- Email: [email protected]
Emergence Delirium (ED) in Children
Review Article
EMERGENCE DELIRIUM (ED) IN CHILDREN K Raghavendran Senior Consultant & Coordinator, Apollo Children’s Hospitals, 21, Greams Lane, Off Greams Road, Chennai 600 006, India. Emergence delirium in children is a state of mental dissociation that occurs while recovering from anesthetic agents and manifests as disorientation, restlessness, irritability, screaming and involuntary activity. It usually evolves in the first half hour after awakening from anesthesia, often lasts up to 20 minutes and usually resolves on its own. Many factors have been suggested to play a potential role in the development of such an event. Post anesthesia agitation has been noted more often with the newer, less soluble, inhaled anesthetics, such as desflurane and sevoflurane, than with other volatile ones; however administration of other anesthetic agents can also cause this disturbing recovery phenomenon. Emergence delirium occurs more often in preschool children and seen frequently after head and neck surgeries like tonsillectomy, adenoidectomy, tongue tie release, strabismus surgery, nasal operations etc. Treatment is with pharmacological and environmental. Prevention may be the best treatment but no one medication is entirely effective. Key words: Post anesthetic, Emergence delirium, Sevoflurane, Desflurane.
INTRODUCTION
consciousness in which the child is inconsolable, irritable, uncompromising or uncooperative, typically thrashing, crying, moaning, or incoherent [2]. Additionally paranoid ideation has been observed in combination with these emergence behaviors. Characteristically these children do not recognize or identify familiar and known objects or people. Parents who witness this state claim the behavior is unusual and uncustomary for the child. Although generally self limiting (5-15 min) ED can be severe and may result in physical harm to the child and particularly the site of surgery.
The introduction of a new generation of inhaled anesthetics like sevoflurane and desflurane into pediatric clinical practice has been associated with a greater incidence of ED, a short-lived, but troublesome clinical phenomenon of uncertain etiology [1]. A variety of anesthesia-, surgery-, patient-, and adjunct medication-related factors have been suggested to play a potential role in the development of such an event. Restless behavior upon emergence causes not only discomfort to the child, but also makes the caregivers and parents feel unhappy with the quality of recovery from anesthesia. Although the severity of agitation varies, it often requires additional nursing care, as well as treatment with analgesics or sedatives, which may delay discharge from hospital. To reduce the incidence of this adverse event, it is advisable to identify children at risk and take preventive measures, such as reducing preoperative anxiety, removing postoperative pain, and providing a quiet, stress-free environment for post anesthesia recovery.
Emergence delirium has been reported after the introduction of every new anesthetic including most inhalational agents and intravenous agents including midazolam, remifentanil and propofol. Other drugs known to be associated with ED include (i) atropine or scopolamine, (ii) ketamine, (iii) droperidol, (iv) barbiturates and possibly, (v) benzodiazepines [3]. The incidence of emergence delirium in all postoperative patients is 5.3% with a more frequent incidence in children (12-13%). The incidence of emergence delirium after halothane, isoflurane, sevoflurane and desflurane ranges from 2-55%. It has been postulated that this phenomenon has become more acutely noticed with the increased use of agents such as sevoflurane and desflurane that have a rapid emergence profile due to their low blood gas solubility profile. It was thought that rapid emergence with lack of adequate pain control before emergence contributed or was the cause of this problem. This has been supported by the finding that
Emergence delirium (ED) also referred to as emergence agitation (EA) is a well documented phenomenon occurring in children and adults in the immediate postoperative period. With the recent popularity of the newer inhalation agent’s desflurane and sevoflurane, numerous clinical studies have been published questioning the association of these anesthetics with an increased incidence of emergence delirium. Emergence delirium is defined as a dissociated state of 99
Apollo Medicine, Vol. 8, No. 2, June 2011
Review Article
ketorolac administration decreased the incidence of emergence delirium three to fourfold after myringotomy with either halothane or sevoflurane anesthesia. Several studies have documented a reduction in ED with the administration of fentanyl 2.5 μg/kg intraoperatively or 2.0 μg/kg fentanyl administered intranasal, 1 μg/kg in each nostril after the induction of anesthesia. However, other studies have noted emergence delirium in children after sevoflurane anesthesia despite effective regional blocks to prevent postoperative pain. These studies demonstrated that delirium occurred more frequently in preschool age children, 1 to 5 years of age, lasted 5-15 minutes in the recovery room and often resolved spontaneously. Studies that have also called into question whether adequate pain management is the cause of ED include sevoflurane vs. halothane administration in patients undergoing MRI (no surgery) where the incidence of ED was 33% in sevoflurane treated patients versus 0% in halothane treated children. Post operative agitation can indicate any number of sources, including pain, physiological compromise, or anxiety. Delirium may be confused with agitation, but it may also be a cause of agitation. As most of the literature on this subject cannot differentiate between these two terms, we refer to the problem as EA/ED for the purpose of this article. Possible etiological factors of pediatric emergence delirium •
Rapid emergence
•
Intrinsic characteristics of an anesthetic
•
Postoperative pain
•
Surgery type
•
Age
•
Preoperative anxiety
•
Child temperament
•
Adjunct medication
ANESTHESIA-RELATED FACTORS Rapid emergence Post anesthesia agitation has been noted more often with the newer, less soluble, inhaled anesthetics, such as desflurane and sevoflurane, than with other volatile ones. It has been postulated that rapid awakening after the use of the insoluble anesthetics may initiate EA/ED by worsening a child’s underlying sense of apprehension when finding him in an unfamiliar environment. Some parents claim the patient’s behavior upon emergence was the same as when he was suddenly awakened from deep sleep. Older children and adults usually become oriented rapidly, whereas Apollo Medicine, Vol. 8, No. 2, June 2011
preschool aged children, who are less able to cope up with environmental stresses, tend to become agitated and delirious. However, recovery from propofol anesthesia which is also rapid is smooth and pleasant. Several studies have shown that sevoflurane anesthesia is associated with a higher incidence of EA/ED compared with propofol. Similar results were obtained when desflurane/nitrous oxide anesthesia was compared with protocol/remifentanil anesthesia. Delaying emergence by a slow, stepwise decrease in the concentration of inspired sevoflurane at the end of surgery did not reduce the incidence of EA, and thus questions the role of abrupt awakening in the development of EA. Studies have shown a similar incidence of EA among children who entered the post anesthesia care unit (PACU) still asleep and those who entered awake. Intrinsic characteristics of an anesthetic Most authors have documented that EA/ED occurs more often after sevoflurane than after halothane anesthesia which has been confirmed by the manufacturer itself .Some authors have speculated that two unique, intrinsic characteristics of sevoflurane might account for the development of EA/ED. First, this anesthetic exerts an irritating side effect on the central nervous system (CNS). Second, although sevoflurane degradation products appear to cause no organ damage themselves, data are lacking on their possible interactions with other types of medications. Epileptiform activity has been reported during the use of sevoflurane anesthesia in both patients and volunteers with no medical history of seizures [4]. However, such cases have been sporadic and have had an uneventful recovery. Furthermore, desflurane,which has no proconvulsant properties, has been associated with a similar, if not a greater incidence of EA when compared with sevoflurane. These facts suggest that the causality between theCNS effects of sevoflurane and EA/ED is unlikely. As for the eventual neurotoxic influence of sevoflurane degradation products, there is no supporting scientific evidence. Postanesthesia agitation has been described not only with sevoflurane and desflurane, but also with isoflurane and, to a much lesser extent, with halothane. In a prospective trial that included 521 children aged 3-7 year who were scheduled for elective outpatient surgery, isoflurane was identified as an independent risk factor for EA.Children who received sevoflurane/isoflurane for the induction/maintenance of anesthesia were twice as likely to develop EA when compared with children who had any other anesthetic regimen. Considering that sevoflurane-induced electroencephalogram changes are similar to those observed during the administration of either desflurane or isoflurane, but different from changes recorded with halothane, EA/ED may be related to the similar CNS effects of these anesthetics, which may affect brain activity by interfering
100
Review Article
with the balance between neuronal synaptic inhibition and excitation in the CNS . SURGERY-RELATED FACTORS Pain Postoperative pain has been the most confounding variable when assessing a child’s behavior upon emergence because of the overlapping clinical picture with EA/ED. Inadequate pain relief may be the cause of agitation, particularly after short surgical procedures for which peak effects of analgesics may be delayed until the child is completely awake. In several studies, the preemptive analgesic approach successfully reduced EA/ED, suggesting that pain may be its major source.Intraoperative administration of IV ketorolac 1 mg/kg for minor otorhinolaryngological procedures decreased the incidence of EA three to four times after both halothane (42% vs. 12%) and sevoflurane anesthesia (38% vs. 14%). Fentanyl, given either IV 2.5μg/kg or intranasal 2μg/kg during moderately painful surgery, also decreased EA.Alpha2 receptor agonists may offer advantages in preventing EA because they have both analgesic and sedative properties. On the other hand, post anesthesia agitation has been observed when pain was efficiently treated or even when absent. Surgery type Surgical procedures that involve the tonsils, thyroid, middle ear, and eye have been reported to have higher incidences of postoperative agitation and restlessness [5]. It has been speculated that a sense of suffocation during emergence from anesthesia may contribute to EA in patients undergoing head and neck surgery. However, there are no supporting scientific data to date. PATIENT-RELATED FACTORS Age Aono, et al. found that ED appeared more often with sevoflurane than with halothane in pre schoolboys aged 3-5 year (40% vs 10%) [6]. The difference was not observed in the school-aged population. All children received oral diazepam for premedication and a caudal block for preoperative pain control. The authors speculated that the psychological immaturity of pre-school children, coupled with the rapid awakening in a strange environment, may have been the main cause of ED.Generally, younger children are more likely to show altered behavior upon recovery from anesthesia. The sub population of those aged 2-5 year seems to be the most vulnerable as they are easily confused and frightened by unexpected and unpredictable experiences [7]. In a recent commentary on the diagnosis of delirium in pediatric patients, Martini addressed the role of
brain maturation in the genesis of this phenomenon [8]. He pointed out that the pediatric brain is almost a mirror image of a normal age-related regressive process with a consequent decline in nor epinephrine, acetylcholine, dopamine, and gamma amino butyric acid (GABA). Thus, the development of cholinergic function and the hippocampus may suggest clues about the relative susceptibility of younger children to delirium. Preoperative anxiety Intense preoperative anxiety, both in children and their parents, has been associated with an increased likelihood of restless recovery from anesthesia. Kain, et al. retrospectively searched their database to determine the relationship between preoperative anxiety, ED, and postoperative maladaptive behaviors [9]. They recruited 791 children who were not premedicated and underwent surgery and genera anesthesia using sevoflurane. The odds of having marked symptoms of ED were increased by 10% for each increment of 10 points in the child’s state anxiety score. However, a cause effect relationship between the two phenomena could not be demonstrated. Other authors failed to show a correlation between preanesthetic distress and ED, possibly because of the small total number of patients studied and the use of a self-developed, no standardized observational scale for evaluating children’s distress. Temperament Children who are more emotional, more impulsive, less social, and less adaptable to environmental changes were identified to be at risk for developing post anesthesia agitation [10]. It is likely that there is some substrate innate to each child that will elicit, to a larger or lesser extent, a fearful response to outside stimuli, depending on the interaction between the child and the environment. This reactivity, which describes the excitability, responsivity, or arousability of the child , might be the underlying substrate from which both preoperative anxiety and ED arise. Patientrelated factors are an important source of variability among studies in the incidence of EA/ED as they are most difficult to control when investigating this phenomenon. In general children who are calm and quiet upon arrival to the preoperative area and do not show any signs of distress for procedures like venepuncture or inhalational induction with face mask hardly show any signs of ED/EA in the post operative period. This is a consistent finding in our hospital. ADJUNCT MEDICATION Numerous drugs, including anticholinergics, droperidol, barbiturates, opioids, benzodiazepines, and metoclopramide, may contribute to behavioral disturbances after anesthesia.
101
Apollo Medicine, Vol. 8, No. 2, June 2011
Review Article
In summary, none of the above-discussed factors has been proven to be the sole underlying cause of EA/ED. However, each factor, especially when combined with the others, may influence the behavior of a child emerging from anesthesia. The greatest barrier to a better understanding of the EA/ED etiology arises from the difficulty in comparing studies that used different definitions, age spans, surgical procedures, and measuring tools, as well different sedative, analgesic, and other adjunct medication. ASSESSMENT TOOLS FOR MEASURING EA/ED Applying more than 15 different rating scales to measure EA/ED in clinical investigations suggests that none are sufficiently specific and sensitive to assess children’s behavior upon emergence In addition, it is difficult to interpret behavior in small children who are not able to verbalize pain,anxiety, hunger, or thirst. Finally, opinions diverge on the point at which emergence extends beyond “normal”. Agitation, which is simple to assess, is the most frequently used descriptor for emergence behavior in children Most authors developed 3-5 point rating scales that used either crying or thrashing requiring restraint as their threshold for agitation, which had a significant influence on the calculated incidence of the event. Thus, Cravero, et al. recorded EA in 80% of sevoflurane patients when crying was used as a threshold, but in 33% of patients only when thrashing was applied as the threshold for agitation [5]. Several studies have tried to distinguish pain-related agitation from other sources by incorporating both pain and agitation scales into the methodology. Postoperative agitation alone, however, does not always indicate significant behavioral changes associated with delirium. An accurate differen-tiation of delirium from other sources of agitation requires the identification of more complex symptoms of an acute mental disturbance. This differentiation may be difficult in young children who are often oppositional and unable or unwilling to answer. Przybylo, et al. described an assessment tool that is based on the items listed in the Diagnostic and Statistical Manual of Mental Disorders-IV for the diagnosis of delirium, but eliminated signs and symptoms that required verbalization or skill demonstration [11]. Their scoring system studied perceptual disturbances, hallucinations, and psychomotor agitation in 25 children aged 2-9 years who were premedicated with midazolam and randomized to receive either isoflurane or remifentanil for strabismus surgery. Rectal acetaminophen was given for postoperative pain relief. The authors concluded that while 44% of children showed altered behavior upon emergence, only 20% had complex symptoms that were consistent with delirium. Furthermore, none of these children either verbalized pain or received pain medication during the assessment period, reflecting the measurement of the phenomenon that was Apollo Medicine, Vol. 8, No. 2, June 2011
independent of pain induced agitation.Sikich and Lerman developed the pediatric anesthesia emergence delirium (PAED) rating scale that consists of five psychometric items for the measurement of ED in children [12]. According to the Diagnostic and Statistical Manual of Mental Disorders IV, three of these items are an important part of delirium and may be crucial to its differentiation from pain .A decreased ability of the child to make eye contact with the caregiver and a declined awareness of his surroundings reflect disturbances in consciousness with a reduced ability to focus, sustain, or shift attention. Less purposeful actions suggest cognitive changes that include perception and memory impairment as well as disorganized thinking patterns. Two other items, restlessness and inconsolable crying, reflect a disturbance in psychomotor behavior and emotion, although they may also suggest pain or apprehension. The PAED scale score correlated negatively with the child’s age and time to awakening and was significantly greater in children who received sevoflurane than in those who received halothane. These results and those of another study support the reliability and validity of the PAED scale. Unfortunately, the authors did not define the ED threshold, which makes the calculation of its incidence impossible and the development of therapeutic approaches rather difficult. PREVENTION AND TREATMENT Given that the EA/ED etiology is still unknown, a clear cut strategy for its prevention has not been developed. Data on the possible role of premedication in reducing EA/ED have been conflicting. Preoperative administration of midazolam decreased postoperative agitation after both sevoflurane and desfluraneanesthesia, with no delay in discharge from hospital. When analyzing those rare trials that failed to reveal the difference between sevoflurane and halothane in the incidence of EA/ED, it was striking to note that midazolam was used consistently, although at different dosages and via different routes of administration. Sevoflurane at high concentrations has been shown to enhance, and at low concentrations to block, GABA A receptor-mediated inhibition of neurotransmission in the CNS. Olsen, et al. Suggested that midazolam may improve recovery after sevoflurane administration by enhancing the inhibitory effects of GABA A receptors [13]. This proposition is supported by findings of a calmer recovery from sevoflurane-maintained anesthesia when induced with propofol but not with sevoflurane. Another possible explanation is that stressful induction and/or a rapid return to consciousness in non-premedicated children may result in more behavioral disturbances upon emergence .On the other hand, there are studies in which midazolam premedication did not show any benefit on the quality of recovery from anesthesia.This finding may possibly be the
102
Review Article
result of applying a nonspecific measuring tool or a provision of inadequate pain control. The combination of midazolam and a small dose of diazepam may extend the beneficial effects of premedication until the recovery phase, which decreases the incidence of EA/ED. Paradoxically, Cole, et al. reported an almost nine fold higher risk of the development of EA in children who were premeditated with midazolam over those who were not premedicated before outpatient surgery under either isoflurane or halothane anesthesia [7]. Benzodiazepines themselves are associated with paradoxical reactions and agitation that are reversed with flumazenil. Furthermore, theantianalgesic effects of midazolam might worsen pain and increase the incidence of nonspecific agitation that resembles ED. Premedication with melatonin has proven to be a good alternative to midazolam in reducing postoperative excitement Oxycodone has been shown to decrease the frequency of agitation in children undergoing halothane, but not sevoflurane, anesthesia for myringotomy procedures. Both oral ketamine and oral transmucosal fentanyl citrate were also helpful, although the latter increased the incidence of side effects. Some authors have advocated switching anesthetics after induction, despite a lack of scientific evidence supporting this practice.Various preemptive analgesic approaches, including caudal block, fentanyl, ketorolac, clonidine, and dexmedetomidine, have been recommended to eliminate pain as a potential source of discomfort and agitation. One trial suggests that IV fentanyl 1μg/kg before the conclusion of sevoflurane anesthesia decreases EA even after no painful procedures, while leaving the time of discharge unchanged [14]. On the other hand, parental presence in the operating theater appeared to have no influence on the incidence and/or severity of distress behavior upon emergence. As for managing EA/ ED, certain steps should be taken to protect the child from self-injury. Holding, as a means of providing physical restraint, and engaging more than one caregiver are often necessary. As the child may be upset by environmental stimuli, it is important to provide a quiet, darkened recovery room. The decision of whether to treat EA/ED with additional medication depends upon the severity and duration of symptoms. Many studies have shown that EA/ ED is self-limited, resolving without pharmacological intervention over time. Rescue medication includes analgesics, benzodiazepines, and hypnotics. Fentanyl IV 12μg/kg, propofol IV 0.5-1.0 mg/kg, and midazolam IV 0.02–0.10 mg/kg have all been used for the treatment of ED [15]. A single bolus dose of dexmedetomidine 0.5μg/kg was also shown to be efficient in the PACU forED. VoepelLewis, et al. found that PACU nurses caring for agitated children most often administered analgesics/sedatives as the first intervention, irrespective of the primary cause of agitation [16]. However, the most effective intervention was
reuniting with a parent. The authors also developed the postoperative agitation algorithm, which may serve as a guide for the assessment and treatment of ED in the PACU. LONG-TERM CONSEQUENCES There is no evidence that EA/ED has any impact on long-term outcome [17]. Akin, et al. suggested that ED and new-onset postoperative maladaptive behavior changes are closely associated. The authors found that the odds ratio of having one or more new onset postoperative maladaptive behavior changes is 1.43 for children with marked emergence status when compared with children with no symptoms of ED, but did not suggest a cause effect relationship between these two phenomena. SUMMARY It appears that almost half a century after the first cases of emergence agitation/emergence delirium(EA/ED) were reported [18], we do not know much more about its etiology, nor do we have a reliable assessment tool or clear-cut preventive strategy for this short lived but troublesome clinical event. Both sevoflurane and desflurane (and possibly isoflurane) are indisputably associated with a higher incidence of altered behavior upon emergence than are either halothane or propofol. It is doubtless that younger age, preoperative anxiety, and pain are all important contributory factors. However, there are still many questions that deserve answers. What links the abovementioned inhaled anesthetics to EA/ED? Are we able to identify a child who is at risk for the development of ED without engaging psychologists to interpret extensive questionnaires about their temperaments? Will the use of complicated psychometric tests for the evaluation of a child’s mental status upon emergence change our therapeutic approach when either agitation or delirium occurs? Finally, shall we wait for this behavior to resolve spontaneously and risk a child’s self injury and parental distress, or treat it routinely and face potential adverse effects of the given medication? Obviously, further trials are necessary to discover the underlying causes of EA/ED and to determine which factors might help predict and potentially prevent it. For consistency, it seems reasonable for studies to target the most vulnerable population of preschool aged children scheduled for similarly painful surgical procedures and to stratify patients with regard to their temperament. In addition, pain must be tightly controlled and standardized measuring tools used to evaluate post anesthesia behavior. It is important to remember that several life threatening considerations (e.g., hypoxia, severe hypercarbia, hypotension, hypoglycemia, increased intracranial pressure) may also result in disorientation and altered mental status.
103
Apollo Medicine, Vol. 8, No. 2, June 2011
Review Article
These entities must be diagnosed and treated promptly. Bladder distention may also yield a similar clinical picture. REFERENCES 1. Holzki J, Kretz FJ (editorial). Changing aspects of sevoflurane in pediatric anesthesia: 1975-1999. Paediatr Anaesth 1999; 9:283-286. 2. Jerome EH. Recovery of the pediatric patient from anesthesia. In Gregory GA, ed. Pediatric anesthesia. 2nd Ed. New York: Churchill Livingstone, 1989, 629. 3. Gordano P. Vlajkovic, Radomir P. Sindjelic. Emergence Delirium in Children: Many Questions, Few Answers. Anesth Analg 2007; 104: 84-91. 4. Bosenberg AT. Convulsions and sevoflurane. Pediatric Anaesth 1997; 7: 477-478. 5. Davis PJ, Greenberg JA, Gendelman M, Fertal K. Recovery characteristics of sevoflurane and halothane in preschool-aged children undergoing bilateral myringotomy and pressure equalization tube insertion. Anesth Analg 1999; 88:34-38.
premedication: which intervention is more effective? Anesthesiology 1998; 89:1147-1156. 10. Cravero JP, Beach M, Dodge CP, Whalen K. Emergence characteristics of sevoflurane compared to halothane in pediatric patients undergoing bilateral pressure equalization tube insertion. J Clin Anesth 2000; 12: 397401. 11. Przybylo HJ, Martini DR, Mazurek AJ, et al. Assessing behavior in children emerging from anesthesia: can we apply psychiatric diagnostic techniques? Pediatric Anaesth 2003; 13:609-616. 12. Sikich N, Lerman J. Development and psychometric evaluation of the pediatric anesthesia emergence delirium scale. Anesthesiology 2004; 100: 1138-1145. 13. Olsen RW, Yang J, King RG, et al. Barbiturate and benzodiazepine modulation of GABA receptor binding and function. Life Sci 1986; 39:1969-1976. 14. Cravero JP, Beach M, Thyr B, Whalen K. The effect of small dose fentanyl on the emergence characteristics of pediatric patients after sevoflurane anesthesia without surgery. Anesth Analg 2003; 97:364-367.
6. Aono J, Mamiya K, Manabe M. Preoperative anxiety is associated with a high incidence of problematic behavior on emergence after halothane anesthesia in boys. Acta Anaesthesiol Scand 1999; 43: 542-544.
15. Cohen IT, Finkel JC, Hannallah RS, et al. The effect of fentanyl on the emergence characteristics after desflurane or sevoflurane anesthesia in children. Anesth Analg 2002; 94:1178-1181.
7. Cole JW, Murray DJ, McAllister JD, Hirschberg GE. Emergence behavior in children: defining the incidence of excitement and agitation following anesthesia. Pediatric Anaesth 2002; 12: 442-447.
16. Voepel-Lewis T, Burke C. Differentiating pain and delirium is only part of assessing the agitated child. J Perianesth Nurse 2004; 19: 298-299.
8. Martini DR. Commentary: the diagnosis of delirium in pediatric patients. J Am Acad Child Adolescent Psychiatry 2005; 44: 395-398. 9. Kain ZN, Mayes LC, Wang SM, et al. Parenteral presence during induction of anesthesia versus sedative
Apollo Medicine, Vol. 8, No. 2, June 2011
17. Kain Z. Postoperative maladaptive behavioral changes: incidence, risks factors, and interventions. Acta Anesthesia Scand 2000; 51:217-226. 18. Eckenhoff JE, Kneale DH, Dripps RD. The incidence and etiology of post anesthetic excitement. Anesthesiology 1961; 22:667-673.
104
EMERGENCE DELIRIUM (ED) IN CHILDREN K Raghavendran Senior Consultant & Coordinator, Apollo Children’s Hospitals, 21, Greams Lane, Off Greams Road, Chennai 600 006, India. Emergence delirium in children is a state of mental dissociation that occurs while recovering from anesthetic agents and manifests as disorientation, restlessness, irritability, screaming and involuntary activity. It usually evolves in the first half hour after awakening from anesthesia, often lasts up to 20 minutes and usually resolves on its own. Many factors have been suggested to play a potential role in the development of such an event. Post anesthesia agitation has been noted more often with the newer, less soluble, inhaled anesthetics, such as desflurane and sevoflurane, than with other volatile ones; however administration of other anesthetic agents can also cause this disturbing recovery phenomenon. Emergence delirium occurs more often in preschool children and seen frequently after head and neck surgeries like tonsillectomy, adenoidectomy, tongue tie release, strabismus surgery, nasal operations etc. Treatment is with pharmacological and environmental. Prevention may be the best treatment but no one medication is entirely effective. Key words: Post anesthetic, Emergence delirium, Sevoflurane, Desflurane.
INTRODUCTION
consciousness in which the child is inconsolable, irritable, uncompromising or uncooperative, typically thrashing, crying, moaning, or incoherent [2]. Additionally paranoid ideation has been observed in combination with these emergence behaviors. Characteristically these children do not recognize or identify familiar and known objects or people. Parents who witness this state claim the behavior is unusual and uncustomary for the child. Although generally self limiting (5-15 min) ED can be severe and may result in physical harm to the child and particularly the site of surgery.
The introduction of a new generation of inhaled anesthetics like sevoflurane and desflurane into pediatric clinical practice has been associated with a greater incidence of ED, a short-lived, but troublesome clinical phenomenon of uncertain etiology [1]. A variety of anesthesia-, surgery-, patient-, and adjunct medication-related factors have been suggested to play a potential role in the development of such an event. Restless behavior upon emergence causes not only discomfort to the child, but also makes the caregivers and parents feel unhappy with the quality of recovery from anesthesia. Although the severity of agitation varies, it often requires additional nursing care, as well as treatment with analgesics or sedatives, which may delay discharge from hospital. To reduce the incidence of this adverse event, it is advisable to identify children at risk and take preventive measures, such as reducing preoperative anxiety, removing postoperative pain, and providing a quiet, stress-free environment for post anesthesia recovery.
Emergence delirium has been reported after the introduction of every new anesthetic including most inhalational agents and intravenous agents including midazolam, remifentanil and propofol. Other drugs known to be associated with ED include (i) atropine or scopolamine, (ii) ketamine, (iii) droperidol, (iv) barbiturates and possibly, (v) benzodiazepines [3]. The incidence of emergence delirium in all postoperative patients is 5.3% with a more frequent incidence in children (12-13%). The incidence of emergence delirium after halothane, isoflurane, sevoflurane and desflurane ranges from 2-55%. It has been postulated that this phenomenon has become more acutely noticed with the increased use of agents such as sevoflurane and desflurane that have a rapid emergence profile due to their low blood gas solubility profile. It was thought that rapid emergence with lack of adequate pain control before emergence contributed or was the cause of this problem. This has been supported by the finding that
Emergence delirium (ED) also referred to as emergence agitation (EA) is a well documented phenomenon occurring in children and adults in the immediate postoperative period. With the recent popularity of the newer inhalation agent’s desflurane and sevoflurane, numerous clinical studies have been published questioning the association of these anesthetics with an increased incidence of emergence delirium. Emergence delirium is defined as a dissociated state of 99
Apollo Medicine, Vol. 8, No. 2, June 2011
Review Article
ketorolac administration decreased the incidence of emergence delirium three to fourfold after myringotomy with either halothane or sevoflurane anesthesia. Several studies have documented a reduction in ED with the administration of fentanyl 2.5 μg/kg intraoperatively or 2.0 μg/kg fentanyl administered intranasal, 1 μg/kg in each nostril after the induction of anesthesia. However, other studies have noted emergence delirium in children after sevoflurane anesthesia despite effective regional blocks to prevent postoperative pain. These studies demonstrated that delirium occurred more frequently in preschool age children, 1 to 5 years of age, lasted 5-15 minutes in the recovery room and often resolved spontaneously. Studies that have also called into question whether adequate pain management is the cause of ED include sevoflurane vs. halothane administration in patients undergoing MRI (no surgery) where the incidence of ED was 33% in sevoflurane treated patients versus 0% in halothane treated children. Post operative agitation can indicate any number of sources, including pain, physiological compromise, or anxiety. Delirium may be confused with agitation, but it may also be a cause of agitation. As most of the literature on this subject cannot differentiate between these two terms, we refer to the problem as EA/ED for the purpose of this article. Possible etiological factors of pediatric emergence delirium •
Rapid emergence
•
Intrinsic characteristics of an anesthetic
•
Postoperative pain
•
Surgery type
•
Age
•
Preoperative anxiety
•
Child temperament
•
Adjunct medication
ANESTHESIA-RELATED FACTORS Rapid emergence Post anesthesia agitation has been noted more often with the newer, less soluble, inhaled anesthetics, such as desflurane and sevoflurane, than with other volatile ones. It has been postulated that rapid awakening after the use of the insoluble anesthetics may initiate EA/ED by worsening a child’s underlying sense of apprehension when finding him in an unfamiliar environment. Some parents claim the patient’s behavior upon emergence was the same as when he was suddenly awakened from deep sleep. Older children and adults usually become oriented rapidly, whereas Apollo Medicine, Vol. 8, No. 2, June 2011
preschool aged children, who are less able to cope up with environmental stresses, tend to become agitated and delirious. However, recovery from propofol anesthesia which is also rapid is smooth and pleasant. Several studies have shown that sevoflurane anesthesia is associated with a higher incidence of EA/ED compared with propofol. Similar results were obtained when desflurane/nitrous oxide anesthesia was compared with protocol/remifentanil anesthesia. Delaying emergence by a slow, stepwise decrease in the concentration of inspired sevoflurane at the end of surgery did not reduce the incidence of EA, and thus questions the role of abrupt awakening in the development of EA. Studies have shown a similar incidence of EA among children who entered the post anesthesia care unit (PACU) still asleep and those who entered awake. Intrinsic characteristics of an anesthetic Most authors have documented that EA/ED occurs more often after sevoflurane than after halothane anesthesia which has been confirmed by the manufacturer itself .Some authors have speculated that two unique, intrinsic characteristics of sevoflurane might account for the development of EA/ED. First, this anesthetic exerts an irritating side effect on the central nervous system (CNS). Second, although sevoflurane degradation products appear to cause no organ damage themselves, data are lacking on their possible interactions with other types of medications. Epileptiform activity has been reported during the use of sevoflurane anesthesia in both patients and volunteers with no medical history of seizures [4]. However, such cases have been sporadic and have had an uneventful recovery. Furthermore, desflurane,which has no proconvulsant properties, has been associated with a similar, if not a greater incidence of EA when compared with sevoflurane. These facts suggest that the causality between theCNS effects of sevoflurane and EA/ED is unlikely. As for the eventual neurotoxic influence of sevoflurane degradation products, there is no supporting scientific evidence. Postanesthesia agitation has been described not only with sevoflurane and desflurane, but also with isoflurane and, to a much lesser extent, with halothane. In a prospective trial that included 521 children aged 3-7 year who were scheduled for elective outpatient surgery, isoflurane was identified as an independent risk factor for EA.Children who received sevoflurane/isoflurane for the induction/maintenance of anesthesia were twice as likely to develop EA when compared with children who had any other anesthetic regimen. Considering that sevoflurane-induced electroencephalogram changes are similar to those observed during the administration of either desflurane or isoflurane, but different from changes recorded with halothane, EA/ED may be related to the similar CNS effects of these anesthetics, which may affect brain activity by interfering
100
Review Article
with the balance between neuronal synaptic inhibition and excitation in the CNS . SURGERY-RELATED FACTORS Pain Postoperative pain has been the most confounding variable when assessing a child’s behavior upon emergence because of the overlapping clinical picture with EA/ED. Inadequate pain relief may be the cause of agitation, particularly after short surgical procedures for which peak effects of analgesics may be delayed until the child is completely awake. In several studies, the preemptive analgesic approach successfully reduced EA/ED, suggesting that pain may be its major source.Intraoperative administration of IV ketorolac 1 mg/kg for minor otorhinolaryngological procedures decreased the incidence of EA three to four times after both halothane (42% vs. 12%) and sevoflurane anesthesia (38% vs. 14%). Fentanyl, given either IV 2.5μg/kg or intranasal 2μg/kg during moderately painful surgery, also decreased EA.Alpha2 receptor agonists may offer advantages in preventing EA because they have both analgesic and sedative properties. On the other hand, post anesthesia agitation has been observed when pain was efficiently treated or even when absent. Surgery type Surgical procedures that involve the tonsils, thyroid, middle ear, and eye have been reported to have higher incidences of postoperative agitation and restlessness [5]. It has been speculated that a sense of suffocation during emergence from anesthesia may contribute to EA in patients undergoing head and neck surgery. However, there are no supporting scientific data to date. PATIENT-RELATED FACTORS Age Aono, et al. found that ED appeared more often with sevoflurane than with halothane in pre schoolboys aged 3-5 year (40% vs 10%) [6]. The difference was not observed in the school-aged population. All children received oral diazepam for premedication and a caudal block for preoperative pain control. The authors speculated that the psychological immaturity of pre-school children, coupled with the rapid awakening in a strange environment, may have been the main cause of ED.Generally, younger children are more likely to show altered behavior upon recovery from anesthesia. The sub population of those aged 2-5 year seems to be the most vulnerable as they are easily confused and frightened by unexpected and unpredictable experiences [7]. In a recent commentary on the diagnosis of delirium in pediatric patients, Martini addressed the role of
brain maturation in the genesis of this phenomenon [8]. He pointed out that the pediatric brain is almost a mirror image of a normal age-related regressive process with a consequent decline in nor epinephrine, acetylcholine, dopamine, and gamma amino butyric acid (GABA). Thus, the development of cholinergic function and the hippocampus may suggest clues about the relative susceptibility of younger children to delirium. Preoperative anxiety Intense preoperative anxiety, both in children and their parents, has been associated with an increased likelihood of restless recovery from anesthesia. Kain, et al. retrospectively searched their database to determine the relationship between preoperative anxiety, ED, and postoperative maladaptive behaviors [9]. They recruited 791 children who were not premedicated and underwent surgery and genera anesthesia using sevoflurane. The odds of having marked symptoms of ED were increased by 10% for each increment of 10 points in the child’s state anxiety score. However, a cause effect relationship between the two phenomena could not be demonstrated. Other authors failed to show a correlation between preanesthetic distress and ED, possibly because of the small total number of patients studied and the use of a self-developed, no standardized observational scale for evaluating children’s distress. Temperament Children who are more emotional, more impulsive, less social, and less adaptable to environmental changes were identified to be at risk for developing post anesthesia agitation [10]. It is likely that there is some substrate innate to each child that will elicit, to a larger or lesser extent, a fearful response to outside stimuli, depending on the interaction between the child and the environment. This reactivity, which describes the excitability, responsivity, or arousability of the child , might be the underlying substrate from which both preoperative anxiety and ED arise. Patientrelated factors are an important source of variability among studies in the incidence of EA/ED as they are most difficult to control when investigating this phenomenon. In general children who are calm and quiet upon arrival to the preoperative area and do not show any signs of distress for procedures like venepuncture or inhalational induction with face mask hardly show any signs of ED/EA in the post operative period. This is a consistent finding in our hospital. ADJUNCT MEDICATION Numerous drugs, including anticholinergics, droperidol, barbiturates, opioids, benzodiazepines, and metoclopramide, may contribute to behavioral disturbances after anesthesia.
101
Apollo Medicine, Vol. 8, No. 2, June 2011
Review Article
In summary, none of the above-discussed factors has been proven to be the sole underlying cause of EA/ED. However, each factor, especially when combined with the others, may influence the behavior of a child emerging from anesthesia. The greatest barrier to a better understanding of the EA/ED etiology arises from the difficulty in comparing studies that used different definitions, age spans, surgical procedures, and measuring tools, as well different sedative, analgesic, and other adjunct medication. ASSESSMENT TOOLS FOR MEASURING EA/ED Applying more than 15 different rating scales to measure EA/ED in clinical investigations suggests that none are sufficiently specific and sensitive to assess children’s behavior upon emergence In addition, it is difficult to interpret behavior in small children who are not able to verbalize pain,anxiety, hunger, or thirst. Finally, opinions diverge on the point at which emergence extends beyond “normal”. Agitation, which is simple to assess, is the most frequently used descriptor for emergence behavior in children Most authors developed 3-5 point rating scales that used either crying or thrashing requiring restraint as their threshold for agitation, which had a significant influence on the calculated incidence of the event. Thus, Cravero, et al. recorded EA in 80% of sevoflurane patients when crying was used as a threshold, but in 33% of patients only when thrashing was applied as the threshold for agitation [5]. Several studies have tried to distinguish pain-related agitation from other sources by incorporating both pain and agitation scales into the methodology. Postoperative agitation alone, however, does not always indicate significant behavioral changes associated with delirium. An accurate differen-tiation of delirium from other sources of agitation requires the identification of more complex symptoms of an acute mental disturbance. This differentiation may be difficult in young children who are often oppositional and unable or unwilling to answer. Przybylo, et al. described an assessment tool that is based on the items listed in the Diagnostic and Statistical Manual of Mental Disorders-IV for the diagnosis of delirium, but eliminated signs and symptoms that required verbalization or skill demonstration [11]. Their scoring system studied perceptual disturbances, hallucinations, and psychomotor agitation in 25 children aged 2-9 years who were premedicated with midazolam and randomized to receive either isoflurane or remifentanil for strabismus surgery. Rectal acetaminophen was given for postoperative pain relief. The authors concluded that while 44% of children showed altered behavior upon emergence, only 20% had complex symptoms that were consistent with delirium. Furthermore, none of these children either verbalized pain or received pain medication during the assessment period, reflecting the measurement of the phenomenon that was Apollo Medicine, Vol. 8, No. 2, June 2011
independent of pain induced agitation.Sikich and Lerman developed the pediatric anesthesia emergence delirium (PAED) rating scale that consists of five psychometric items for the measurement of ED in children [12]. According to the Diagnostic and Statistical Manual of Mental Disorders IV, three of these items are an important part of delirium and may be crucial to its differentiation from pain .A decreased ability of the child to make eye contact with the caregiver and a declined awareness of his surroundings reflect disturbances in consciousness with a reduced ability to focus, sustain, or shift attention. Less purposeful actions suggest cognitive changes that include perception and memory impairment as well as disorganized thinking patterns. Two other items, restlessness and inconsolable crying, reflect a disturbance in psychomotor behavior and emotion, although they may also suggest pain or apprehension. The PAED scale score correlated negatively with the child’s age and time to awakening and was significantly greater in children who received sevoflurane than in those who received halothane. These results and those of another study support the reliability and validity of the PAED scale. Unfortunately, the authors did not define the ED threshold, which makes the calculation of its incidence impossible and the development of therapeutic approaches rather difficult. PREVENTION AND TREATMENT Given that the EA/ED etiology is still unknown, a clear cut strategy for its prevention has not been developed. Data on the possible role of premedication in reducing EA/ED have been conflicting. Preoperative administration of midazolam decreased postoperative agitation after both sevoflurane and desfluraneanesthesia, with no delay in discharge from hospital. When analyzing those rare trials that failed to reveal the difference between sevoflurane and halothane in the incidence of EA/ED, it was striking to note that midazolam was used consistently, although at different dosages and via different routes of administration. Sevoflurane at high concentrations has been shown to enhance, and at low concentrations to block, GABA A receptor-mediated inhibition of neurotransmission in the CNS. Olsen, et al. Suggested that midazolam may improve recovery after sevoflurane administration by enhancing the inhibitory effects of GABA A receptors [13]. This proposition is supported by findings of a calmer recovery from sevoflurane-maintained anesthesia when induced with propofol but not with sevoflurane. Another possible explanation is that stressful induction and/or a rapid return to consciousness in non-premedicated children may result in more behavioral disturbances upon emergence .On the other hand, there are studies in which midazolam premedication did not show any benefit on the quality of recovery from anesthesia.This finding may possibly be the
102
Review Article
result of applying a nonspecific measuring tool or a provision of inadequate pain control. The combination of midazolam and a small dose of diazepam may extend the beneficial effects of premedication until the recovery phase, which decreases the incidence of EA/ED. Paradoxically, Cole, et al. reported an almost nine fold higher risk of the development of EA in children who were premeditated with midazolam over those who were not premedicated before outpatient surgery under either isoflurane or halothane anesthesia [7]. Benzodiazepines themselves are associated with paradoxical reactions and agitation that are reversed with flumazenil. Furthermore, theantianalgesic effects of midazolam might worsen pain and increase the incidence of nonspecific agitation that resembles ED. Premedication with melatonin has proven to be a good alternative to midazolam in reducing postoperative excitement Oxycodone has been shown to decrease the frequency of agitation in children undergoing halothane, but not sevoflurane, anesthesia for myringotomy procedures. Both oral ketamine and oral transmucosal fentanyl citrate were also helpful, although the latter increased the incidence of side effects. Some authors have advocated switching anesthetics after induction, despite a lack of scientific evidence supporting this practice.Various preemptive analgesic approaches, including caudal block, fentanyl, ketorolac, clonidine, and dexmedetomidine, have been recommended to eliminate pain as a potential source of discomfort and agitation. One trial suggests that IV fentanyl 1μg/kg before the conclusion of sevoflurane anesthesia decreases EA even after no painful procedures, while leaving the time of discharge unchanged [14]. On the other hand, parental presence in the operating theater appeared to have no influence on the incidence and/or severity of distress behavior upon emergence. As for managing EA/ ED, certain steps should be taken to protect the child from self-injury. Holding, as a means of providing physical restraint, and engaging more than one caregiver are often necessary. As the child may be upset by environmental stimuli, it is important to provide a quiet, darkened recovery room. The decision of whether to treat EA/ED with additional medication depends upon the severity and duration of symptoms. Many studies have shown that EA/ ED is self-limited, resolving without pharmacological intervention over time. Rescue medication includes analgesics, benzodiazepines, and hypnotics. Fentanyl IV 12μg/kg, propofol IV 0.5-1.0 mg/kg, and midazolam IV 0.02–0.10 mg/kg have all been used for the treatment of ED [15]. A single bolus dose of dexmedetomidine 0.5μg/kg was also shown to be efficient in the PACU forED. VoepelLewis, et al. found that PACU nurses caring for agitated children most often administered analgesics/sedatives as the first intervention, irrespective of the primary cause of agitation [16]. However, the most effective intervention was
reuniting with a parent. The authors also developed the postoperative agitation algorithm, which may serve as a guide for the assessment and treatment of ED in the PACU. LONG-TERM CONSEQUENCES There is no evidence that EA/ED has any impact on long-term outcome [17]. Akin, et al. suggested that ED and new-onset postoperative maladaptive behavior changes are closely associated. The authors found that the odds ratio of having one or more new onset postoperative maladaptive behavior changes is 1.43 for children with marked emergence status when compared with children with no symptoms of ED, but did not suggest a cause effect relationship between these two phenomena. SUMMARY It appears that almost half a century after the first cases of emergence agitation/emergence delirium(EA/ED) were reported [18], we do not know much more about its etiology, nor do we have a reliable assessment tool or clear-cut preventive strategy for this short lived but troublesome clinical event. Both sevoflurane and desflurane (and possibly isoflurane) are indisputably associated with a higher incidence of altered behavior upon emergence than are either halothane or propofol. It is doubtless that younger age, preoperative anxiety, and pain are all important contributory factors. However, there are still many questions that deserve answers. What links the abovementioned inhaled anesthetics to EA/ED? Are we able to identify a child who is at risk for the development of ED without engaging psychologists to interpret extensive questionnaires about their temperaments? Will the use of complicated psychometric tests for the evaluation of a child’s mental status upon emergence change our therapeutic approach when either agitation or delirium occurs? Finally, shall we wait for this behavior to resolve spontaneously and risk a child’s self injury and parental distress, or treat it routinely and face potential adverse effects of the given medication? Obviously, further trials are necessary to discover the underlying causes of EA/ED and to determine which factors might help predict and potentially prevent it. For consistency, it seems reasonable for studies to target the most vulnerable population of preschool aged children scheduled for similarly painful surgical procedures and to stratify patients with regard to their temperament. In addition, pain must be tightly controlled and standardized measuring tools used to evaluate post anesthesia behavior. It is important to remember that several life threatening considerations (e.g., hypoxia, severe hypercarbia, hypotension, hypoglycemia, increased intracranial pressure) may also result in disorientation and altered mental status.
103
Apollo Medicine, Vol. 8, No. 2, June 2011
Review Article
These entities must be diagnosed and treated promptly. Bladder distention may also yield a similar clinical picture. REFERENCES 1. Holzki J, Kretz FJ (editorial). Changing aspects of sevoflurane in pediatric anesthesia: 1975-1999. Paediatr Anaesth 1999; 9:283-286. 2. Jerome EH. Recovery of the pediatric patient from anesthesia. In Gregory GA, ed. Pediatric anesthesia. 2nd Ed. New York: Churchill Livingstone, 1989, 629. 3. Gordano P. Vlajkovic, Radomir P. Sindjelic. Emergence Delirium in Children: Many Questions, Few Answers. Anesth Analg 2007; 104: 84-91. 4. Bosenberg AT. Convulsions and sevoflurane. Pediatric Anaesth 1997; 7: 477-478. 5. Davis PJ, Greenberg JA, Gendelman M, Fertal K. Recovery characteristics of sevoflurane and halothane in preschool-aged children undergoing bilateral myringotomy and pressure equalization tube insertion. Anesth Analg 1999; 88:34-38.
premedication: which intervention is more effective? Anesthesiology 1998; 89:1147-1156. 10. Cravero JP, Beach M, Dodge CP, Whalen K. Emergence characteristics of sevoflurane compared to halothane in pediatric patients undergoing bilateral pressure equalization tube insertion. J Clin Anesth 2000; 12: 397401. 11. Przybylo HJ, Martini DR, Mazurek AJ, et al. Assessing behavior in children emerging from anesthesia: can we apply psychiatric diagnostic techniques? Pediatric Anaesth 2003; 13:609-616. 12. Sikich N, Lerman J. Development and psychometric evaluation of the pediatric anesthesia emergence delirium scale. Anesthesiology 2004; 100: 1138-1145. 13. Olsen RW, Yang J, King RG, et al. Barbiturate and benzodiazepine modulation of GABA receptor binding and function. Life Sci 1986; 39:1969-1976. 14. Cravero JP, Beach M, Thyr B, Whalen K. The effect of small dose fentanyl on the emergence characteristics of pediatric patients after sevoflurane anesthesia without surgery. Anesth Analg 2003; 97:364-367.
6. Aono J, Mamiya K, Manabe M. Preoperative anxiety is associated with a high incidence of problematic behavior on emergence after halothane anesthesia in boys. Acta Anaesthesiol Scand 1999; 43: 542-544.
15. Cohen IT, Finkel JC, Hannallah RS, et al. The effect of fentanyl on the emergence characteristics after desflurane or sevoflurane anesthesia in children. Anesth Analg 2002; 94:1178-1181.
7. Cole JW, Murray DJ, McAllister JD, Hirschberg GE. Emergence behavior in children: defining the incidence of excitement and agitation following anesthesia. Pediatric Anaesth 2002; 12: 442-447.
16. Voepel-Lewis T, Burke C. Differentiating pain and delirium is only part of assessing the agitated child. J Perianesth Nurse 2004; 19: 298-299.
8. Martini DR. Commentary: the diagnosis of delirium in pediatric patients. J Am Acad Child Adolescent Psychiatry 2005; 44: 395-398. 9. Kain ZN, Mayes LC, Wang SM, et al. Parenteral presence during induction of anesthesia versus sedative
Apollo Medicine, Vol. 8, No. 2, June 2011
17. Kain Z. Postoperative maladaptive behavioral changes: incidence, risks factors, and interventions. Acta Anesthesia Scand 2000; 51:217-226. 18. Eckenhoff JE, Kneale DH, Dripps RD. The incidence and etiology of post anesthetic excitement. Anesthesiology 1961; 22:667-673.
104