiting. [11] Page 13 of 22 Table 11 Alfentanil There are positive results regarding the use of alfentanil on the incidence of emergence delirium. One hundred and five children, were randomly allocated to receive normal saline (control group), alfentanil 10 µg/kg (A10) or 20 µg/kg (A20), 1 minute post sevoflurane induction. [24] The incidence of severe agitation was significantly lower in the A10 and A20 groups compared with those in the control group (11/32 and 12/34 vs. 24/34, respectively) (P=0.007, 0.006, respectively). PAED scales were significantly different between the three groups (P=0.008), and lower in the A10 and A20 groups than that in the control group (P=0.044, 0.013, respectively).Table 12 There was also no significant delay in recovery, no significant hypotension and no difference in the side effects of alfentanil such as cough or chest wall rigidity between groups. Table 12 Remifentanil In preschool aged children undergoing adenotonsillectomy with sevoflurane general anaesthesia, after propofol and fentanyl induction, intraoperative remifentanil decreased the incidence of emergence agitation. [25] The incidence of emergence agitation in group S was 66.7% (20/30) and in group R 23.3% (7/30), Page 14 of 22 P <0.01 Table 13 Group S received no other medication(saline) while group R received remifentanil 1 μg/kg/minute intraoperatively. Table 13 The influence of remifentanil on emergence agitation may be that more profound intraoperative suppression of pharyngeal and laryngeal reflexes during adenotonsillectomy might reduce emergence agitation. However in this study, there is no mention of administration of another analgesic and this technique may be cumbersome and expensive in clinical practice. 5HT3 antagonist It has also been shown that tropisetron, a 5HT3 antagonist, decreases emergence agitation compared to placebo (32% vs 62%). However, the mechanism of action is unclear as described by Lankinen et al.[35] Non-pharmacologic tools It is important to maintain a quiet environment for the child. If ED occurs, holding the child and physical restraint may be necessary sometimes to protect the child. A very effective method is reuniting with the parent or caregiver during awakening. However, if an emergence delirium reaction occurs, it is best to remove and counsel the parent on the child's condition as this is a distressing event to witness. Acupuncture Acupuncture therapy may be effective in diminishing both pain and emergence agitation in children. In a prospective randomized controlled trial, Yuan-Chi et al showed that acupuncture markedly reduces emergence agitation in children after sevoflurane and nitrous oxide anaesthesia for bilateral myringotomy and tympanostomy tube insertion without producing adverse events. [41] Table 14 Page 15 of 22 Table 14 RELATIONSHIP BETWEEN EMERGENCE DELIRIUM AND LONG-TERM POSTOPERATIVE MALADAPTIVE BEHAVIOURS Following discharge to home, another perioperative complication that has been seen in up to 50% of children postoperatively is the development of negative postoperative behavioural changes (NBC) [40]. These behaviours include generalized anxiety, nighttime crying, enuresis, separation anxiety, and temper tantrums. Kain et al suggests that patients with emergence delirium are seven times more likely to have new onset postoperative maladaptive behavioural changes including eating problems, sleep disturbances, separation anxiety and apathy.[36] He reported that 54% of all children undergoing general anaesthesia exhibit negative behavioural responses 2 weeks after the surgery and continues up to 6 months in 20% and up to one year in 7%.[36] In another study he found no difference in behaviour between children exposed to sevoflurane or halothane.[39] Faulk et al revealed no correlation between the length of time under deep hypnosis defined as BIS<45 and the incidence of ED or negative postoperative behavioural changes [37]. In a prospective randomized control trial involving 120 patients, Keany et al showed that there was a significant decrease in the incidence over time with 58.3, 46.7 and 38.3% of all children exhibiting negative changes on postoperative days 1, 7 and 30, respectively (P < 0.03). [38] Children under the age of 4 years were significantly more likely to develop postoperative negative behavioural changes(NBC) than older children. Page 16 of 22 Table 15 [38] Fortier et al examined children’s anxiety across the perioperative setting. Anxiety levels of 261 children aged 2–12 was rated prior to surgery, immediately after surgery, and for 2 weeks at home following surgery using the modified Yale preoperative anxiety scale (mYPAS) and the post hospitalization behavioural questionnaire (PHBQ). The mYPAS is a structured, observational measure of preoperative anxiety in children that has been validated and has demonstrated good to excellent inter- and intraobserver reliability. The PHBQ is a questionnaire measuring post hospitalization behavioural changes in children and has acceptable validity and test–retest reliability. Questions evaluate maladaptive behaviour patterns such as an increase in temper tantrums, loss of appetite and sleep disturbances. It also appraises behavioural regression including the loss of previously gained milestones (e.g. return to bedwetting). The PHBQ consists of 27 items rated by parents relative to behaviour before surgery. Child anxiety increased significantly prior to surgery, peaked at mask introduction, and decreased in the immediate postoperative setting and over the 2 weeks at home (P < 0.001). (Figure 1) It is important to remember that a hospital admission for a child has many stressful events and emergence delirium is not a sole contributor to the occurrence of negative postoperative behavioural changes. Page 17 of 22 PREVENTION AND MANAGEMENT As previously described in detail, numerous medications have been studied to prevent or reduce emergence delirium in children. No one effective method has been shown to be highly superior. It is very difficult to compare studies as each uses different assessment tools, type of surgical procedure, or even anaesthetic techniques. However, it is no doubt that a young anxious preschool child undergoing a painful surgical procedure without adequate pain control will most likely suffer from emergence delirium. There is a relationship linking preoperative anxiety, emergence delirium, and postoperative maladaptive behaviour changes. Children who are at high risk of developing all of these clinical phenomena are younger, more emotional, more impulsive, and less social.36] Parental anxiety is a significant predictor of perioperative anxiety and thus has implications for treatment. [36] Children’s temperament may also be a modifiable target. Emphasis is placed on identifying ways to mitigate parental anxiety, such as developing preoperative preparation programs directed at parents and patients. It is vital for the anaesthetist to be aware of this phenomenon and to add awareness to the recovery room staff. If a child has emergence delirium, the first step is to secure the drip site for intravenous drug administration. The next step is to call for help and to prevent injury to the child. The caregiver should be removed and counselled if already present. Administer propofol in 5 to 10mg increments and be prepared to support the child's ventilation with an ambubag, oxygen and an oropharyngeal airway if apnoea occurs. Page 18 of 22 CONCLUSION In summary, ED remains a significant post anaesthetic problem that interferes with the child’s recovery and challenges the anaesthetist and the recovery room staff in terms of assessment and treatment. An understanding of potential risk factors is important to appropriately differentiate and treat agitation in the paediatric recovery unit. As studies are ongoing trying to discover the underlying causes or trying to treat and prevent the occurrence of emergence delirium, it is the role of the anaesthetist to recognize patients at risk, involve the parents preoperatively as well as postoperatively and use adjuvant drugs as deemed necessary. 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Paediatric Anaesthesia; 2010, 20:704-711 Aono J, Ueda W, Mamiya K, Takimoto E, Manabe M: Greater incidence of delirium during recovery from sevoflurane anaesthesia in preschool boys. Anaesthesiology; 1997, 87:1298-1300. Fortier Ma, Del Rosario A, Martin S, Kain ZN: Perioperative anxiety in children. Pediatr Anesth; 2010, 20:318-322. Voepel-Lewis T, Malviya S, Tait AR: A prospective cohort study of emergence agitation in the paediatric post anaesthesia care unit. Anesth Analg; 2003, 96:1625-1630. Weldon BC, Bell M, Craddock T. The effect of caudal analgesia on emergence agitation in children after sevoflurane versus halothane anaesthesia. Anaesthesia and Analgesia 2004 Feb;98(2):321-6. Berrin Isik Md, Mustafa Arslan MD, et al : Dexmedetomidine decreases emergence agitation in paediatric patients after sevoflurane anaesthesia without surgery. Paediatric Anaesthesia 2006 16: 748–753 Key, K. L., C. Rich, et al. (2010). "Use of propofol and emergence agitation in children: a literature review." AANA J 78(6): 468-473. Cohen It, Finkel Jc, Hannallah Rs, Hummer Ka, Patel KM: Rapid emergence does not explain agitation following sevoflurane anaesthesia in infants and children: a comparison with propofol. Paediatr Anaesth; 2003, 13:63-67. OH A, Seo K, Kim C, Kim H: Delayed emergence process does not result in a lower incidence of emergence agitation after sevoflurane anaesthesia in children. Acta Anaesthesiol Scand; 2005, 49:297-299. Grundmann U, Uth M, Eichner A, Wilhelm W, Larsen R: Total intravenous anaesthesia with propofol and remifentanil in paediatric patients: a comparison with desflurane-nitrous oxide inhalation anaesthesia. Acta Anaesthesiol Scand; 1998, 42:845-50. Page 20 of 22 16. Ibrahim Abu-Shahwan Md : Effect of propofol on emergence behaviour in children after sevoflurane general anaesthesia. Paediatric Anaesthesia 2008 18: 55–59 17. Breschan, C., M. Platzer, et al. (2007). "Midazolam does not reduce emergence delirium after sevoflurane anaesthesia in children." Paediatr Anaesth 17(4): 347-352. 18. McGraw T, Kendrick A. Oral midazolam premedication and postoperative behaviour in children. Paediatr Anaesth 1998; 8:117–121. 19. Ko YP, Huang CJ, Hung YC et al. Premedication with low-dose oral midazolam reduces incidence and severity of emergency agitation in paediatric patients following sevoflurane anaesthesia. Acta Anaesthesiol Sin 2001; 39: 169–177. 20. Cravero JP, Beach M, Thyr B, Whalen K: The effect of small dose fentanyl on the emergence characteristics of paediatric patients after sevoflurane anaesthesia without surgery. Anesth Analg; 2003, 97:364-7. 21. Inomata T, Maeda T, Shimizu T, Satsumae T, Tanaka M: Effects of fentanyl infusion on tracheal intubation and emergence agitation in preschool children anaesthetized with sevoflurane. Br J Anaesth; 2010, 105(3):361-7. 22. 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