RETRACTED ARTICLE: Desflurane anesthesia worsens emergence agitation in adult patients undergoing thyroid surgery compared to sevoflurane anesthesia

Background The effect of volatile anesthetics on emergence agitation in adults remains unclear. We compared the degree of emergence agitation between desflurane and sevoflurane anesthesia in adults undergoing thyroid surgery. Findings One hundred and sixteen patients with American Society of Anesthesiologists status 1 or 2 were randomized into two groups: the desflurane group (group D) and the sevoflurane group (group S). After induction of anesthesia with fentanyl (1–2 μg/kg) and propofol (1.5–2.5 mg/kg), tracheal intubation was facilitated with suxamethonium (0.5–1.0 mg/kg). In group D, anesthesia was maintained with desflurane in 66% nitrous oxide and 33% oxygen supplemented with fentanyl when necessary; in group S, sevoflurane was used instead of desflurane. After the end of the surgery, emergence agitation was evaluated with a modified pediatric anesthesia emergence delirium scale (ranging from 0 to 16, with higher scores indicating more severe emergence agitation) before extubation. Time to extubation from the end of the surgery, postoperative pain (evaluated by a numerical rating scale [NRS]), and postoperative nausea and vomiting (PONV) after surgery were examined. The degree of emergence agitation was more severe in group D than in group S (median [interquartile range]: 5 [4–7] vs 4 [2–6], p = 0.008). Time to extubation, NRS scores, and PONV rates were similar between the two groups. Conclusions Desflurane anesthesia worsened emergence agitation as compared with sevoflurane in adult patients undergoing thyroid surgery, but did not affect time to extubation, postoperative pain, or PONV. Trial registration UMIN000014215 Electronic supplementary material The online version of this article (doi:10.1186/s40981-017-0106-5) contains supplementary material, which is available to authorized users.


Introduction
Emergence agitation is a transient state of mental perturbation that occurs during recovery from general anesthesia in pediatric and adult patients [1][2][3]. Emergence agitation is characterized by hallucinations, excitation, delusions, and confusion, and can cause various adverse events, such as increased bleeding due to hypertension, injury to the surgical site and the patients themselves, removal of drains or intravenous catheters, and self-extubation, which can lead to severe complications [4,5].
For general anesthesia, some anesthesiologists prefer desflurane to sevoflurane, because the former allows prompt emergence from anesthesia and speedy recovery of the cough reflex, especially in elderly patients [6]. Although a previous study reported that desflurane increases the incidence of emergence agitation in children compared to sevoflurane [7], the effect of

R E T R A C T E D A R T I C L E
inhalational anesthetics on emergency agitation in adults has not been fully elucidated.
The aim of this study was to compare the degree of emergence agitation between desflurane and sevoflurane anesthesia in adult patients undergoing thyroid gland surgery; a surgical procedure associated with a high incidence of emergence agitation [3].

Methods
This prospective randomized study was conducted from October 2014 to April 2015 in Ito Hospital in Tokyo, Japan. The hospital's operating room has two beds, where nearly 2000 surgical procedures for thyroid disease are performed each year. This study was approved by the regional ethics committee (9/01/2014, No 60, Chairman: Dr. M. Nagahama in Ito Hospital in Tokyo, Japan), which waved informed consent since the anesthetic method with volatile anesthetics was well established in terms of efficacy and safety. The study was registered at UMIN Clinical Trials Registry (http://www.umin.ac.jp/umin/UMIN, registration number UMIN000014215).

Anesthetic protocol
Patients with American Society of Anesthesiologists (ASA) physical status 1 or 2 who underwent elective thyroid surgery under general anesthesia were enrolled in this study. Patients less than 20 years of age, with body mass index (BMI) more than 35, and with psychiatric diseases, mental retardation, history of asthma, and contraindication for suxamethonium administration, were excluded from the study. No premedication was administered before operation. Patients were assigned into the desflurane group (group D) or the sevoflurane group (group S) according to the bed number in which they underwent operation as determined by the head of the nursing staff in the operating room (that is, patients in bed #1 received desflurane whereas patients in bed #2 received sevoflurane). The head of the nursing staff was blinded to the study protocol. Anesthesia was induced with fentanyl 1-2 μg/kg and propofol 1.5-2.5 mg/kg, and orotracheal intubation was facilitated with suxamethonium 0.5-1.0 mg/kg. Local anesthesia (10 mL of 1% lidocaine) was injected into the cervical region before skin incision. For the maintenance of anesthesia, desflurane 3-8% (group D) or sevoflurane 1-3% (group S) with nitrous oxide 66% in oxygen was given with additional fentanyl bolus administration if necessary. The adjustment of volatile anesthetic concentration was left to the discretion of the attending anesthesiologists. Mechanical ventilation was adjusted to maintain end-tidal carbon dioxide between 35 and 40 mmHg. If continuous, catecholamine infusion or blood transfusion was required to maintain hemodynamics due to major bleeding, patients were excluded from the study. Immediately before the end of the surgery, 50 mg flurbiprofen axetil were administered to reduce postoperative pain, unless contraindicated. At the end of the surgery, volatile anesthetics and nitrous oxide were discontinued, and then manual ventilation with 100% oxygen was performed without any attempt to stimulate the patients. When patients began to breathe spontaneously and opened their eyes or moved their limbs with gentle tapping of their shoulder after the end-tidal concentration of volatile anesthetics fell below the minimum alveolar concentration (MAC) awake (less than 0.4% for sevoflurane and less than 1.0244% for desflurane), emergence agitation was evaluated before extubation by the attending anesthesiologists who were not blinded to patient allocation, using a modified pediatric anesthesia emergence delirium (PAED) scale that comprises four parameters (ranging from 0 to 16, with a higher score indicating more severe emergence agitation; Table 1). One of the original parameters was excluded from the PAED scale, even though its reliability and validity had been shown in children previously [8]. A detailed description of the modified PAED scale is presented in Additional file 1: Table S1. After evaluation of emergence agitation and confirmation of cough reflex, patients were extubated and transferred to the recovery room next to the operating room. 15 min after transfer to the recovery room, the degree of postoperative pain was evaluated using a numerical rating scale (NRS), and the presence of postoperative nausea and vomiting (PONV) was assessed by the attending nurse who was blinded to patient allocation.

Outcomes
The primary outcome of this study was the degree of emergence agitation evaluated by a modified PAED scale in the two groups (group D and group S). The secondary outcomes were time to extubation from the end of the surgery, postoperative pain evaluated by NRS, and PONV rates.

Statistical analysis
Based on the result of our preliminary study including 20 subjects, the mean ± standard error (SE) value of a modified PAED scale for patients undergoing thyroid surgery under sevoflurane anesthesia was 5 ± 3.9. With a power of 80% and a 5% significant level, we estimated that 60 patients per group were required to detect a 2point increase in the modified PAED scale in patients receiving desflurane anesthesia compared to those receiving sevoflurane anesthesia. Statistical analysis was performed using SigmaStat software. Results are presented as the mean ± standard deviation (SD) for variables with a normal distribution, or the median (interquartile range) for variables with a non-normal distribution. Comparisons were performed using Student's t test or Mann-Whitney's U test, as appropriate. Categorical variables were compared with Fisher's exact test. A p value less than 0.05 was considered statistically significant.

Results
One hundred twenty-two patients were screened for eligibility. After two patients who met the exclusion criteria were excluded, a total of 120 patients were enrolled in this study. Of those, 60 received desflurane and 60 received sevoflurane anesthesia (Fig. 1). All patients completed the study, and no adverse events were observed in either group. Patient characteristics and operative procedures of each group are shown in Table 2. There were no significant differences between the two groups regarding gender, age, height, body weight, and ASA physical status. The total dose of fentanyl, duration of surgery, and anesthesia time were also similar between the two groups.
As shown in Table 3 and Fig. 2, the degree of emergency agitation evaluated by the modified PAED scale was more severe in group D than in group S (median [interquartile range]: 5 [4][5][6][7] vs 4 [2][3][4][5][6], p = 0.008). Time to extubation from the end of the surgery, and NRS scores and PONV rates evaluated in the recovery room, were similar between the two groups ( Table 3). The scores for each of the four components of the modified PAED scale are presented in Table 3. Among the four components, the scores of eye contact and awareness of surroundings were higher in group D than in group S (2 [2-2] vs 2 [1][2], p = 0.001; and 1 [1-2] vs 1 [0-2], p = 0.041, respectively). No severe adverse events were observed in any of the patients.

Discussion
The major finding of this study was that desflurane anesthesia worsened the degree of emergence agitation after thyroid surgery in adult patients, as compared with sevoflurane anesthesia. Patients receiving desflurane anesthesia were not able to establish eye contact and presented with worse disorientation as compared with those receiving sevoflurane anesthesia. Anesthesiologists should pay attention to worsened emergence-agitation condition when using desflurane for thyroid surgery.
The incidence of emergence agitation after general anesthesia has been reported to be up to 20% in adult patients [3,4]. However, the percentages vary widely. This is likely to be attributed to the characteristics of the patients, the type of surgery, the anesthetic methods, Fig. 1 Flow diagram of patient assignment to study group. D desflurane, S sevoflurane. Two patients were excluded from the study due to a history of psychological disorder. All eligible patients completed the study and the timing and tools for evaluation. Some possible factors, including male gender, preschool age, type of surgery, short time to awakening, inhalational anesthetics, adjuvant medications, post-surgical pain, and presence of tracheal tube, are considered to be associated with postoperative emergency agitation [5,9], but the exact mechanisms of emergence agitation remain to be elucidated. Emergence agitation causes adverse events that can lead to physical harm to patients, additional treatment and stress on patients and their families, and increased nursing workload [5,10,11]. Thus, it is very important for anesthesiologists to recognize risk factors for emergence agitation and to prevent major complications.
While we have shown that desflurane is inferior to sevoflurane with regard to worsening emergence agitation, some previous studies demonstrated conflicting results regarding the effect of inhalational anesthesia on emergence agitation. Wellborn et al. observed a higher incidence of emergency agitation in desflurane anesthesia than in sevoflurane anesthesia in children undergoing adenoidectomy, albeit they showed a faster recovery from general anesthesia [7]. Cohen et al.
reported an incidence of emergency agitation of more than 50% in children receiving adenotonsillectomy under desflurane anesthesia, which could not be prevented by midazolam or propofol pretreatment [12]. On the other hand, the type of inhalational anesthesia had no effects on the frequency of emergence agitation in a few other studies [13][14][15]. A recent meta-analysis has shown that desflurane anesthesia causes less agitation than sevoflurane anesthesia [16]. Although the exact reason why the results were different between these studies, these studies have focused on children with a wide range of age who underwent different surgical procedures and used various rating scales for evaluation of emergence agitation. To our knowledge, few studies have compared the effects of different inhalational anesthetics on the degree of emergence agitation in adult patients undergoing similar surgical procedures. Choi et al. demonstrated that the incidence of emergence agitation was lower in desflurane anesthesia compared with sevoflurane anesthesia in orthognathic surgery [17], which was contrary to our results. This discrepancy seems to be attributable to differences in the type of surgery, the timing of evaluation, and the method to assess emergence agitation, as with the case of children. Although the exact mechanisms resulting in worsened emergence agitation by desflurane anesthesia than with sevoflurane have not been elucidated, some possible reasons should be considered. One possible reason is that rapid emergence from general anesthesia, which is one of the main characteristics of desflurane [6], might not allow patients sufficient time to recognize their current situation, or the acute emergence of surgical pain or discomfort in the tracheal tube due to the rapid elimination of desflurane may cause more agitation. Another possible reason for the agitation in patients during the emergence from general anesthesia is desflurane-induced trachea stimulation, which has been reported to be more severe than that induced by sevoflurane [18]. However, given that the end-tidal concentrations of both volatile anesthetics were below the MAC awake when emergence agitation was evaluated, desflurane-induced trachea stimulation was unlikely to be a possible reason for the increased degree of emergence agitation in desflurane anesthesia. Further studies are warranted to examine whether the effects of volatile anesthetics on emergence agitation also differ in other types of surgery.
There is no gold-standard rating scale for evaluating the degree of emergence agitation in adult patients. Therefore, we applied a modified PAED scale to evaluate the degree of emergence agitation in this study. The original PAED scale, which was developed to measure emergence agitation in children, consists of five parameters (each with scores ranging from 0 to 4) reflecting the overall degree of emergence agitation [8,14,15]. The   scores are summed to obtain a total score (ranging from 0 to 20, with a higher score indicating a greater severity of emergence agitation). In this study, we excluded inconsolableness from the PAED scale for evaluating the severity of emergence agitation in adults. Several limitations should be taken into account when interpreting the results of this study. First, we examined the degree of emergence agitation before extubation after general anesthesia, not after extubation. In general, emergence agitation is evaluated after extubation in the postoperative care unit, as described previously [12][13][14][15]17]. However, we intended to evaluate emergence agitation immediately before extubation, since it is very important to prevent agitation or subsequent hypertension prior to extubation in order to reduce the rate of severe complications after thyroid surgery, such as wound dehiscence and severe postoperative bleeding, which can be life threatening. Furthermore, the duration of this observation was rather short. Thus, it is unknown whether the difference in the degree of emergence agitation between the two anesthetics could have affected the clinical course or the incidence of adverse events, such as postoperative bleeding, wound healing, and occurrence of delirium or post-traumatic distress syndrome. However, we have accomplished the aim of this study, which was to evaluate the quality of emergence from general anesthesia. Second, anesthetic technique parameters other than the type of volatile anesthetics (e.g., depth of anesthesia, dose and timing of fentanyl and flurbiprofen axetil administration, duration of surgery, and method for promoting recovery from general anesthesia) could have affected the degree of emergence agitation, since anesthetic management was at the discretion of the attending anesthesiologist, without monitoring the depth of anesthesia using the bispectral index (BIS). However, the attending anesthesiologists had much experience in the anesthetic management of thyroid surgery. Thus, adjustment of the depth of anesthesia was appropriate, as reflected by the short interval from the end of surgery to extubation in both groups. Furthermore, there were no significant differences regarding the dose of fentanyl and the duration of surgery between the two groups. Flurbiprofen axetil was administered at the same dose and timing. Although timing of fentanyl administration might influence the degree of emergence agitation, the difference in fentanyl concentration at the emergence from general anesthesia was likely to have little effect on the degree of emergence agitation, given that the median dose of fentanyl was low (150 μg) and most of the fentanyl was administered before the initiation of surgery (1-2 μg/kg). Moreover, we standardized the protocol for stimulating patients after the surgery. Therefore, it is unlikely that the anesthetic technique other than the type of volatile anesthetics contributed to the difference between the groups. Third, anesthesiologists in charge of patients were not blinded to group assignment. However, it is unpractical to perform an anesthetic management blinded to the volatile anesthetic used. Fourth, it seems unusual that time to extubation in group D was slightly longer than that in group S, even though early emergence is one of the major advantages of desflurane anesthesia. This implies evaluation of emergence agitation in group D might have been performed too late after complete emergence from general anesthesia, leading to higher PAED scores compared to group S. However, we evaluated emergence agitation in the same way after confirming that the concentration of volatile anesthetics was below the MAC awake in both groups. Thus, we consider that the depth of anesthesia was virtually at the same level when emergence agitation was evaluated in the two groups. Fifth, evaluation of emergence agitation was performed by the attending anesthesiologists themselves, which could have led to bias. We believe that the effect of such bias was small, since the modified PAED scale is an easy-to-use objective scoring system. Finally, it is not clear whether a median difference of only one point on the modified PAED scale between the two groups is clinically relevant, since we did not examine whether this small difference affected the longterm clinical outcomes. However, this result can be helpful to urge anesthesiologists to pay attention to emergence agitation when they use desflurane for thyroid surgeries.
In conclusion, desflurane anesthesia worsened the degree of emergence agitation in adult patients undergoing thyroid surgery as compared with sevoflurane anesthesia. Prevention of emergence agitation should be considered during desflurane anesthesia.

Additional file
Additional file 1: Table S1. Detailed description of a modified paediatric anaesthesia emergence delirium scale. (DOCX 17 kb)

Funding
This study received funding from our department.