Emergence agitation is a common phenomenon in children recovering from general anaesthesia with a reported incidence ranging from 10 to 80%.1–4 Emergence agitation is a term used to describe nonpurposeful restlessness, thrashing, crying or moaning, disorientation and incoherence.1,5 An emergence agitation reaction increases the risk of patients damaging their surgical wound and injuring themselves or their caregivers. Moreover, patients exhibiting emergence agitation often require constant nursing supervision, which strains nursing staff resources. The prevention and treatment of emergence agitation, therefore, remain important challenges in paediatric anaesthesia.6
Acupuncture at the heart 7 (HT7) point, which is located on the ulnar side of the wrist, has been reported to affect anxiety7 and insomnia.8 Previous studies have reported that emergence agitation was effectively prevented by stimulating the HT7 acupuncture site using a capsicum plaster or needle.9,10 However, HT7 stimulation is currently not widely used, probably because anaesthesiologists are not familiar with these stimulation methods and special techniques are required.
In routine clinical practice, peripheral nerve stimulator (PNS) devices are widely used to assess the level of neuromuscular blockade during general anaesthesia, without serious adverse effects. Electrical stimulation generated by a PNS and delivered to acupuncture sites such as P6 is known to reduce postoperative nausea and vomiting (PONV) to a similar degree to that achieved via needle stimulation.11 We hypothesised that electrical stimulation of HT7 would also be effective. The objective of this randomised controlled trial was to investigate the effectiveness of electrical stimulation of the HT7 acupuncture site using PNS in the prevention of emergence agitation in paediatric patients.
This study was approved by the institutional review board of Kanagawa Children's Medical Centre (No. 80-03) on 5 September 2013, and the study protocol was registered with the UMIN Clinical Trial Registry (registration number UMIN000011704, principal investigator T. Hijikata, date of registration 14 September 2013). Written informed consent was obtained from the parents of all patients. The study was conducted in accordance with the principles of the Declaration of Helsinki.
This study was a prospective, double-blinded, parallel-group, randomised controlled trial. Patients who were 18 to 96 months of age, American Society of Anesthesiologists physical status I or II and scheduled to undergo an operation under general anaesthesia with sevoflurane were prospectively included in this study. The operations included inguinal hernia repair, adenoidectomy and/or tonsillectomy, unilateral strabismus surgery, cryptorchidism repair, tympanostomy tube insertion and other minor procedures. Patients with developmental delays, neurological or psychological disorders, abnormal airways, reactive airway diseases and those receiving sedatives were excluded from the study. Patients undergoing bilateral strabismus surgery were also excluded, because both the eyes are covered with patches after that procedure at our institution, making it impossible to derive a score via the Paediatric Anaesthesia Emergence Delirium (PAED) scale.
The enrolled patients were randomly assigned in a 1 : 1 ratio to either an HT7 acupuncture site-stimulated group or a control group. Randomisation was performed using sequentially numbered sealed, opaque, envelopes with a computer-generated random allocation. The envelope was opened after induction of anaesthesia. We performed block randomisation with a block size of six. Both patients and observers were blinded to group allocation. Although attending anaesthesiologists were blinded to group allocation until the completion of anaesthetic induction, they could not be blinded after starting electrical stimulation of HT7 in patients who did not receive muscle relaxation for surgery. This is because electrical stimulation of HT7 evoked movements of the patients’ hands during surgery, whereas the patients’ hands did not move in the control group. To reduce bias, we used a standardised anaesthetic protocol throughout the study. All patients fasted for at least 8 h, with the opportunity to drink clear fluids up to 2 h before the operation. The patients were not premedicated. Upon arrival at the operating theatre, the patients were monitored by pulse oximetry, noninvasive blood pressure measurement and electrocardiography. The child's preoperative behaviour was then briefly evaluated by an attending anaesthesiologist via the following four-point scale: 1. crying, needs restraint; 2. moderate fear and reassured with difficulty; 3. slight fear, but reassured easily and 4. asleep, calm or awake, cooperative and accepting a face mask.12 Anaesthesia was induced by inhalation of 8% sevoflurane with 4 l min−1 nitrous oxide and 2 l min−1 oxygen via a facemask, with monitoring of inhaled and exhaled sevoflurane concentrations. After loss of consciousness, nitrous oxide was discontinued and the inspired concentration of sevoflurane was reduced to 5% in 100% oxygen and an intravenous cannula was inserted. Atropine (0.01 mg kg−1) and fentanyl (2 μg kg−1) were then intravenously administered and rocuronium (0.6 mg kg−1) was administered if tracheal intubation was indicated. A laryngeal mask airway (LMA-Proseal; Teleflex Medical; Research Triangle Park, North Carolina, USA) or tracheal tube was inserted after adequate jaw relaxation was attained. LMA size was determined according to the manufacturer's guidelines: size 2.0 for patients 10 to 20 kg in body weight; size 2.5 for 20 to 30 kg and size 3 for 30 to 50 kg. An anaesthesiologist who was blinded to group allocation decided on the airway device to be used. If LMA insertion failed after three attempts, tracheal intubation was performed. A 30 mg kg−1 paracetamol suppository was administered for postoperative pain control. In addition, we performed caudal blocks with 0.25% ropivacaine 1 ml kg−1 (up to a maximum of 20 ml) for cryptorchidism and ilioinguinal nerve blocks with 0.3 ml kg−1 of a 1 : 1 mixture of 0.375% ropivacaine and 0.5% lidocaine for inguinal hernia repair. We did not perform nerve blocks for the other types of surgery. Nerve blocks were deemed to be inadequate if the patient's heart rate increased by more than 20% within 60 s of skin incision. Patients who did not receive a caudal or ilioinguinal nerve block were administered 2 μg kg−1 of fentanyl before the start of surgery.
During surgery, anaesthesia was maintained with an end-tidal concentration of 2 to 3% sevoflurane in 40 to 50% oxygen with a total inflow of 4 l min−1, and the ventilator was set to maintain tidal volumes between 8 and 10 ml kg−1 with 4 cmH2O positive end-expiratory pressure. If blood pressure or heart rate increased to more than 20% of preinduction baseline values, 1 μg kg−1 of fentanyl was administered. At the completion of surgery, the oxygen concentration was increased to 100% and the end-tidal sevoflurane concentration was maintained at 2 to 3%. Sugammadex was used to reverse neuromuscular blockade if the train-of-four ratio was less than 0.9. When regular breathing with an adequate tidal volume (>6 ml kg−1) was confirmed, the LMA or tracheal tube was removed under anaesthesia.13,14 Sevoflurane was immediately discontinued after LMA or tracheal tube removal and 100% oxygen was administered via a facemask. After an attending anaesthesiologist confirmed that the patient was breathing spontaneously and without any respiratory complications such as breath holding, upper airway obstruction or laryngospasm, they were transferred to the postanaesthesia care unit (PACU). In this study, patients who underwent adenoidectomy and/or tonsillectomy were also extubated during deep anaesthesia.15
The HT7 acupuncture point is located at the wrist crease on the radial side of the flexor carpi ulnaris tendon, between the ulna and pisiform bones. We placed one PNS electrode just above the HT7 acupuncture point and another electrode on the dorsal side of the HT7 acupuncture point (Fig. 1). Electrodes were placed on both the left and right arms of all the patients. In the HT7 stimulation group, we stimulated the HT7 acupuncture site on both the arms using two PNS devices (TOF-Watch; Mammendorfer Institute of Physics and Medicine, Mammendorf, Germany) by connecting the negative cable to the electrode on the HT7 acupuncture point (the flexor side of the wrist) and the positive cable to the electrode on the dorsal side to allow electrical current to flow through the HT7 acupuncture point. Single-twitch stimulation at 1 Hz (over 0.2 ms at a constant current of 50 mA) was applied. We simultaneously switched the two PNS devices on at the time of skin incision and switched them off at the end of surgery. In the control group, the two PNS devices were similarly connected to the electrode attachments, but no electrical stimulation was applied.
On arrival at the PACU, a trained observer who was blinded to patient allocation evaluated the children every 5 min from the time they started crying or opened their eyes in response to a verbal command or light touch, until they left the PACU. The incidence and severity of emergence agitation were evaluated using the PAED scale (Table 1)16,17 and Aono's scale (1. calm; 2. in an easily consoled state; 3. moderately agitated and 4. severely agitated).18 The theoretical total scores for the PAED scale range from 0 to 20. A recorded score of at least 10 on the PAED scale or at least 3 on the Aono's scale was considered to be attributable to emergence agitation.16,18 Postoperative pain was also estimated, using the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS).19 The highest recorded score was used for evaluation. Adverse effects of stimulation and duration of PACU stay were also recorded. Patients were allowed to leave the PACU when their modified Aldrete score was more than 8 points.20 The following were also recorded: duration of the operation, duration of anaesthesia (from the start of induction to the end of administration of oxygen using a closed-circuit anaesthesia machine) and time from the end of the operation to tracheal extubation.
The primary outcome was the incidence of emergence agitation, evaluated in the PACU using the PAED scale. The secondary outcomes were the incidence of emergence agitation evaluated using Aono's scale, the absolute value of the PAED or Aono's score, time to extubation, PACU stay duration and postoperative pain.
Assuming a 54% incidence of emergence agitation in the control group (based on a pilot investigation) and a 50% reduction using HT7 stimulation,9 a power analysis indicated that 55 patients were required in each group (α = 0.05, β = 0.20). Allowing for a 20% dropout rate, we aimed to recruit 66 patients to each group. A P value of less than 0.05 was considered statistically significant. The Shapiro–Wilk test was used to assess the normality of the data distributions. Continuous data are reported as the mean ± SD and were analysed using unpaired t tests. Categorical data are reported as percentages and were analysed using Fisher's exact test or a χ2 test as appropriate. Nonparametric data such as those derived from the PAED scale and Aono's scale are reported as median (interquartile range) and were analysed using the Mann–Whitney U test. In addition, risk ratio (RR) and number needed to treat with a 95% confidence interval (CI) were calculated for our primary outcome.
As a sensitivity analysis, we conducted multivariate logistic regression analysis to determine whether the results pertaining to our primary outcome were affected by a difference in the total dose of fentanyl between the groups. In this logistic regression analysis, the incidence of emergence agitation evaluated by the PAED scale was set as a dependent factor, the presence or absence of HT7 stimulation was set as an independent factor and the total dose of fentanyl during surgery was set as a covariate. We calculated an adjusted RR from the adjusted odds ratio derived from the logistic regression.21 For this calculation, we used the rate of emergence agitation in the control group. Statistical analyses were performed using the R statistical software package, version 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria).
Recruitment of patients was stopped when the target sample size was reached. Initially, 132 patients were enrolled in the study, but 12 were subsequently excluded prior to randomisation. Six of these patients had developmental delays, three had their operations cancelled or postponed and the parents of three did not consent to their participation in the study. Thus, a total of 120 patients were eligible for the study (Fig. 2). Stimulation failure occurred in one patient in the HT7 group because of the PNS electrode disconnection during the operation. That patient was included in the HT7 group in the intention-to-treat analysis.
There were no significant differences in patient characteristics, type of operation, duration of anaesthesia, duration of surgery or consumption of fentanyl during the operation between the two groups (Table 2). We also assessed preoperative behaviour using a four-point scale, and there was no statistically significant difference between the two groups [median (range) 3.5 (1 to 4) in the HT7 group and 3.0 (2 to 4) in the control group; P = 0.85].
The incidence of emergence agitation was significantly lower in the HT7 group than the control group (31.7 vs. 56.7%; P = 0.010) with RR of 0.56 (95% CI 0.36 to 0.86) and number needed to treat of 4 (95% CI 3 to 13) (Table 3). The RR adjusted by the multivariate logistic regression analysis was 0.55 (95% CI 0.30 to 0.86; P = 0.006).
Although the PAED scale scores were lower in the HT7 group than the control group, the difference was not statistically significant [median (interquartile range) scores 5.5 (1 to 14) vs. 11 (3 to 16), respectively; P = 0.062]. The incidence of emergence agitation in the HT7 group was significantly lower than in the control group based on Aono's scale scores (33.3 vs. 56.7%, respectively; P = 0.017) (Table 4). Time to tracheal extubation, duration of stay in the PACU and CHEOPS scores were comparable in the two groups (Table 4). No adverse effects of stimulation such as pain, paralysis or skin erythema occurred during the study.
In the current study, electrical stimulation of HT7 using PNS significantly reduced the incidence of emergence agitation in paediatric patients after sevoflurane anaesthesia. This result held true regardless of which of two different scales was used to evaluate emergence agitation.
Our results are consistent with those of the previous reports that needle or capsicum plaster stimulation of HT7 reduced the incidence of emergence agitation.9,10 The stimulation methods used in the previous studies are difficult to apply in daily clinical practice because they require special techniques or medications. Our method, however, is easy to apply in daily practice because it only requires PNS devices that are regularly used in operating theatres.
With regard to the secondary outcomes, the stimulation of HT7 did not prolong the time to tracheal extubation or PACU stay duration. Pharmacological prophylaxis for emergence agitation has been reported in the previous studies.22–26 A recent Cochrane review reported that administration of propofol or fentanyl at the end of anaesthesia reduces the incidence of emergence agitation [RR (95% CI) 0.58 (0.38 to 0.89) and 0.37 (0.27 to 0.50), respectively].26 Kim et al.23 also reported that the administration of propofol or fentanyl at the end of surgery reduced the incidence of emergence agitation in patients undergoing inguinal hernia repair; this did, however, result in a delay in awakening from anaesthesia. Furthermore, fentanyl administration prolonged PACU stay duration and increased the incidence of PONV. Aouad et al.24 reported that administration of propofol at the end of anaesthesia reduced the incidence of emergence agitation, but prolonged the time to tracheal extubation. In contrast, our method neither delayed awakening from anaesthesia nor prolonged the time to tracheal extubation or duration of the PACU stay. In addition, because our method does not require drugs that potentially increase the risk of respiratory depression and PONV, it may be advantageous for patients with respiratory disorders, airway problems or a history of PONV. However, these results pertaining to the secondary outcomes need to be reproduced by other future studies before firm conclusions can be drawn.
We used two scales to evaluate emergence agitation, namely the PAED scale and the Aono's scale. The PAED scale is a typical evaluation tool for emergence agitation and its reliability and validity have been established.16 However, previous studies showed that the incidence of emergence agitation might differ according to the evaluation tool17,22 and we therefore used not only the PAED scale but also the Aono's scale. In this study, electrical stimulation of HT7 reduced the incidence of emergence agitation as evaluated by both the scales. The difference in PAED scores between the two groups did not reach statistical significance (P = 0.062), whereas that of the Aono's score was significant (P = 0.016). Our sample size was designed to have adequate power to detect a difference in our primary outcome (the incidence of emergence agitation evaluated using the PAED scale), thus we surmised that our sample size did not have adequate power to detect a difference in raw PAED scores, although notably, HT7 stimulation reduced PAED scores by half.
Beringer et al.27 suggested that preoperative behaviour was associated with the incidence of emergence agitation. In their prospective observational study, they estimated the preoperative behaviour using a three-point scale during the induction of anaesthesia and showed that preoperative behaviour highly correlated with PAED score. Preoperative behaviour in paediatric patients is, therefore, considered an important confounding factor in studies assessing emergence agitation. In this study, patients were randomly assigned to one of the two groups, and thus patient characteristics, including preoperative behaviour, were expected to be similar in each group. We estimated the patients’ preoperative behaviour using four-point scales and confirmed that there was no significant difference between the two groups. Postoperative pain has also been reported as a confounding factor when assessing emergence agitation.28 Thus, we estimated postoperative pain using a CHEOPS score and confirmed that there was no significant difference between the two groups.
Several studies have reported that stimulating HT7 reduces the incidence of emergence agitation9,10,29 although there are still many unanswered questions about the underlying mechanism. Evidence from several noninvasive functional MRI studies on acupuncture at commonly used acupuncture points for pain relief has revealed significant modulatory effects at widespread cerebrocerebellar brain regions. These regions process information in circuits that can broadly be supposed to engage endogenous antinociceptive limbic networks.30 In addition, a previous study reported that stimulating HT7 significantly decreased both dopamine release in the nucleus accumbens and behavioural hyperactivity induced by systemic morphine administration in rats.31 It is possible that stimulating HT7 inhibits the effects of opiates on dopaminergic neurons via γ-aminobutyric acid neurons in the ventral tegmental area. We speculate that dopamine release in the nucleus accumbens might be reduced by electrical stimulation of HT7 in humans.
In the current study, all patients were anaesthetised with sevoflurane. Thus, the findings of our study may not be applicable to other types of anaesthesia such as total intravenous anaesthesia. In addition, HT7 stimulation was administered at 1 Hz (50 mA) to both the left and right arms in this study; our results, therefore, do not justify the use of other types of stimulation (e.g. unilateral stimulation or lower/higher stimulation frequencies) for preventing emergence agitation. Further studies investigating other types of stimulation are needed.
This study has some limitations. First, the attending anaesthesiologists could not be blinded to the group allocations after starting electrical stimulation of HT7. To reduce bias, we used a standardised anaesthetic protocol throughout the study; consequently, there were no differences in the consumption of fentanyl during the operation or in CHEOPS score between the groups. In addition, to ensure data integrity, the patients and the observers were blinded to the group allocations. Moreover, the RR adjusted by the multivariate logistic regression analysis was similar to the nonadjusted RR, suggesting that the bias introduced from the unblinded anaesthesiologists was minimal. Second, we included a wide variety of procedures, which potentially affected the internal validity of the study. From a clinical perspective, prevention of emergence agitation is especially important for high-risk (e.g. strabismus surgery or tonsillectomy) and day-case procedures (e.g. inguinal hernia repair). Including a single procedure in the study would be ideal for internal validity, but it would diminish the external validity. Thus, we decided to include multiple procedures in the current study. In addition, the distribution of surgery type in the current study was equal between the groups because of randomisation and we believe that the internal validity was not affected. Finally, we attached electrodes to the HT7 point in the control group. It was possible that the HT7 point was stimulated solely by electrode attachment. However, the electrodes we used in this study did not contain stimulants such as capsaicin and did not have projections that might stimulate the HT7 point. In addition, the incidence of emergence agitation in the control group (56.7%) was similar to that in our pilot investigation (54%). Therefore, we consider that the effect of HT7 stimulation by attached electrodes in the control group was minimal.
In conclusion, we have demonstrated that electrical stimulation of HT7 using PNS decreases the incidence of emergence agitation in paediatric patients, without prolonging time to tracheal extubation or PACU stay duration.
Acknowledgements relating to this article
Assistance with this study: we would like to thank Editage (http://www.editage.jp) for English language editing.
Financial support and sponsorship: none.
Conflicts of interest: none.
Presentation: preliminary data for this study was presented as a poster at the European Society of Anaesthesiology (ESA) Euroanaesthesia, 2015, Berlin, Germany.
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