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Anesth Analg 2003;96:1625-1630
© 2003 International Anesthesia Research Society

PEDIATRIC ANESTHESIA

A Prospective Cohort Study of Emergence Agitation in the Pediatric Postanesthesia Care Unit

Terri Voepel-Lewis, MSN RN, Shobha Malviya, MD, and Alan R. Tait, PhD

Department of Anesthesiology, Section of Pediatrics, C. S. Mott Children’s Hospital, Ann Arbor, Michigan

Address correspondence and reprint requests to Terri Voepel-Lewis, MSN, RN, Department of Anesthesiology, F3900/Box 0211, C. S. Mott Children’s Hospital, University of Michigan Medical Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0211. Address e-mail to terriv{at}umich.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Emergence agitation (EA) is a postanesthetic problem that interferes with a child’s recovery and presents a challenge in terms of assessment and management. In this prospective cohort study, we sought to determine the incidence of EA, evaluate factors associated with and predictive of EA, and describe associated outcomes in healthy children. Children aged 3–7 yr who were undergoing general anesthesia for elective outpatient procedures were included. All perioperative care was documented, and postoperative behaviors in the postanesthesia care unit were recorded. Parents completed the Behavioral Style Questionnaire for 3- to 7-yr-olds. Five-hundred-twenty-one children were studied, of whom 96 (18%) had EA. Agitation lasted up to 45 min in some cases (range, 3–45 min; mean, 14 ± 11 min), required pharmacologic intervention in 52% of children, and was associated with a prolonged postanesthesia care unit stay (117 ± 66 min versus 101 ± 61 min for nonagitated children; P = 0.02). Ten factors were found to be associated with EA, including age, previous surgery, adaptability, ophthalmology and otorhinolaryngology procedures, sevoflurane, isoflurane, sevoflurane/isoflurane, analgesics, and time to awakening. Of these, otorhinolaryngology procedures, time to awakening, and isoflurane were shown to be independent risk factors.

IMPLICATIONS: Children may become agitated after general anesthesia. This study describes several factors that may increase the risk for agitation. These data are important in planning anesthesia care for young children.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Emergence from general anesthesia (GA) can be complicated by the presence of agitation in some children and thus presents a challenging situation for the postanesthesia care provider. Postanesthetic excitement, emergence delirium, and emergence agitation (EA) are terms used interchangeably to describe this acute phenomenon, during which the patient exhibits nonpurposeful restlessness and agitation, thrashing, crying or moaning, disorientation, and incoherence (1–3). Additionally, paranoid ideation has been observed in combination with these abnormal emergence behaviors (3). Although generally self-limiting, EA can be severe and may result in physical harm to the child and, in particular, to the site of surgery (2,4). In rare cases, EA-associated agitation and restlessness have lasted for longer than 2 days (5), yet long-term psychological implications of EA remain unknown (4).

Early epidemiologic studies demonstrated a 5.3% incidence of EA in all postoperative patients, with a more frequent incidence in children (12%–13%) (6,7). This phenomenon has been associated with specific anesthetics, in particular sevoflurane (8–14), a variety of perioperative medications (7,15–17), pain (10,18–21), and patient-related factors (22), yet the etiology remains unclear. This prospective cohort study was undertaken to determine the incidence of EA, evaluate factors associated with and predictive of EA, and describe outcomes related to EA in healthy children undergoing GA for elective procedures.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
With approval from the IRB and parental consent, healthy children (3–7 yr old) undergoing GA for an outpatient surgical procedure were included. A nonprobability, consecutive-sampling technique was used to include all children with an ASA physical status of I–II who were cognitively intact. To reduce the possibility of bias related to trends in practice, patients were recruited during two separate 4- to 5-mo study periods. Before surgery, demographics and data regarding the child’s medical and surgical history were recorded. All perioperative care was at the discretion of the anesthesiologist or other care providers per routine practice and was not influenced or intentionally altered as a result of participation in this study. The child’s behavior during separation from parents and the induction of GA was rated as calm/cooperative, slightly anxious/tearful, or agitated/uncooperative by the attending anesthesiologist. Anesthetics and perioperative medications, the duration of anesthesia, and time to awakening (i.e., time from anesthetic off to time of initial arousal) were documented. During the postanesthesia recovery, a trained observer recorded all emergence behaviors by using a comprehensive checklist. Additionally, experienced postanesthesia care unit (PACU) nurses documented the presence or absence of EA (i.e., yes/no), which was defined as agitation with nonpurposeful movement, restlessness, or thrashing; incoherence; inconsolability; and unresponsiveness. Children who complained of or localized pain were not considered to have EA. When EA was present, the duration was documented. All pharmacologic and nonpharmacologic interventions, adverse events, and the time to discharge from the PACU were also recorded. Discharge criteria were in accordance with routine practice and at the discretion of the PACU nurse. These criteria are similar to Chung’s (23) modified postanesthesia discharge scoring system and additionally included 1) child’s pain level can be easily managed at the discharge location and 2) stable fluid status.

Parents of a subset of 250 consecutively recruited children completed the Behavioral Style Questionnaire for 3- to 7-yr-olds while the child was in surgery (24). This standardized survey contains 100 items that, when combined, yield numerical scores (1 [low/positive] to 6 [high/negative]) for 9 dimensions of temperament. The questionnaire has been shown to have reliability and validity in a variety of populations. The tool has been used in numerous studies, including clinical studies designed to determine the relationship of response to pain, hospitalization, and sedation (25–27). All caregivers were blinded to responses on this survey.

All data were analyzed with SPSS® software (SPSS Inc., Chicago, IL). Parametric data, such as age, duration of anesthesia, and temperament scores, are presented as mean ± SD and were compared by using unpaired Student’s t-tests. Chi-square tests with Fisher’s exact tests were used to compare nonparametric data such as sex and use of anesthetics. The relative risk (RR) and confidence intervals (CI) are presented for each variable with a significant association with EA. RR was calculated as the incidence of EA in the exposed group (e.g., received sevoflurane) versus that in the unexposed group (e.g., received no sevoflurane). Anesthetic and demographic variables that were found to be significantly associated with EA were entered into a logistic regression analysis to determine the independent risk factors for EA. P values of <=0.05 were considered significant.

Several theoretical assumptions and general guidelines for multiple regression (28,29) were applied to determine the sample size for this study. As a general rule, 100 children with the outcome would be needed to allow analysis of 10 predictor variables (28,29). Assuming a 20% incidence of EA in healthy 3- to 7-yr-olds, a sample of 500 would be needed to yield 100 children with this outcome. This sample size is large enough to establish the incidence of this dichotomous variable (expected proportion, 0.20; precision, 0.10; CI, 95%) (30) and sufficient to allow meaningful analysis of 10 predictor variables. Because temperament was of secondary interest, and to reduce participant burden associated with completion of the Behavioral Style Questionnaire, only half the sample were given this survey.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Five-hundred-twenty-one children were included in this study over a 1-yr period. Ninety-six (18%) of these exhibited EA. The demographics of the sample are presented in Table 1. Children who experienced EA were significantly younger and less likely to have had previous surgery compared with those who awakened without agitation. Temperament scores are presented in Table 2. Children who experienced EA were significantly less adaptable compared with nonagitated children. Forty-two (26%) and 23 (28%) children who underwent otorhinolaryngologic and ophthalmologic procedures, respectively, experienced EA, compared with urologic (15%), orthopedic (15%), general surgical (12%), and other (6%) procedures (P <= 0.02).


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  		Table 1. Demographics and Characteristics of the Study Groups
 

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  		Table 2. Mean Temperament Scores of the Study Groupsa
 
Agitation lasted up to 45 min in some cases (range, 3–45 min; mean, 14 ± 11 min) and was associated with a prolonged postanesthesia recovery (117 ± 66 min versus 101 ± 61 min for nonagitated children; P = 0.02). Most of these children were thrashing (86%) and kicking (64%), whereas a smaller percentage (14%) were simply restless and incoherent. Fifty-six (60%) children in the EA group required physical restraint (i.e., held down by a nurse), and many (42%) required two or more nurses until the agitation subsided. EA subsided without pharmacologic intervention in 48% of cases, and the duration of EA in these children was shorter (11 ± 10 min) than those with EA who were treated (16 ± 10 min; P = 0.02). Fifty children (52%) required an opiate (n = 46), benzodiazepine (n = 2), or both (n = 2), whereas only 77 (18%) nonagitated children required intervention with an opiate or benzodiazepine (P < 0.0001). Finally, EA was associated with five adverse events. These included increased bleeding from the surgical site (n = 1), pulling out a surgical drain or an IV (n = 2), increased pain at the operative site (n = 1), and minor injury of the nurse (n = 1).

Table 3 presents the relationship between perioperative factors and the presence of EA. Children who underwent otorhinolaryngology or ophthalmology procedures and those who received sevoflurane or isoflurane experienced EA significantly more frequently than other children. Sodium pentothal, however, was associated with a less-frequent incidence of EA. Children who received a combination of sevoflurane and isoflurane for induction/maintenance were more than twice as likely to have EA compared with those having another anesthetic regimen (P < 0.0001). Almost all children (98%) who had EA had received intraoperative analgesics, compared with 86% of nonagitated children (P = 0.001). There was no difference in the duration of anesthesia between children who experienced EA and those who did not (61 ± 28 min versus 68 ± 48 min, respectively). However, children with EA had a significantly shorter time to awakening (14 ± 14 min versus 26 ± 23 min; P = 0.0001).


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  		Table 3. Incidence of Emergence Agitation (EA) Relative to Perioperative Factors
 
Ten variables were found, by univariate analysis, to be associated with an increased incidence of EA. These included young age, no previous surgery, poor adaptability, ophthalmology procedures, otorhinolaryngology procedures, sevoflurane, isoflurane, sevoflurane/isoflurane, analgesics, and short time to awakening. These factors (and their interactions) were subsequently entered into a logistic regression model with backward selection. Multivariate analysis of these factors yielded three that were predictive of EA. These are described in Table 4.


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  		Table 4. Factors Predictive of Emergence Agitation
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Agitation on emergence from GA is a frequent phenomenon in children that demands increased nursing care in the PACU, delays reunion with parents, and may lead to adverse sequelae in some cases. An understanding of the risk factors for EA is important to minimize contributory factors and to appropriately manage agitation when it occurs. This study identified multiple factors associated with EA in young children and found that the use of isoflurane, short time to awakening, and otorhinolaryngologic procedures were independent risk factors for this outcome. Although EA in this sample was of relatively short duration, pharmacologic intervention was required in 52% of cases, and EA was associated with a prolonged PACU stay and resulted in adverse events in 1% of all cases.

Several studies that have addressed EA as a postoperative complication in children have generally focused on the volatile anesthetics (sevoflurane and desflurane) as primary risk factors (8–11,14,21,31–36). The reported incidence of EA has ranged from 24% to 66% in children who received these anesthetics; however, variations in protocols and in the definition and classification of EA in these studies make it difficult to compare results. Indeed, a recent investigation by Cole et al. (37) showed that when the definition of EA was expanded to include children who were inconsolable and crying, as well as restless and disoriented, the incidence increased from 10% to 30% in one sample. Still, most data suggest that anesthetics with a low solubility are associated with an increased incidence of agitation that is, in some manner, related to abrupt emergence. Our findings are consistent with these studies in that short time to awakening and the use of sevoflurane were associated with a frequent incidence (24%) of EA. We further demonstrated that maintenance with isoflurane was significantly associated with agitation (23%). Cravero et al. (13) suggested that marked agitation on emergence may negate the advantage of rapid emergence, demonstrating that despite a quicker emergence with sevoflurane, the time to discharge was prolonged compared with halothane. Others have similarly found shorter emergence times but no difference in discharge times between sevoflurane and halothane groups (9,31,34). In this study, we found that EA significantly prolonged the PACU stay, which may have resulted from additional pharmacologic treatment and other supportive therapies necessary to manage agitation.

Several investigators have argued that pain during impaired consciousness contributes to severe EA in some children (35,36); however, a clear relationship has not been established (3–5,12). The administration of ketorolac, acetaminophen, tramadol, or fentanyl has been shown to reduce the agitation associated with sevoflurane anesthesia in children undergoing otorhinolaryngology surgery (10,18–21), suggesting a potential relationship between pain and EA. However, Murray et al. (34) demonstrated that preemptive oxycodone reduced postanesthesia agitation for children who had received halothane but not for those who received sevoflurane. Furthermore, several studies have demonstrated a clinically significant incidence of EA in presumably pain-free patients (3,5,9,12,14,22,34,37,38), suggesting that analgesics cannot completely attenuate postanesthetic agitation. Although it remains difficult to differentiate pain-related agitation from other sources, several studies have attempted to do so by incorporating pain scales, in addition to agitation scales, into the methodology (9,20,35). In this study, children were classified as having EA if they demonstrated agitation behaviors but did not localize or complain of pain. Furthermore, 98% of children who experienced EA had received a preemptive analgesic, and in 48%, the agitated behaviors resolved without pharmacologic intervention. Although pain cannot be entirely excluded as a contributory factor for EA, these data suggest the influence of another mechanism. Consideration of pain as a potentiating factor for agitation is important, particularly in children undergoing short surgical procedures for which the peak effects of analgesics may be delayed until well after they awake.

There are no recent data to help clarify the relationship between surgical procedure and EA; however, early anecdotal and descriptive reports suggested that EA was encountered more frequently in young people who underwent tonsillectomy or head and neck surgery (7,39). Furthermore, most recent investigations that address EA have selectively studied children undergoing ear, nose, and throat procedures (10,11,13,19–21,33,35,36,40,41). The choice of this study sample may have been at least partially influenced by the premise that this population is at risk for postanesthetic agitation. Our data indeed demonstrate that otorhinolaryngology procedures pose an independent risk for EA, but the explanation for this remains unclear. Eckenhoff et al. (7) and Bastron and Moyers (39) speculated that a "sense of suffocation" may contribute to EA in patients undergoing head and neck procedures, yet there are no scientific data to support this.

Several patient-related factors have also been associated with an increased incidence of EA, including young age (9,13,22,31) and anxiety or distress (11). Recent studies demonstrated that preoperative administration of midazolam reduced the incidence of EA compared with placebo (11) and with clonidine premedication (40); however, this may have been related to slowed awakening rather than anxiety. Indeed, other data have contradicted this notion (33,37,42,43). One study found that children who received midazolam experienced EA more frequently than those who did not and that the observed agitation lasted longer (37). Although Kain et al. (42) demonstrated a decreased incidence of maladaptive behaviors at two postoperative weeks after midazolam, there was no difference in EA between children who received midazolam and those who did not. Furthermore, benzodiazepines have themselves been associated with paradoxical reactions and agitation (15,44–46) that have been reversed with flumazenil (47). Our data demonstrate a similar incidence of EA in those who received preoperative midazolam compared with those who did not (15% versus 19% respectively). Furthermore, there was no relationship between behaviors at separation and induction and those at emergence. Taken together, these data raise doubts about a potential relationship between preoperative anxiety and EA.

Although the child’s temperament has not been previously studied in relation to EA, several studies have shown a relationship between certain traits and the child’s response to medical procedures or hospitalization. Kain et al. (48) demonstrated that children who were not enrolled in daycare, those with no siblings, and those who were very impulsive were at greater risk for developing negative behavior changes, such as separation anxiety, nightmares, and bedwetting, at two or more weeks after surgery. Other studies have reported that children with lower thresholds (i.e., sensitivity) (25) and those with low adaptability (i.e., inability to readily adapt to new situations) (26) displayed more distress behaviors during venipuncture or immunization. Low adaptability has also been associated with sedation failures (27). Our data demonstrated that low adaptability was associated with but was not an independent risk factor for EA. Further study in this area may provide more insight into the interaction between temperament and emergence behaviors.

This study was intended to describe emergence phenomenon in a routine clinical setting, and data are therefore subject to the limitations posed by observational, noncontrolled study designs. Because observers were not blinded to many of the factors under investigation, these data are subject to observer bias. Additionally, the MAC of anesthetics was not controlled, nor were the doses and timing of analgesics. Although consecutive sampling over two separate time periods was used to reduce the possibility of secular trends in practice, one cannot overlook the possibility of a selection bias in our sample. Our sample represented only 20% of our annual patient population with these inclusion criteria. However, our sample size was more than sufficient to detect an expected 20% incidence of EA with a CI of 99% (30). Although these limitations reduce the generalizability of our findings, the fact that our data are consistent with previous studies, many of which used randomized, controlled designs, lends external validity to our results and reduces the likelihood that these associations were due to bias.

In summary, EA remains a significant postanesthetic problem that interferes with the child’s recovery and challenges the PACU care provider in terms of assessment and treatment. An understanding of potential risk factors is important to appropriately differentiate and treat agitation in the pediatric PACU. This study identifies multiple factors associated with EA, of which short time to awakening, use of isoflurane, and otorhinolaryngologic procedures were independent risk factors. Further investigation of these factors as potential predictors is necessary before data can be generalized to other settings or populations.


   Acknowledgments
 
Funded in part by a grant from Sigma Theta Tau International, Honor Society of Michigan, Rho Chapter.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication February 3, 2003.




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Desflurane Anesthesia After Sevoflurane Inhaled Induction Reduces Severity of Emergence Agitation in Children Undergoing Minor Ear-Nose-Throat Surgery Compared with Sevoflurane Induction and Maintenance
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Clonidine Treatment for Agitation in Children After Sevoflurane Anesthesia
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PILOT: RCT OF ADJUNCTS TO GENERAL ANESTHESIA IN PEDIATRIC DENTISTRY
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Hyperresponsiveness on Washout of Volatile Anesthetics from Isolated Spinal Cord Compared to Withdrawal from Ethanol
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Z. N. Kain, A. A. Caldwell-Andrews, I. Maranets, B. McClain, D. Gaal, L. C. Mayes, R. Feng, and H. Zhang
Preoperative Anxiety and Emergence Delirium and Postoperative Maladaptive Behaviors
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press