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PEDIATRIC ANESTHESIA

Clonidine Treatment for Agitation in Children After Sevoflurane Anesthesia

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.

	Abstract

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Clonidine is effective in treating sevoflurane-induced postanesthesia agitation in children. We conducted a study on 169 children to quantify the risk reduction of clonidine agitation in patients admitted to our day-surgery pediatric clinic. Children were randomly allocated to receive clonidine 2 µg/kg or placebo before general anesthesia with sevoflurane that was also supplemented with a regional or central block. An observer blinded to the anesthetic technique assessed recovery variables and the presence of agitation. Pain and discomfort scores were significantly decreased in the clonidine group; the incidence of agitation was reduced by 57% (P = 0.029) and the incidence of severe agitation by 67% (P = 0.064). Relative risks for developing agitation and severe agitation were 0.43 (95% confidence interval, 0.24–0.78) and 0.32 (0.09–1.17), respectively. Clonidine produces a substantial reduction in the risk of postsevoflurane agitation in children.

	Introduction

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Sevoflurane is frequently used for anesthesia of children undergoing day-surgery procedures. Its rapid intake and elimination, as well as an absence of pungent odor, allow for a fast and smooth induction of anesthesia and short patient recovery. However, in pediatric patients, sevoflurane has been associated with emergence agitation, especially in preschool-aged children. A variety of drugs have been used to prophylactically treat this problem; recently, clonidine has emerged as a possible alternative. Clonidine is effective, has minimal impact on ventilation, and does not seem to prolong recovery time. Because its efficacy has been proven in relatively small cohorts (1,2), we designed this study to determine its usefulness in a pediatric ambulatory surgical population. We evaluated the effect of clonidine in 169 children of various ages subjected to sevoflurane anesthesia for minor surgery.

	Methods

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The study was approved by the local ethics committee, and written informed consent was obtained from the parents. The participating children were ASA status I-II admitted to the pediatric day-surgery clinic of our hospital. Patients were excluded if there was a history of seizures or mental retardation. No age limit was set. After 3 h of fasting, all children were premedicated with 0.5 mg/kg of oral midazolam, and anesthesia was induced with 8% sevoflurane in air. At 1.5 mean alveolar anesthetic concentration (MAC) sevoflurane, a laryngeal mask airway was inserted, and vascular access was established. Depending on the type of surgery, a regional or central block was performed using ropivacaine 2.5 mg/kg to provide postoperative pain relief. If a block was not feasible, then wound infiltration was performed at the completion of surgery (Table 1).

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.

	Results

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Of the 171 patients enrolled, 2 were discontinued from the study. One patient had an inadequate caudal block, and the second patient seemed to have seizures and trismus at anesthetic induction. Of the remaining 169 patients, 91 received clonidine, and 78 did not. The two groups were comparable with respect to age, type and duration of surgery, and time to emergence (Table 1). No hypoxemic episodes occurred throughout the study period. All patients began taking oral fluids 2 or 3 h after the procedure, and no patient had nausea or vomiting during the recovery period. One patient developed fever in the recovery room and was discharged on the following day.

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.

	Discussion

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Our data show that premedication with clonidine 2 mg/kg effectively sedates children in the postoperative period without prolonging recovery. The slight decrease in the Steward score that was evidenced at 30 minutes after surgery had normalized by the end of the 2-hour recovery period. However, the PDS scores were significantly decreased in the treated group. Our data also indicate a significant reduction of the incidence of agitation; that in the treated group decreased to less than half that of the controls.

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.

	Footnotes

 
Accepted for publication June 16, 2005.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Tesoro, S. Articles by Peduto, V. A. Search for Related Content PubMed PubMed Citation Articles by Tesoro, S. Articles by Peduto, V. A. Related Collections Pediatrics Pharmacology