Characteristics of clinical–behavioural signs
First body movement was recorded in 97% children (n = 92/95), coughing in 86% (n = 76/88) and facial grimacing in 90% (n = 55/61) (Fig. 1).
First body movement, cough and grimace occurred close together in time and generally followed an orderly sequence of events across all ages. Eye signs showed no systematic pattern (see below). Children who emerged from sevoflurane in air/O2 exhibited a median time from end of surgery to body movement of 6.4 min (95% CI, 4.5 to 8.9 min, n = 61/64) cough at 5.5 min (95% CI, 4.3 to 8.3 min, n = 50/60) and grimace at 9.3 min (95% CI, 7.8 to 16.0 min, n = 34/39) (Fig. 2a).
N2O was most commonly administered briefly around the end of surgery, and very few children had high expired N2O concentrations (>50%) when body movement, cough or grimace were observed (Table 2, Fig. 2a). There were no significant differences in the time of events with or without N2O.
There were no differences between children who emerged from sevoflurane in air/O2 and children who emerged from sevoflurane in N2O/O2 in total time from end of surgery until patient departure from the operating room to the PACU [air/O2 12 min (95% CI, 10 to 14 min) vs. N2O/O2 12 min (95% CI, 10 to 14 min), P = 0.5, Mann–Whitney] or in the time of extubation [air/O2 8.3 min (95% CI, 5.9 to 10.0 min) vs. N2O/O2 8.1 min (95% CI, 5.5 to 14.0 min), P = 0.7; Mann–Whitney].
Time taken to exhibit first clinical–behavioural sign during emergence was independent of postnatal age. There were no associations between age and ETsevoflurane in air/O2for body movement (F1,59 = 0.9; P = 0.3), cough (F1,48 = 0.1; P = 0.7) or grimace (F1,32 = 0.04; P = 0.9), or with ETsevoflurane in N2O/O2 for body movement (F1,29 = 1.1; P = 0.3), cough (F1,24 = 0.6; P = 0.4) or grimace (F1,19 = 0.3; P = 0.6); (Supplemental Digital Content 1, http://links.lww.com/EJA/A135).
First appearance of body movement, cough and grimace endpoints occurred over a narrow ETsevoflurane range across all ages. In children who emerged from sevoflurane in air/O2, first body movement occurred at 0.4% (95% CI, 0.3 to 0.4%), cough at 0.3% (95% CI, 0.3 to 0.4%) and grimace at 0.2% (95% CI, 0 to 0.3%) (Fig. 2b).
In children who emerged from sevoflurane in N2O/O2, first body movement occurred at ETsevoflurane of 0.4% (95% CI, 0.2 to 0.4%), cough at 0.3% (95% CI, 0.2 to 0.4%) and grimace at 0.2% (95% CI, 0 to 0.3%) (Fig. 2b). There were no significant differences in ETsevoflurane when each clinical–behavioural sign first occurred in children who emerged from sevoflurane in air/O2 compared with sevoflurane in N2O/O2 (body movement, P = 0.4; cough, P = 0.3; grimace, P > 0.99; Mann–Whitney).
Forty children who emerged from sevoflurane in air/O2 exhibited all three clinical–behavioural signs. Within-patient comparisons indicated that body movement and cough occur very close together in time (P > 0.9, Dunn's), followed by grimace (vs. body movement, P < 0.0001; vs. cough, P < 0.0001, Dunn's) (Fig. 2c). Grimace occurred at a lower ETsevoflurane than did body movement (P < 0.001, Dunn's), and compared with cough (P < 0.01, Dunn's) (Fig. 2d). Within-patient comparisons of children who emerged with sevoflurane in N2O/O2 (n = 12) indicated no difference in time or ETsevoflurane for each clinical sign (P < 0.01, Dunn's) (Fig. 2e and f).
ETsevoflurane for all clinical–behavioural signs was independent of age, both for children receiving sevoflurane in air/O2, [body movement (F1,59 = 0.5; P = 0.5), cough (F1,48 = 0.1; P = 0.7) or grimace (F1,32 = 0.03; P = 0.97) (Fig. 3a to c)], and for children receiving sevoflurane in N2O/O2 [body movement (F1,29 = 2; P = 0.2), cough (F1,24 = 0.04; P = 0.8) or grimace (F1,19 = 0.06; P = 0.8) (Fig. 3d to f)].
Eye positions were assessed an average of five times per patient (95% CI, 4 to 5). Dysconjugate eye gaze was observed between ETsevoflurane 1 to 0%, and was poorly correlated with the appearance of clinical signs and ETsevoflurane in either air/O2 or N2O/O2 (Fig. 4). Individual eye gaze assessments are shown in Supplemental Digital Content 2, http://links.lww.com/EJA/A135.
Characteristics of frontal electroencephalographic frequency bands
Individual frontal EEG spectrograms computed at F7 are shown in age-matched patients (Fig. 5). The relative time course of clinical-behaviour recovery and ETsevoflurane are illustrated in the same figure.
Frontal slow-delta (0.1 to 4 Hz) oscillations were present from ETsevoflurane 2.0% and throughout emergence in children of all ages. Frontal alpha (8 to 12 Hz) oscillations were present during ETsevoflurane 2.0% – suitable for maintenance of a surgical state of anaesthesia – in all 63 children who were older than 3 months. In children less than 3 months, frontal EEG frequency bands shifted in power with decreasing ETsevoflurane. Specifically, frontal alpha power decreased with a simultaneous, but transient, increase in beta oscillations (13 to 30 Hz); (Fig. 5).
In children who emerged from sevoflurane in air/O2, alpha oscillations disappeared before the start of body movement in 73% of children (n = 30/41; body movement was not observed in one patient). The time between the disappearance of alpha oscillations and the onset of body movement was 2.2 min (95% CI, 0.6 to 3.7 min). In 99% of patients, body movement occurred within 5 min of loss of alpha oscillations. The time between the disappearance of beta oscillations and the onset of body movement was 0.9 min (95% CI, 0.2 to 2.3). Both frontal alpha and beta oscillations disappeared at ETsevoflurane 0.5% (95% CI, 0.4 to 0.6%).
Frontal EEG in children who emerged from sevoflurane in N2O/O2 followed a similar pattern. Alpha oscillations disappeared before the start of body movement in 95% of children (n = 19/20). The time between disappearance of alpha oscillations and onset of body movement was 6.3 min (95% CI, 2.2 to 8.7 min). Body movement occurred within 5 min of loss of alpha oscillations in all patients. The time between disappearance of beta oscillations and onset of body movement was 2.1 min (95% CI, 0.6 to 7.1 min). Frontal alpha oscillations disappeared at a median ETsevoflurane of 0.6% (95% CI, 0.5 to 0.6%), and beta oscillations disappeared at a median ETsevoflurane of 0.5% (95% CI, 0.4 to 0.6%).
For children more than 3 months of age (who exhibit alpha oscillations), the cumulative percentage who exhibited recovery of body movement, cough, grimace and alpha oscillation disappearance and the associated ETsevoflurane are summarised in Fig. 6a. Exploratory calculations were performed to estimate sensitivity and specificity of ETsevoflurane, frontal alpha EEG power and frontal EEG beta power in predicting the occurrence of body movement. By incorporating all variables into the ROC model, the area under the curve (AUC) was 81 (95% CI, 77 to 85) (Fig. 6b). Independent AUC values were 81 (95% CI, 77 to 85) for ETsevoflurane, 64 (95% CI, 5 to 69) for alpha EEG power and 69 (95% CI, 64 to 74) for beta EEG power (Fig. 6b). At ETsevoflurane 0.4%, the probability of body movement occurring can be predicted with 75% sensitivity and 68% specificity. Significantly, when ETsevoflurane was more than 0.5%, and alpha oscillations disappeared, body movement had a positive predictive value of 0.75.
Three clinical–behavioural signs, namely gross body movement, cough and grimace, generally occurred in a close sequence and over a narrow range of ETsevoflurane during the time course of clinical signs and their dependence on ETsevoflurane did not vary with postnatal age. Dysconjugate gaze can occur over a wide range of ETsevoflurane and can either precede or follow the occurrence of body movement, cough or grimace. EEG alpha power decreases around the time of body movement in children aged more than 3 months. Finally, N2O administration at the end of surgery had a negligible effect on the time course or ETsevoflurane at which children showed body movement, grimace or cough.
Early studies of sevoflurane in children showed a weak age dependence of minimum alveolar concentration (MAC) to prevent response to surgical incision.7 In one of the first studies evaluating sevoflurane in children, Lerman et al.7 demonstrated rapid emergence, with a mean time from the end of sevoflurane administration to spontaneous eye openings reported as 9.6 and 10.8 min at 6 to 12 months and 1 to 3 years, respectively; no data were available for neonates. Previous studies that examined emergence have reported a limited number of clinical signs, narrower age ranges or grouped data across ages.8–15
Few studies have evaluated age-specific recovery characteristics of sevoflurane in children younger than 6 months of age, and analyses were not stratified by age.7,13–15 Although the age dependence of sevoflurane MAC for surgical incision was reported previously,7 we found that there were no significant age-related differences in the dependence of behavioural signs of emergence on ETsevoflurane. We have provided novel data on the eye gaze position during emergence in this population and showed wide variability in its time course and relationship to ETsevoflurane.
Similar to the findings in a previous study,9 N2O administration at the end of surgery had no significant impact on the time course of clinical–behavioural signs. Also, N2O had no discernible impact on EEG patterns during emergence (see below).
In adult volunteer studies with sevoflurane or propofol anaesthesia, recovery of consciousness is associated with a reduction in alpha power, an increase in peak alpha frequency and an increase in beta power,19–21 although individual patients can show variable patterns.21 Emergence involves re-establishment of cortical and thalamocortical connection strength.20–23 Alpha oscillations during general anaesthesia have been interpreted mathematically in models that emphasise inhibitory thalamocortical circuitry.24,25
The normal infant EEG during sleep and wakefulness changes rapidly during the first year of life, coincident with maturation and refinement of cortico-cortical and thalamocortical circuits.26–30 Previous paediatric studies of EEG during anaesthesia have used variable designs and analytical methods, which may account for some of the discrepancies in their conclusions.1–6
Davidson et al. evaluated spectral edge and integrated EEG total power over the entire 2 to 20 Hz range at 2 min after the time at which anaesthetic gas was turned off, and before and after the first purposeful movement in 64 children aged 0 to 12 years. Children at 6 months to 12 years exhibited significant decreases in forehead power during emergence compared with children at 0 to 6 months.3
Sury et al. evaluated central–parietal EEG power in the 5 to 20 Hz range in 20 infants aged 0 to 10 months during sevoflurane emergence. They reported that in infants older than 3 months, decreases in power occurred in the 5 to 20 Hz range before awakening occurred.4
Previous work by our group investigated age-varying EEG properties in 30 infants 0 to 6 months of age during sevoflurane anaesthesia.1 Frontal alpha EEG power is present during maintenance of surgical anaesthesia in infants older than 3 months of age, and decreases through emergence.1 Akeju et al.2 also reported similar findings in their study of 54 children and young adults during sevoflurane anaesthesia.
In the current study, and similar to the adult studies of EEG dynamics under general anaesthesia,19–21 we found that reductions in frontal alpha oscillatory power and increases in frontal beta oscillatory power occurred nearly coincident with clinical–behavioural signs of emergence in most infants older than 3 months of age (Figs. 5 and 6). In contrast to our work and the studies cited above, Lo et al.5 reported that global alpha power increased during emergence. The reasons for this discrepancy are not clear.
Our interpretation of the ROC models is that, overall, ETsevoflurane is a good predictor of the first body movement during emergence from sevoflurane anaesthesia in infants and young children. Future studies may clarify whether the addition of EEG indices such as the disappearance of frontal alpha oscillations or increase in beta oscillations may improve prediction compared with ETsevoflurane alone, especially for the subset of infants and children whose first movement occurs at above-average ETsevoflurane.
Age-related differences in the raw EEG have been shown in several studies of children receiving general anaesthesia, with respect to sevoflurane1,2 and more recently with propofol.31 Many clinically available perioperative brain monitors of anaesthetic depth, such as bispectral index, are based on algorithms derived from adult data and may not accurately represent brain state in the youngest paediatric patients.32 Children less than 3 months of age show different EEG signatures compared with older children, for example a lack of alpha oscillations, and these features cannot predict onset of emergence. Future studies that use systems-neuroscience-based strategies and incorporate features of brain development to accurately define anaesthetic depth are warranted in these young patients.
Anaesthetic management was given according to the discretion of the anaesthesiologist according to clinical need and consequently included combinations of anaesthetic agents and techniques. There was variability in the time course of the reduction in inspired sevoflurane concentration, in the flow rates and in the use of N2O during emergence. Our analysis stratified patients based on whether they received N2O exposure during emergence. Measuring anaesthesia recovery or recovery of consciousness in nonverbal populations is indirect in nature, and unlike adults, cannot be assessed using a response to a verbal command. Observation of clinical–behavioural signs is a useful alternative although scoring of video data is subjective. To overcome this pitfall, three cameras were time-locked and positioned in locations in the operating room to detect subtle body movement and facial expression from several camera angles. Eye signs assessments were intermittently evaluated when clinically permitted.
The current study characterised clinical–behavioural features of emergence from sevoflurane anaesthesia in children 0 to 3 years and correlated these features with continuous EEG spectra. Our results demonstrate that clinical–behavioural signs tend to occur sequentially with ETsevoflurane, and are independent of postnatal age and exposure to N2O. Eye gaze assessments are variable across a wide range of ETsevoflurane. Although current EEG indices provide information regarding maturation of information processing during anaesthesia in young children, the clinical use of paediatric brain monitors remains contentious.32 Further investigation is required before these, or other mathematically derived measures, can be recommended as a unitary clinical monitor of unconsciousness or an anaesthetic state in infants and children.
Acknowledgements relating to this article
Assistance with the study: we thank the Preoperative and Operating Room staff at BCH for their assistance, and the families who took part in these studies.
Financial support and sponsorship: this study was supported by the International Anesthesia Research Society (IARS) Mentored Research Award (LC); Harvard Medical School Scholars in Medicine Office and Harvard-MIT Division of Health Sciences & Technology (JML); University of California San Francisco Pathways Explore Grant (NEL); and the Sara Page Mayo Endowment for Pediatric Pain Research & Treatment (CBB). Research equipment was financed by the Boston Children's Hospital Anesthesia Research Trailblazer Award (LC & AB).
Conflicts of interest: none.
Presentation: preliminary data for this study were presented as a poster presentation at the SPA-AAP Paediatric Anaesthesiology conference, 1 to 3 April 2016.
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