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Section of Anesthesia, Analgesia and Intensive Care, Department of Clinical and Experimental Medicine, University of Perugia, Italy
Address correspondence and reprint requests to Simonetta Tesoro, Section of Anesthesia, Analgesia and Intensive Care, Department of Clinical and Experimental Medicine, University of Perugia, Italy. Address e-mail to simonettatesoro{at}virgilio.it.
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Introduction |
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Methods |
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Just before the start of surgery, all patients in the treatment group received clonidine 2 µg/kg diluted in 10 mL of saline infused over 5 min. Patients in the control group received only saline. Patients were randomly assigned to a treatment group, and the anesthesiologist caring for the child was blinded to the patient's group assignment. Anesthesia was maintained with sevoflurane 1.5 MAC in nitrogen/oxygen at 0.35 fraction of inspired oxygen (Fio2). Patients breathed spontaneously, but minute ventilation was manually adjusted if required to maintain an end-expiratory CO2 partial pressure of 35 mm Hg. Intraoperative monitoring included electrocardiogram, oxygen saturation, end-tidal CO2, noninvasive arterial blood pressure, temperature, and inspired/expired anesthetic gas concentrations. An increase in heart rate or arterial blood pressure by more than 15% from the start of surgery was considered an indicator of insufficient block and caused the patient to be excluded from the study. At the completion of surgery, the anesthetic gases were discontinued, and the laryngeal mask airway was removed at MAC-awake (0.78%). All patients were administered rectal acetaminophen (30 mg/kg) and then transferred to the recovery room where they were followed for 2 h or until complete anesthetic recovery was assured by a second anesthesiologist also blinded to the treatment group. In the recovery room, the children's oxygen saturation, arterial blood pressure, and heart rate were monitored. To limit the interfering effect of pain in the evaluation of agitation, the anesthesiologist performed a systematic search for signs of insufficient blockade or pain, if possible, asking the child to report verbally or signal (e.g., to squeeze eyes tight if in pain), looking for reaction to pin prick in blocked areas, and identifying posture or behaviors indicative of pain, such as stiffness or grimacing. Fentanyl 2 µg/kg was administered if pain was suspected or if agitation was present together with signs of insufficient blockade. Agitation without pain was treated with midazolam 0.1 mg/kg.
Outcome was measured as presence of severe agitation (defined as nonpurposeful movements that could not be calmed and required restraint) or agitation (defined as the presence of nonpurposeful movements that could be calmed or did not require restraint), both for 
5 min, and as scores on the Steward Recovery Score and on the three objective components of the Pain Discomfort Score (PDS) (3). We assigned scores usually 30 min after transfer in the recovery room. This time limit was chosen because in a preceding smaller pilot trial, this was the moment of maximal prevalence of agitation of a similar group of children. However, if the patients developed early severe agitation without signs of pain, the PDS score was noted and therapy commenced before the 30-min time limit, whereas if signs of pain were present, the scores were assigned after a suitable time from the administration of fentanyl (approximately 15 min). Patients were discharged from the recovery room when they had a Steward score of 6.
Continuous variables were compared with a one-way analysis of variance, scores with the Mann-Whitney U-test, and frequencies with Fisher's exact test. Interaction among multiple variables was assessed with generalized linear model analysis. A P < 0.05 was considered significant. Sample size was calculated for an 80% power of detecting a reduction in the incidence of agitation from an expected 40% in the untreated group to 20%, yielding a sample size of 82 patients in each group.
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Results |
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Patients receiving clonidine showed a statistically significant, but clinically trivial, decrease in heart rate (116 ± 32 versus 112 ± 28) and mean arterial blood pressure (92 ± 18 versus 87 ± 21) during the recovery period. The Steward Recovery Score at 30 min was slightly lower in the clonidine group (mean 3.6 versus 4; Mann-Whitney U-test; P = 0.086), but all patients attained a full score at the end of the 2-h period. The PDS score at 30 min was significantly decreased in the clonidine group (mean 1.98 versus 2.87; Mann-Whitney U-test; P = 0.00018). Thirteen patients (14.2%) developed agitation in the clonidine group versus 26 (33.3%) in the untreated group, and 3 (3.3%) patients developed severe agitation in the clonidine group versus 8 (10.3%) in the untreated group (Fisher exact 
2; P = 0.029 for any agitation and P = 0.064 for severe agitation). Relative risks (RR) for developing agitation were thus 0.43 (95% confidence interval [CI], 0.24–0.78) for any agitation and 0.32 (95% CI, 0.09–1.17) for severe agitation; numbers needed to treat are 5.2 patients treated to prevent one occurrence of agitation (14.4 for severe agitation).
The incidence of agitation was not significantly different in the patients older than 3 yr of age compared with those younger than 3 yr (18 of 50 versus 21 of 80; Fisher's exact test; P = 0.25). A generalized linear model analysis of agitation with treatment and age as factors confirmed the significant effect of clonidine (P = 0.003) but not of age (P = 0.17). When this analysis was conducted on severe agitation, neither factor was significant (clonidine, P = 0.067; age, P = 0.26). Four patients required administration of fentanyl in the recovery room—two in each group. None of these was classified as agitated in the analysis.
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Discussion |
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Agitation is a common problem in the pediatric postanesthesia care unit. Cole et al. (4) noted, in a study of 260 children, that agitation was present in 30% of the patients. In a cohort study conducted on 521 children undergoing outpatient anesthesia, Voepel-Lewis et al. (5) noted an overall incidence of 18%. In this study, the major predicting factors were a short awakening time, the use of isoflurane, ophthalmologic/otologic surgery, and low patient adaptability scores.
Sevoflurane is particularly prone to engender postanesthesia agitation in children, and this effect is more pronounced in preschool boys (6). Several studies conducted on postsevoflurane agitation in children have reported proportions ranging from 9% to 100%, with a majority reporting incidences around 35%–45% (6–11). Emergence agitation from sevoflurane has been thought to be related to the anesthetic's ability to produce a fast emergence (10), but this speculation has been questioned because, in a randomized study, the incidence of agitation in children was less frequent after propofol anesthesia, despite similar recovery times (12). Davis et al. (11) noted that in ultrashort procedures (<10 minutes), the incidence of emergence agitation with sevoflurane and halothane were similar.
Several studies have investigated the frequency, intensity, and risk factors associated with postoperative sevoflurane agitation. The role of pain, analgesics, opioids, and preanesthetic medications have also been studied. These studies have given conflicting results (6,8,11,13–15). Specifically, sevoflurane agitation has been attributed to postoperative pain by some, but others have found that it may arise even when pain is not present (8,15). Pain and agitation may be difficult to discriminate, especially in preschool children. A hierarchical evaluation of pain indicators, e.g., self-report, causes of pain, behavior, parent's judgement, and vital signs, has been found helpful in these situations (16). Apart from the absence of parents, we followed the same logic when trying to discriminate painless from painful agitation.
Preoperative sedation, most often accomplished by means of midazolam premedication, also fails to exert a consistent effect on emergence agitation. In a study of 100 children comparing halothane and sevoflurane, Lapin et al. (9) noted the incidence of agitation decreases from 67% to 39% in those children anesthetized with sevoflurane and premedicated with midazolam. This result has been confirmed by some (17), whereas others have actually found a paradoxical increase of both duration and number of patients affected (18) or no effect at all (19).
Differences between anesthetics may be related to a diversity in the dynamic pattern of recovery of brain subsystems during awakening. When the electroencephalogram signal is quantitatively analyzed, the schema obtained during sevoflurane and propofol recovery is clearly different (20). Several inhaled anesthetics may increase noradrenaline content in adrenergic areas of the brain. This effect is prominent under sevoflurane or isoflurane anesthesia (21,22) and may persist in some areas during the recovery phase (22). This is particularly intriguing when considered together with clonidine's mechanism of action.
The effect of clonidine is complex and incompletely characterized in humans. At the spinal level, analgesia is mediated mainly by 
2 subtype A receptor agonist action, whereas subtype C seems involved in enhancement and opioid synergy (23). Supraspinal action is prominent at the locus coeruleus, where activation of receptor subtype A inhibits the diffuse adrenergic projections that originate there. Modulation by 2 agonists can be found in several other neurotransmitter systems, including serotoninergic pathways, and this mechanism seems to play a role in anxiolysis (24). Central antagonism of 2 receptors produces diffuse adrenergic activation along with subjective feelings of anxiety, panic attacks, restlessness, and agitation (25).
Clonidine reduced postsevoflurane agitation in two other studies conducted in settings comparable with our own. The first one (Kulka et al. (1) was a randomized, controlled trial (RCT) conducted on 40 children aged 2–7 years, and the second one (Bock et al. (2) was also an RCT conducted on 72 children. In this study, clonidine was administered either IV or as an adjunct to a caudal block with local anesthetic. These studies are sufficiently similar to ours regarding type of anesthesia, use of regional or central block, and duration of surgery to allow a pooled analysis that shows a combined RR for developing any agitation after clonidine administration of 0.25 (95% CI, 0.1–0.63).
Kulka et al. (1) have found that clonidine decreased the incidence of agitation from 80% to 10%, whereas Bock et al. (2) reported a less striking absolute reduction but with similar relative magnitude (from 39% to 5.5%, considering controls versus the clonidine IV group). We noted the effect to be even less pronounced but, nevertheless, highly significant. Our study was conducted on a larger sample and on a relatively wider variety of surgical procedures, reflecting the more normal day-to-day activity of an outpatient pediatric surgery clinic. Another difference among the three studies was the use of acetaminophen in both Bock et al.'s (2) and our study. In addition, the patients in our study were slightly younger. However, these differences do not seem to have produced some coherent bias, e.g., according to a postulated greater sensitivity of younger children, we should have observed more agitated patients in both groups with respect to the other studies, but we did not, nor were there differences between children receiving acetaminophen and those who did not.
We demonstrated that IV clonidine markedly reduces postsevoflurane agitation in children aged 0–6 years, with minimal effect on hemodynamic variables and recovery times. Clonidine treatment decreases the risk of agitation after sevoflurane anesthesia in children.
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Footnotes |
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References |
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2-adrenoceptors. Part II. Influence on monoaminergic transmission, motor function, and anxiety in comparison with dexmedetomidine and clonidine J Pharmacol Exp Ther 2000;295:1206–22.This article has been cited by other articles:
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  N. Tazeroualti, F. De Groote, S. De Hert, A. De Ville, A. Dierick, and P. Van der Linden Oral clonidine vs midazolam in the prevention of sevoflurane-induced agitation in children. A prospective, randomized, controlled trial Br. J. Anaesth., May 1, 2007; 98(5): 667 - 671. [Abstract] [Full Text] [PDF]
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 G. P. Vlajkovic and R. P. Sindjelic Emergence Delirium in Children: Many Questions, Few Answers Anesth. Analg., January 1, 2007; 104(1): 84 - 91. [Abstract] [Full Text] [PDF]
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