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Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial
Brain Stimulation xxx (xxxx) xxx
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Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial Rohan Taylor a, b, c, d, *, Harry Wark a, e, g, h, John Leyden e, i, Brett Simpson a, e, f, Jenny McGoldrick e, Dusan Hadzi-Pavlovic a, b, Hank Ke Han e, Stevan Nikolin a, b, Donel Martin a, b, Colleen Loo a, b, e, f, j a
School of Psychiatry, University of New South Wales, Randwick, NSW, 2031, Australia Black Dog Institute, Hospital Road, Randwick, NSW, 2031, Australia c Concord Centre for Mental Health, Concord, NSW, 2137, Australia d Health Education & Training Institute, Gladesville, NSW, 2111, Australia e The Wesley Hospital, 7 Blake St, Kogarah, NSW, 2217, Australia f St. George Hospital, Gray St, Kogarah, NSW, 2217, Australia g The Sydney Clinic, 22-24 Murray St, Bronte, NSW, 2024, Australia h Children’s Hospital Westmead, Hawkesbury Road & Hainsworth Street, Westmead, NSW, 2145, Australia i Royal North Shore Hospital, Reserve Rd, St Leonards, NSW, 2065, Australia j Northside Group St Leonards Clinic, 2 Frederick St, St Leonards, NSW, 2065, Australia b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 6 August 2019 Received in revised form 14 November 2019 Accepted 15 December 2019 Available online xxx
Background: The anaesthetic approach adopted in ECT practice has the potential to influence patient outcomes. However, the impact of the time interval between anaesthetic induction and ECT stimulus administration has not been studied prospectively to date. This variable may represent an indirect measure of anaesthetic concentration at the time of stimulation, and therefore may influence the quality of seizures induced. Objective: To examine the impact of the anaesthetic to ECT stimulus time interval, and ventilation rate pre-treatment, on ictal seizure quality. Methods: In a prospective, crossover trial, 54 depressed participants were randomised to variations in anaesthetic technique at four sequential ECT treatment sessions, in a 2 x 2 design: randomisation to a short or long anaesthetic-ECT time interval, and randomisation to normal ventilation or hyperventilation during anaesthetic induction with thiopentone. Ictal EEG data were collected at each study session and assessed by a blinded rater for ictal quality (seizure amplitude, regularity, post-ictal suppression and general seizure quality), using a quantitative-qualitative structured rating scale. Linear mixed effects models were used to analyse the effect of the anaesthetic-ECT time interval, and that of ventilation rate, on seizure quality indices. Results: The anaesthetic-ECT time interval had a significant impact on ictal EEG quality indices (p < 0.01), with longer time intervals producing higher quality seizures. Ventilation rate did not significantly influence quality measures. Conclusion: The time between anaesthetic induction and ECT stimulus administration has a significant impact on ictal EEG seizure quality. Conversely, manipulations of ventilation rate did not significantly affect seizure quality. These results suggest the anaesthetic-ECT time interval should be routinely monitored clinically and potentially optimised for maximising seizure quality with ECT. © 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Electroconvulsive therapy Seizure Electroencephalogram Anaesthesia Thiopentone Time interval
* Corresponding author. School of Psychiatry, University of New South Wales, Randwick, NSW, 2031, Australia. E-mail address: [email protected] (R. Taylor). https://doi.org/10.1016/j.brs.2019.12.012 1935-861X/© 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ ).
Please cite this article as: Taylor R et al., Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.12.012
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Introduction ECT (Electroconvulsive Therapy) is a highly effective treatment for depression, with use often preferred when there is a rapid response required or in cases of treatment resistance [1,2]. ECT dosing is complex, due to competing priorities of efficacy and potential adverse cognitive effects of treatment [3]. ECT dosing should be considered in the context of anaesthetic technique, as commonly used induction agents have strong anticonvulsant properties, and anticonvulsant medications have been shown to affect seizure duration and treatment efficacy in ECT [4e6]. Research to date has primarily focused on the choice of anaesthetic agent and the absolute dose administered [7e9]. However, as unconsciousness is induced by bolus intravenous injection, it follows that plasma and brain anaesthetic levels will decline after an initial peak. Thus timing of the ECT stimulus delivery in relation to brain anaesthetic levels may be important in terms of minimising the anticonvulsant impact of anaesthesia on ECT efficacy. Recently, the time interval between anaesthetic induction and ECT stimulus administration (the anaesthetic-ECT time interval) has been studied due to its potential influence on seizure manifestation [10,11]. Galvez et al. demonstrated that longer anaesthetic-ECT time intervals produced higher quality seizures in a retrospective sample of 84 patients (771 ECT treatment sessions) receiving propofol anaesthesia [10]. This result was not replicated by Jorgensen et al. when thiopentone anaesthesia was utilised, though the authors noted the limited sample size (i.e. 22 patients, 73 ECT treatment sessions) may have led to a type II error (i.e. false negative finding) [12]. In a larger sample (42 patients, 413 ECT treatment sessions) in patients receiving thiopentone anaesthesia, Taylor et al. found longer anaesthetic-ECT time intervals produced higher quality seizures, consistent with the results of Galvez et al. [11]. However, limitations to these prior studies included the utilisation of retrospective designs which limited the ability to control for other aspects of anaesthetic technique. For example, these studies could not dissociate the effects of variation in the anaesthetic-ECT time interval and variation in ventilation rate; that is, while longer time intervals were associated with higher quality seizures, this may have been due to prolonged ventilation (and the resultant effects on end tidal CO2 levels) during these sessions. Indeed, there is some evidence to suggest that the ventilation approach alone may influence ictal seizure quality and other outcomes [13]. Hyperventilation pre-treatment has been associated with longer seizure duration, reduced need to increase charge across a course of ECT to maintain seizure duration, and a trend towards shorter time to orientation [14e16]. Notwithstanding, this research has also been limited by the retrospective design of studies and a failure to adequately control for the anaesthetic-ECT time interval, limiting interpretation of the effects of each respective factor. Current evidence suggesting the influence of the anaestheticECT time interval (on ictal seizure quality) is relevant to the clinical dosing decisions made during an ECT course. Clinical guidelines often recommend serial examination of the ictal EEG throughout an ECT course, in conjunction with monitoring of patient mood and cognition [17e19]. It is worth noting that there is significant interindividual variation in ictal EEG manifestation during ECT, as well as variation related to the type of ECT treatment administered [20e23]. Importantly, ictal seizure quality appears to deteriorate concurrent with increases in seizure threshold across a treatment course [24,25]. As such, serial ictal EEG examination may be used clinically to assist in identifying when a rise in seizure threshold has occurred and when dose adjustments may be considered. However, if the anaesthetic-ECT time interval significantly influences ictal seizure manifestation, and varies randomly between ECT sessions
in clinical services where the time interval is not noted, this may cast doubt on the reliability of dosing decisions based on seizure quality. Further, some studies have found an association between ictal seizure quality and therapeutic outcome, though the strength of this relationship has been questioned [23,26e29]. Given that clinical guidelines recommend serial monitoring of seizure quality, and that seizure quality may deteriorate with increases in seizure threshold across a course of treatment (thus indicating an increase in ECT dosage may be required), a thorough knowledge of factors impacting seizure manifestation is important. This study aimed to assess the influence of the anaesthetic-ECT time interval (time from anaesthetic induction to ECT stimulus delivery) and ventilation rate pre-stimulation on ECT seizure quality. We hypothesised that longer anaesthetic-ECT time intervals would result in higher quality seizures (amplitude, regularity, post-ictal suppression and general seizure quality) when controlling for pre-treatment ventilation rate. Secondary analyses examined for potential effects on seizure duration and recovery of orientation. Material and methods Sample & Study Design. Patients were recruited from Wesley Hospital Kogarah, Sydney, Australia, between March 15, 2017 and March 15, 2019. Patients were eligible if they were: prescribed an acute course of ECT by their treating psychiatrist, aged 18 or over, not receiving non-standard anaesthetic agents (e.g. ketamine or remifentanil), and able to give informed consent. An initial sample size of 72 was estimated, to allow for attrition prior to study completion and with N ¼ 50 calculated to provide sufficient power (>80%) to detect a main effect of the anaesthetic-ECT time interval on seizure quality. Required sample size was estimated using the data of Galvez (N ¼ 82)10. This is observational data so that neither the timing of ECT, the number of sessions which correspond to a short or long interval, nor the order of short/long intervals was controlled. In this study, timing was categorized as short (<2 min) or long ( 2 min). In addition to timing, session sequence (1st, 2nd, etc.) was added in to the models, and then age and charge were also added. Sample size was estimated for PIS and GSQ (transformed). To estimate power for a particular sample size (N) we took random samples of subjects of size N from the larger cohort, fitted a mixed effects model (random intercept for subjects, autoregressive correlation between sessions), and then calculated power; this was repeated 5000 times to obtain an average power. These analyses suggested that with 8 sessions, for the effect size observed in Galvez, that is, for the difference between the two time intervals, 80% power would require around 50 subjects, and 90% would be require around 70. The target sample size was set at N ¼ 72. Recruitment was ceased at N ¼ 54 as there was limited attrition throughout the study period, and randomisation was limited to 4 sessions only due to clinical concerns about potential compromised clinical effect with short time interval sessions. All participants provided informed consent prior to study enrolment. The study was approved by the University of New South Wales Human Research Ethics Committee. The study was registered with the ClinicalTrials. gov website (Identifier: NCT03105245). Randomisation & Masking. Over four consecutive ECT treatment sessions, in an intraindividual crossover, randomised design, participants received one each of four anaesthetic approaches. In a 2 x 2 design, the randomisation factors were time interval (short: 1.5 min; long: 2.5 min) and ventilation (normoventilation, hyperventilation). The order of the four anaesthetic approaches was determined using a computer-generated randomisation sequence. Participants were blind to the order of treatment approaches, as was the rater performing ictal seizure quality ratings. Clinicians
Please cite this article as: Taylor R et al., Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.12.012
R. Taylor et al. / Brain Stimulation xxx (xxxx) xxx
administering ECT (anaesthetist and psychiatrist) were not blind to treatment order, as necessitated by the study design. ECT & Anaesthetic procedures. Participants received the type of ECT clinically prescribed by their treating psychiatrist. As such, study patients received a variety of forms of ECT administered in the clinical service e these included right unilateral (RUL) 1.0 ms, RUL 0.3 ms, bitemporal (BT) 1.0 ms and bifrontal (BF) 1.0 ms. ECT was given using a Mecta device (MECTA Spectrum 5000Q, maximum output 1152 mC, Mecta Corp, Lake Oswego, OR). Anaesthesia given was thiopentone (2e4 mg/kg), with succinylcholine administered (0.5e1 mg/kg) for muscle relaxation. For all patients, thiopentone was administered over 4e6 s, in a standardised fashion. If additional thiopentone was administered (after initial bolus) prior to stimulation, due to clinical concerns over patient awareness, these sessions were excluded from analysis. The patient’s airway was managed with a facemask. End-tidal carbon dioxide (ETCO2) levels were sampled via a nasopharyngeal catheter (40 cm oxygen catheter, OC-7010, Pennine healthcare, Derby, UK), inserted after the patient was anaesthetised, and measured using a monitoring device (B40 Patient Monitor, GE Health, Shanghai). Seizure threshold was established by the titration method at the first treatment session. Subsequent treatment was delivered at 1.5 times seizure threshold (for BT & BF 1.0 ms treatments), 3e6 times seizure threshold (for RUL 1.0 ms treatments) and 6 times seizure threshold (for RUL 0.3 ms treatments), according to the service’s clinical dosing protocols. All participants were free of benzodiazepine use for at least 12 h prior to each ECT treatment session, as per the clinical service protocol. For all sessions, the anaesthetic-ECT time interval (in minutes and seconds) was measured from the commencement of thiopentone bolus administration to the start of the delivery of the ECT stimulus, in a standardised manner. ECT nursing staff recorded the anaesthetic-ECT time interval for each ECT treatment session, to the nearest second, using a stopwatch. This information was recorded in the clinical file by the treating psychiatrist for each session, consistent with the routine clinical practice in the ECT service. For sessions in which participants were randomised to a “short” anaesthetic-ECT time interval, the anaesthetist and psychiatrist aimed to ensure delivery of the ECT stimulus as close to 1 min and 30 s after anaesthetic administration as possible. For sessions requiring a “long” anaesthetic-ECT time interval, the anaesthetist and psychiatrist aimed to ensure delivery of the ECT stimulus as close to 2 min and 30 s after anaesthetic administration as possible. In all sessions, if there were concerns regarding the delivery of the stimulus at the time designated by the randomisation allocation, the clinical safety of the patient was deemed paramount and the ECT stimulus was only administered when this was clinically appropriate. For those sessions in which participants were randomised to receive a “normal” ventilation approach, the anaesthetist ventilated the patient at a rate of approximately 8e10 breaths per minute (from the cessation of spontaneous respiration until just prior to ECT stimulus administration). For those sessions requiring a “hyperventilation” approach, the anaesthetist ventilated the patient at a rate of approximately 25 breaths per minute. The end-tidal CO2 values were recorded for all sessions, immediately following the last breath administered by the anaesthetist (before ECT stimulus administration). The 10-Item Orientation Questionnaire score, assessed 30 min after ECT, was also recorded at every treatment session [30]. Scores of 0, indicating that the participant was too sedated to complete the assessment, were excluded from analysis. EEG Ratings e At each session, two channel EEG recordings were made (left and right fronto-mastoid), after recording sites had been cleaned with normal saline. For all treatments the gain setting
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remained at 0.02 mV/mm. EEG data recorded from the Mecta device was converted into PDF format for blinded ratings. Using the procedures described in Taylor et al. [11], seizure quality indices (peak mid-ictal amplitude (mm), regularity (0e6 scale), post-ictal suppression (0e3 scale), and general seizure quality (1e5 scale)) were rated utilising a quantitative-qualitative scale [10,31]. Of these indices, post ictal suppression was utilised for power analysis, on the basis of research findings indicating its clinical significance, and GSQ was included as an overall measure of ictal quality that can be easily used by clinicians [21,27,28,32]. Seizure duration was also recorded for each session. All seizure quality ratings were performed by a single trained rater, an experienced ECT psychiatrist (RT); good inter-rater reliability had previously been established with a second trained rater in a retrospective sample [11]. All ratings were performed blind to the anaesthetic-ECT time interval and ventilation data, as well as other ECT and clinical data. Data & Statistical Analysis. All statistical analyses were conducted using SPSS software (IBM SPSS Statistics 25 for Windows; SPSS Inc.). Data collected included: the anaesthetic-ECT time interval (sec), end-tidal CO2 (mmHg), ECT electrode placement (RUL/ BT/BF) and pulse width (ms), ECT stimulus charge (mC), initial seizure threshold (mC), ECT treatment number, motor seizure duration, EEG seizure duration, concurrent medication use during ECT [antidepressants (yes/no), lamotrigine (yes/no), lithium (yes/ no) and antipsychotics (yes/no)], and recovery of orientation score post-treatment (0-10). The effect of the anaesthetic-ECT time interval, and ventilation rate, on seizure quality indices was analysed through the use of Linear mixed effects models, with subject as a random effect (covariance structure AR1). For each dependent variable (amplitude, regularity, postictal suppression, and general seizure quality) a separate mixed effect model was produced, controlling for variables that could potentially affect seizure expression: anaesthesia dose (thiopentone mg), ECT treatment number, age (years) and ECT type (electrode placement and pulse width). ECT charge (mC), initial seizure threshold (mC) and concurrent medication [antidepressants (yes/no), lamotrigine (yes/no), lithium (yes/no) and antipsychotics (yes/no)] were considered but not included in the final models, as they did not significantly improve the performance of the models. Separate mixed effects models were also run for seizure duration and for recovery of orientation score, using the same covariates. Primary analyses were conducted in the intentionto-treat sample, with anaesthetic-ECT time interval and ventilation rate as dichotomous variables. Secondary analyses repeated the primary analyses using continuous data for the actual anaestheticECT time interval (seconds) and end-tidal CO2 (mmHg) achieved at each session. Statistical tests were two-tailed and significance was set at p < 0.05 For the primary outcome (ictal seizure quality) the significance level was adjusted to 0.0125 to correct for multiple testing for each of the four ictal quality measures. Results Table 1 displays the basic demographic and clinical data for the sample. A total of 211 ECT sessions from 54 participants were available for analysis (see Fig. 1). Two sessions were subsequently omitted from the analysis as additional thiopentone was administered prior to ECT stimulus administration (due to clinical concerns regarding potential patient awareness) leaving 209 total sessions. The anaesthetic-ECT time interval had a significant impact on ictal seizure quality, with longer time intervals producing higher quality seizures on all measures (amplitude, postictal suppression, regularity and general seizure quality e see Table 2; p < 0.01). Ventilation approach did not significantly influence ictal seizure
Please cite this article as: Taylor R et al., Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.12.012
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R. Taylor et al. / Brain Stimulation xxx (xxxx) xxx
Table 1 Demographic & clinical data. Age, years (mean, SD)
49.8 (16.0)
Gender (no. female, %)
35/54 (64.8%)
Diagnosis (no., %) MDE, unipolar MDE, bipolar I MDE, bipolar II MDE, schizoaffective
35/54 (64.8%) 6/54 (11.1%) 10/54 (18.5%) 3/54 (5.6%)
Concurrent medications (no., %) Antidepressants Antipsychotics Lithium Lamotrigine
45/54 (83.3%) 38/54 (70.4%) 14/54 (25.9%) 8/54 (14.8%)
ECT type (no., %) RUL 1.0 ms RUL 0.3 ms BT 1.0 ms BF 1.0 ms
135/211 (64.0%) 58/211 (27.5%) 6/211 (2.8%) 12/211 (5.7%)
Charge, mC (mean, SD)
306.4 (164.2)
Initial ST, mC (mean, SD)
72.1 (51.7)
Thiopentone dose, mg (mean, SD)
275.0 (36.1)
Succinylcholine dose, mg (mean, SD)
71.0 (11.6)
Anaesthetic-ECT time interval, sec (mean, SD) - short time interval sessions - long time interval sessions
128.6 (30.5) 99.7 (10.1) 157.3 (9.7)
End-tidal CO2, mmHg (mean, SD) - normal ventilation rate sessions - hyperventilation rate sessions
29.8 (9.0) 35.6 (7.1) 24.2 (6.9)
quality for any of the quality indices used in this study. Consistent with prior research, patient age also significantly influenced seizure quality for all indices (amplitude, regularity, postictal suppression and general seizure quality), with older age associated with lower quality seizures (p < 0.01)10,23,32. Thiopentone dose and ECT type did not significantly influence seizure quality. The anaesthetic-ECT time interval also had a significant effect on seizure duration, with longer time intervals being associated with longer seizures (p < 0.01). No other variables had a significant influence on seizure duration. Similarly, none of the variables studied had a significant effect on recovery of orientation scores posttreatment. Results from the secondary analyses (using continuous data for the actual anaesthetic-ECT time interval (seconds) and end-tidal CO2 (mmHg) achieved at each session) were similar to the primary analyses (see Table 3). That is, the anaesthetic-ECT time interval had a significant impact on all ictal quality measures (amplitude, postictal suppression, regularity and general seizure quality; p < 0.01) and also seizure duration (longer time intervals producing higher quality seizures and longer seizures; p < 0.01). Age had a significant effect on all ictal quality measures (p < 0.01), while end tidal CO2 (mmHg) and ECT type did not have a significant effect on any quality measures. Thiopentone dose had a significant effect on seizure amplitude (higher doses associated with lower amplitude), though the magnitude of this effect was small. The distribution of end tidal CO2 (mmHg) and anaesthetic-ECT time interval (sec) values achieved is shown in Fig. 2.
Discussion This prospective randomised trial provides the most compelling and definitive evidence yet for the impact of the anaesthetic-ECT time interval on ictal seizure quality. Consistent with results from
previous retrospective studies with large samples, the anaestheticECT time interval had a significant impact on ictal seizure quality, with longer times leading to higher quality seizures. This effect appears to be due to lengthening the time interval itself (and the diminished anticonvulsant properties at the time of stimulus), rather than the specific ventilation approach used during the time between anaesthetic induction and ECT stimulus administration. That is, there was no significant difference between normal ventilation and hyperventilation approaches for seizure quality, independent of the effect of the time interval. In terms of clinical implications, these results argue strongly for the routine clinical measurement and recording of the anaestheticECT time interval. Given the ease with which this variable is measured, and the strength of the impact observed on seizure quality, this can be easily incorporated into standard practice for any ECT service. Importantly, without monitoring this variable there is a risk that changes in ictal quality observed between sessions may erroneously be thought due to changes in seizure threshold. As previously suggested, this could lead to unnecessary dose increases during an ECT course, when in fact there may have just been different anaesthetic-ECT time intervals between sessions [10]. Importantly, the anaesthetic-ECT time interval and absolute dose of anaesthetic utilised are likely inextricably linked. Therefore, in clinical practice, it will be important to monitor and control both of these variables, as they cannot be considered in isolation. The tolerability of longer time intervals, with the target long time interval chosen in this study (ECT stimulus delivery aimed at 2 min and 30 s from the administration of thiopentone), was good e additional administration of anaesthetic was only required on two occasions due to clinical concerns of potential awareness. Extending the time interval beyond this limit may alter the risk-benefit ratio, as excessively long anaesthetic-ECT time intervals will necessarily increase the risks of patient awareness and inadequate muscle relaxation e the anaesthetic agent used, absolute anaesthetic dose administered, and individual patient pharmacokinetics, will also influence the point at which this occurs. As such, the preferred time interval (to optimise ictal quality) will necessarily be contingent upon a combination of these factors. While the manner of recording ETCO2 was imperfect, the hyperventilation and normal ventilation approaches were applied accurately as required by the study design. Measurement of ETCO2 via nasal catheter was selected as a practical and relatively noninvasive approach. While some prior studies have suggested hyperventilation may influence seizure duration and orientation scores, we did not observe any significant effects of ventilation rate on these variables or the primary outcome measures (of seizure quality). As previously mentioned, prior studies in this area have been limited by small sample sizes, heterogeneity in ventilation techniques (and measurement approaches), and heterogeneity in ECT and anaesthetic factors [33]. Further, the anaesthetic-ECT time interval has generally not been considered in such studies, and may play a role in explaining the results previously observed. This concern may also be raised for previous studies examining the influence of a variety of different variables on ictal seizure quality. Consistent with previous studies examining ictal seizure quality, age had a significant effect for all quality measures examined, with older age being associated with generally poorer quality seizures [10,23,32]. Comparatively, anaesthetic dose (mg) and ECT type did not significantly influence ictal seizure quality. This result is not unexpected for anaesthetic dose, which is tailored for individual patients by weight and other factors, and for which there was very little variation in dosing between the four treatment sessions for each patient. With respect to the influence of ECT type, our sample included only a very small number of sessions with bitemporal or bifrontal treatments (minimising the potential to adequately
Please cite this article as: Taylor R et al., Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.12.012
R. Taylor et al. / Brain Stimulation xxx (xxxx) xxx
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Fig. 1. Participant Flow Diagram. * Note 2 sessions not analysed due to administration of additional anaesthetic (thiopentone) prior to stimulation.
Table 2 Primary intention to treat analysis e mixed effects models examining impact of treatment and patient factors on ictal seizure quality. Covariate/Dependent
Amplitude (mm) Est
Anaesthetic-ECT time interval (Short/Long) Ventilation approach (Norm/Hyper) Age (years) Thiopentone (mg) ECT type - BT brief - BF brief - RUL ultra-brief - RUL brief
SE
p
Post-ictal suppression (0e3)
Regularity (0e6)
Est
Est
SE
p
SE
GSQ (1e5) p
Est
SE
Duration (sec) p
Est
SE
Orientation score (010) p
Est
SE
p
2.214 0.478 0.000 0.316 0.075 0.000 0.274 0.072 0.000 0.327 0.072 0.000 7.923 1.543
0.000 0.214
0.219 0.330
0.301
0.479 0.530 0.135
1.550
0.371 0.364
0.222 0.103
0.237 0.025 e 5.018 0.463 2.818 e
0.034 0.013 e 3.819 2.217 1.156 e
0.132 0.047 e 15.038 8.731 4.554 e
0.398 0.192 0.104 0.267 0.860 0.025 e
0.000 0.054 0.082 0.196 0.836 0.019 e
0.023 0.000 e 0.325 0.109 0.277 e
0.075 0.072 0.062 0.005 0.002 e 0.553 0.321 0.168 e
0.000 0.793 0.359 0.560 0.737 0.106 e
0.027 0.000 e 0.671 0.034 0.157 e
0.072 0.385 0.066 0.005 0.002 e 0.524 0.304 0.159 e
0.000 0.954 0.485 0.207 0.913 0.326 e
0.030 0.001 e 0.128 0.041 0.052 e
0.072 0.354 1.393 0.004 0.001 e 0.465 0.270 0.141 e
0.000 0.438 0.964 0.784 0.879 0.713 e
0.113 0.061 e 16.940 1.551 10.629 e
0.035 0.002 e 2.764 1.250 0.023 e
0.019 0.007 e 2.142 1.239 0.651 e
0.077 0.734 0.433 0.204 0.319 0.972 e
Est (estimate); SE (standard error); GSQ (general seizure quality); ECT (electroconvulsive therapy); BT (bitemporal); BF (bifrontal); RUL (right unilateral); mm (millimetres); sec (seconds); mg (milligrams). * Note: for ECT type, RUL brief used as reference type.
Please cite this article as: Taylor R et al., Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.12.012
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R. Taylor et al. / Brain Stimulation xxx (xxxx) xxx
Table 3 Secondary analysis e mixed effects models examining impact of treatment and patient factors on ictal seizure quality. Covariate/Dependent
Anaesthetic-ECT time interval (min) ETCO2 (mmHg) Age (years) Thiopentone (mg) ECT type - BT brief - BF brief - RUL ultrabrief - RUL brief
Amplitude (mm) p
Post-ictal suppression (0e3)
Regularity (0e6)
Est
Est
Est
SE
2.094
0.480 0.000 0.266
0.081 0.001 0.242
0.075 0.002 0.278
0.053 0.234 0.026 e 4.973 0.537 3.026 e
0.032 0.034 0.013 e 3.838 2.235 1.176 e
0.005 0.005 0.002 e 0.568 0.331 0.175 e
0.005 0.005 0.002 e 0.534 0.311 0.164 e
0.100 0.000 0.046 0.066 0.202 0.811 0.014 e
0.005 0.022 0.000 e 0.350 0.110 0.287 e
SE
p
0.315 0.000 0.958 0.358 0.541 0.742 0.108 e
0.007 0.027 0.000 e 0.660 0.055 0.153 e
SE
GSQ (1e5) p
Est
0.193 0.000 0.908 0.516 0.224 0.859 0.357 e
0.008 0.030 0.001 e 0.110 0.034 0.049 e
SE
Duration (sec) p
SE
p
0.076 0.000 7.918
1.554
0.000 0.101 0.238 0.673
0.005 0.004 0.002 e 0.471 0.274 0.145 e
0.104 0.131 0.046 e 14.527 8.463 4.463 e
0.979 0.364 0.072 0.056 0.217 0.945 0.011 e
0.099 0.000 0.466 0.975 0.816 0.903 0.738 e
Est
Orientation score (010)
0.003 0.120 0.084 e 18.264 0.588 11.906 e
Est
0.011 0.035 0.004 e 2.667 1.132 0.001 e
SE
0.016 0.021 0.007 e 2.232 1.293 0.684 e
p
0.507 0.093 0.543 0.522 0.239 0.387 0.998 e
Est (estimate); SE (standard error); GSQ (general seizure quality); ECT (electroconvulsive therapy); mm (millimetres); sec (seconds); min (minutes); ETCO2 (end tidal CO2); mmHg (millimetres of mercury); mg (milligrams); BT (bitemporal); BF (bifrontal); RUL (right unilateral). * Note: for ECT type, RUL brief used as reference type.
Fig. 2. End tidal CO2 values (mmHg) by ventilation approach and time interval (secs).
investigate the difference between bilateral and unilateral montages). Post ECT Orientation scores were also examined to see if the anaesthetic-ECT time interval or ventilation approach had any effect on post ECT recovery of orientation, given this has been shown to predict retrograde amnesia following ECT [26,34]. No effects were found for either variable, suggesting that any effects, if present, were not marked. Alternatively, it is possible that the post ECT orientation measure used was not sufficiently sensitive to capture differences, or that there are effects on other cognitive domains not examined in this study. One limitation of the current study is the inability to draw clear conclusions regarding the effect of the anaesthetic-ECT time interval on overall clinical outcome in this cohort (in terms of reduction of depressive symptoms). Due to the study design, where each patient acted as their own control and received all four combinations of the intervention (that is, long and short time interval and normoventilation and hyperventilation), we could not assess whether prolonging the time interval over an entire ECT course improves mood or cognitive outcomes. This may be an area for further study, though such a design may potentially put patients at risk of receiving lower efficacy treatment (if randomised to an entire course of shorter time interval treatments). One alternative may be to randomise patients to a course of longer anaesthetic-ECT time intervals or a course with treatment as usual (i.e. clinician determined time interval). Despite this, these findings enhance ECT practitioner knowledge about factors influencing the ictal EEG (and thereby may improve dosing decisions made while considering ictal EEG changes). As previously mentioned, the optimal or preferred anaesthetic-ECT time interval is likely to vary between individuals, and will also be influenced by the anaesthetic agent
used and absolute anaesthetic dose administered. Additionally, the use of thiopentone as the primary anaesthetic agent in this study raises the question of the generalisability of results observed. Prior retrospective findings with propofol in this regard support the importance of the anaesthetic-ECT time interval, though alternative agents with different pharmacological profiles may yield different results [10]. Finally, RUL ECT comprised >90% of treatment sessions analysed in this study, with minimal BF and BT treatments available for analysis. Strengths of the study include the prospective twofactor design, with randomisation of both time interval and ventilation rate, and evaluation of potential confounding factors, which were included in the analysis models. In conclusion, this trial is the first prospective randomised study to examine the influence of the anaesthetic-ECT time interval and ventilation approach on ictal seizure quality. Longer anaestheticECT time intervals were found to produce higher quality seizures for all quality measures examined, while ventilation rate pretreatment showed no significant effect on ictal seizure quality. These results support the routine measurement and recording of the anaesthetic-ECT time interval in clinical practice and suggest the possibility of optimisation on an individual patient basis. Author contributions R.T. prepared the manuscript for publication, coordinated the study & data collection, and contributed to the study design & analysis. H.W, J.L, B.S, J.M and H.K contributed to the data collection & study design. D.H. contributed to the statistical analysis & study design. S.N contributed to the statistical analysis & preparation of figures. C.L and D.M contributed to the study design & analysis. All authors revised and approved the final manuscript. Declaration of competing interest None. Acknowledgements Dr Taylor was supported by a fellowship from the Health Education & Training Institute, NSW, Australia. Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.jretconser.2019.102002.
Please cite this article as: Taylor R et al., Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.12.012
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[18] Coffey CE, Fochtmann LJ, Greenberg RM, et al. The practice of electroconvulsive therapy: recommendations for treatment, training, and privileging: a task force report of the American Psychiatric Association. second ed. Washington DC: American Psychiatric Association; 2001. [19] Weiss A, Hussain S, Ng B, et al. Royal Australian and New Zealand College of Psychiatrists professional practice guidelines for the administration of electroconvulsive therapy. Aust N Z J Psychiatr 2019;53(7):609e23. [20] Krystal AD, Weiner RD, McCall WV, Shelp FE, Arias R, Smith P. The effects of ECT stimulus dose and electrode placement on the ictal electroencephalogram: an intraindividual crossover study. Biol Psychiatry 1993;34(11): 759e67. [21] Nobler MS, Sackeim HA, Solomou M, Luber B, Devanand DP, Prudic J. EEG manifestations during ECT: effects of electrode placement and stimulus intensity. Biol Psychiatry 1993;34(5):321e30. [22] Nobler MS, Luber B, Moeller JR, et al. Quantitative EEG during seizures induced by electroconvulsive therapy: relations to treatment modality and clinical features. I. global analyses. J ECT 2000;16(3):211e28. [23] Perera TD, Luber B, Nobler MS, Prudic J, Anderson C, Sackeim HA. Seizure expression during electroconvulsive therapy: relationships with clinical outcome and cognitive side effects. Neuropsychopharmacology 2004;29(4): 813e25. [24] Krystal AD, Coffey CE, Weiner RD, Holsinger T. Changes in seizure threshold over the course of electroconvulsive therapy affect therapeutic response and are detected by ictal EEG ratings. J Neuropsychiatry Clin Neurosci 1998;10(2): 178e86. [25] Galvez V, Hadzi-Pavlovic D, Waite S, Loo CK. Seizure threshold increases can be predicted by EEG quality in right unilateral ultrabrief ECT. Eur Arch Psychiatry Clin Neurosci 2017;267(8):795e801. [26] Folkerts H. The ictal electroencephalogram as a marker for the efficacy of electroconvulsive therapy. Eur Arch Psychiatry Clin Neurosci 1996;246: 155e64. [27] Suppes T, Webb A, Carmody T, et al. Is postictal electrical silence a predictor of response to electroconvulsive therapy? J Affect Disord 1996;41:55e8. [28] Krystal AD, Holsinger T, Weiner RD, Coffey CE. Prediction of the utility of a switch from unilateral to bilateral ECT in the elderly using treatment 2 ictal EEG indices. J ECT 2000;16(4):327e37. [29] Minelli A, Abate M, Zampieri E, et al. Seizure adequacy markers and the prediction of electroconvulsive therapy response. J ECT 2016;32(2):88e92. lvez V, Loo CK. Predicting retrograde autobiographical memory [30] Martin DM, Ga changes following electroconvulsive therapy: relationships between individual, treatment, and early clinical factors. Int J Neuropsychopharmacol 2015;18(12):1e8. [31] MacPherson RD, Lawford J, Simpson B, Mahon M, Scott D, Loo C. Low dose lignocaine added to propofol does not attenuate the response to electroconvulsive therapy. J Affect Disord 2010;126(1e2):330e3. [32] Krystal AD, Weiner RD, Coffey CE. The ictal EEG as a marker of adequate stimulus intensity with unilateral ECT. J Neuropsychiatry Clin Neurosci 1995;7:295e303. [33] Gomez-Arnau J, Arriba-Arnau A, Correas-Lauffer J, Urretavizcaya M. Hyperventilation and electroconvulsive therapy: a literature review. Gen Hosp Psychiatry 2018;50:54e62. [34] Sobin C, Sackeim HA, Prudic J, Devanand DP, Moody BJ, McElhiney MC. Predictors of retrograde amnesia following ECT. Am J Psychiatry 1995;152(7): 995e1001.
Please cite this article as: Taylor R et al., Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.12.012
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Brain Stimulation journal homepage: http://www.journals.elsevier.com/brain-stimulation
Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial Rohan Taylor a, b, c, d, *, Harry Wark a, e, g, h, John Leyden e, i, Brett Simpson a, e, f, Jenny McGoldrick e, Dusan Hadzi-Pavlovic a, b, Hank Ke Han e, Stevan Nikolin a, b, Donel Martin a, b, Colleen Loo a, b, e, f, j a
School of Psychiatry, University of New South Wales, Randwick, NSW, 2031, Australia Black Dog Institute, Hospital Road, Randwick, NSW, 2031, Australia c Concord Centre for Mental Health, Concord, NSW, 2137, Australia d Health Education & Training Institute, Gladesville, NSW, 2111, Australia e The Wesley Hospital, 7 Blake St, Kogarah, NSW, 2217, Australia f St. George Hospital, Gray St, Kogarah, NSW, 2217, Australia g The Sydney Clinic, 22-24 Murray St, Bronte, NSW, 2024, Australia h Children’s Hospital Westmead, Hawkesbury Road & Hainsworth Street, Westmead, NSW, 2145, Australia i Royal North Shore Hospital, Reserve Rd, St Leonards, NSW, 2065, Australia j Northside Group St Leonards Clinic, 2 Frederick St, St Leonards, NSW, 2065, Australia b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 6 August 2019 Received in revised form 14 November 2019 Accepted 15 December 2019 Available online xxx
Background: The anaesthetic approach adopted in ECT practice has the potential to influence patient outcomes. However, the impact of the time interval between anaesthetic induction and ECT stimulus administration has not been studied prospectively to date. This variable may represent an indirect measure of anaesthetic concentration at the time of stimulation, and therefore may influence the quality of seizures induced. Objective: To examine the impact of the anaesthetic to ECT stimulus time interval, and ventilation rate pre-treatment, on ictal seizure quality. Methods: In a prospective, crossover trial, 54 depressed participants were randomised to variations in anaesthetic technique at four sequential ECT treatment sessions, in a 2 x 2 design: randomisation to a short or long anaesthetic-ECT time interval, and randomisation to normal ventilation or hyperventilation during anaesthetic induction with thiopentone. Ictal EEG data were collected at each study session and assessed by a blinded rater for ictal quality (seizure amplitude, regularity, post-ictal suppression and general seizure quality), using a quantitative-qualitative structured rating scale. Linear mixed effects models were used to analyse the effect of the anaesthetic-ECT time interval, and that of ventilation rate, on seizure quality indices. Results: The anaesthetic-ECT time interval had a significant impact on ictal EEG quality indices (p < 0.01), with longer time intervals producing higher quality seizures. Ventilation rate did not significantly influence quality measures. Conclusion: The time between anaesthetic induction and ECT stimulus administration has a significant impact on ictal EEG seizure quality. Conversely, manipulations of ventilation rate did not significantly affect seizure quality. These results suggest the anaesthetic-ECT time interval should be routinely monitored clinically and potentially optimised for maximising seizure quality with ECT. © 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Electroconvulsive therapy Seizure Electroencephalogram Anaesthesia Thiopentone Time interval
* Corresponding author. School of Psychiatry, University of New South Wales, Randwick, NSW, 2031, Australia. E-mail address: [email protected] (R. Taylor). https://doi.org/10.1016/j.brs.2019.12.012 1935-861X/© 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ ).
Please cite this article as: Taylor R et al., Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.12.012
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Introduction ECT (Electroconvulsive Therapy) is a highly effective treatment for depression, with use often preferred when there is a rapid response required or in cases of treatment resistance [1,2]. ECT dosing is complex, due to competing priorities of efficacy and potential adverse cognitive effects of treatment [3]. ECT dosing should be considered in the context of anaesthetic technique, as commonly used induction agents have strong anticonvulsant properties, and anticonvulsant medications have been shown to affect seizure duration and treatment efficacy in ECT [4e6]. Research to date has primarily focused on the choice of anaesthetic agent and the absolute dose administered [7e9]. However, as unconsciousness is induced by bolus intravenous injection, it follows that plasma and brain anaesthetic levels will decline after an initial peak. Thus timing of the ECT stimulus delivery in relation to brain anaesthetic levels may be important in terms of minimising the anticonvulsant impact of anaesthesia on ECT efficacy. Recently, the time interval between anaesthetic induction and ECT stimulus administration (the anaesthetic-ECT time interval) has been studied due to its potential influence on seizure manifestation [10,11]. Galvez et al. demonstrated that longer anaesthetic-ECT time intervals produced higher quality seizures in a retrospective sample of 84 patients (771 ECT treatment sessions) receiving propofol anaesthesia [10]. This result was not replicated by Jorgensen et al. when thiopentone anaesthesia was utilised, though the authors noted the limited sample size (i.e. 22 patients, 73 ECT treatment sessions) may have led to a type II error (i.e. false negative finding) [12]. In a larger sample (42 patients, 413 ECT treatment sessions) in patients receiving thiopentone anaesthesia, Taylor et al. found longer anaesthetic-ECT time intervals produced higher quality seizures, consistent with the results of Galvez et al. [11]. However, limitations to these prior studies included the utilisation of retrospective designs which limited the ability to control for other aspects of anaesthetic technique. For example, these studies could not dissociate the effects of variation in the anaesthetic-ECT time interval and variation in ventilation rate; that is, while longer time intervals were associated with higher quality seizures, this may have been due to prolonged ventilation (and the resultant effects on end tidal CO2 levels) during these sessions. Indeed, there is some evidence to suggest that the ventilation approach alone may influence ictal seizure quality and other outcomes [13]. Hyperventilation pre-treatment has been associated with longer seizure duration, reduced need to increase charge across a course of ECT to maintain seizure duration, and a trend towards shorter time to orientation [14e16]. Notwithstanding, this research has also been limited by the retrospective design of studies and a failure to adequately control for the anaesthetic-ECT time interval, limiting interpretation of the effects of each respective factor. Current evidence suggesting the influence of the anaestheticECT time interval (on ictal seizure quality) is relevant to the clinical dosing decisions made during an ECT course. Clinical guidelines often recommend serial examination of the ictal EEG throughout an ECT course, in conjunction with monitoring of patient mood and cognition [17e19]. It is worth noting that there is significant interindividual variation in ictal EEG manifestation during ECT, as well as variation related to the type of ECT treatment administered [20e23]. Importantly, ictal seizure quality appears to deteriorate concurrent with increases in seizure threshold across a treatment course [24,25]. As such, serial ictal EEG examination may be used clinically to assist in identifying when a rise in seizure threshold has occurred and when dose adjustments may be considered. However, if the anaesthetic-ECT time interval significantly influences ictal seizure manifestation, and varies randomly between ECT sessions
in clinical services where the time interval is not noted, this may cast doubt on the reliability of dosing decisions based on seizure quality. Further, some studies have found an association between ictal seizure quality and therapeutic outcome, though the strength of this relationship has been questioned [23,26e29]. Given that clinical guidelines recommend serial monitoring of seizure quality, and that seizure quality may deteriorate with increases in seizure threshold across a course of treatment (thus indicating an increase in ECT dosage may be required), a thorough knowledge of factors impacting seizure manifestation is important. This study aimed to assess the influence of the anaesthetic-ECT time interval (time from anaesthetic induction to ECT stimulus delivery) and ventilation rate pre-stimulation on ECT seizure quality. We hypothesised that longer anaesthetic-ECT time intervals would result in higher quality seizures (amplitude, regularity, post-ictal suppression and general seizure quality) when controlling for pre-treatment ventilation rate. Secondary analyses examined for potential effects on seizure duration and recovery of orientation. Material and methods Sample & Study Design. Patients were recruited from Wesley Hospital Kogarah, Sydney, Australia, between March 15, 2017 and March 15, 2019. Patients were eligible if they were: prescribed an acute course of ECT by their treating psychiatrist, aged 18 or over, not receiving non-standard anaesthetic agents (e.g. ketamine or remifentanil), and able to give informed consent. An initial sample size of 72 was estimated, to allow for attrition prior to study completion and with N ¼ 50 calculated to provide sufficient power (>80%) to detect a main effect of the anaesthetic-ECT time interval on seizure quality. Required sample size was estimated using the data of Galvez (N ¼ 82)10. This is observational data so that neither the timing of ECT, the number of sessions which correspond to a short or long interval, nor the order of short/long intervals was controlled. In this study, timing was categorized as short (<2 min) or long ( 2 min). In addition to timing, session sequence (1st, 2nd, etc.) was added in to the models, and then age and charge were also added. Sample size was estimated for PIS and GSQ (transformed). To estimate power for a particular sample size (N) we took random samples of subjects of size N from the larger cohort, fitted a mixed effects model (random intercept for subjects, autoregressive correlation between sessions), and then calculated power; this was repeated 5000 times to obtain an average power. These analyses suggested that with 8 sessions, for the effect size observed in Galvez, that is, for the difference between the two time intervals, 80% power would require around 50 subjects, and 90% would be require around 70. The target sample size was set at N ¼ 72. Recruitment was ceased at N ¼ 54 as there was limited attrition throughout the study period, and randomisation was limited to 4 sessions only due to clinical concerns about potential compromised clinical effect with short time interval sessions. All participants provided informed consent prior to study enrolment. The study was approved by the University of New South Wales Human Research Ethics Committee. The study was registered with the ClinicalTrials. gov website (Identifier: NCT03105245). Randomisation & Masking. Over four consecutive ECT treatment sessions, in an intraindividual crossover, randomised design, participants received one each of four anaesthetic approaches. In a 2 x 2 design, the randomisation factors were time interval (short: 1.5 min; long: 2.5 min) and ventilation (normoventilation, hyperventilation). The order of the four anaesthetic approaches was determined using a computer-generated randomisation sequence. Participants were blind to the order of treatment approaches, as was the rater performing ictal seizure quality ratings. Clinicians
Please cite this article as: Taylor R et al., Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.12.012
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administering ECT (anaesthetist and psychiatrist) were not blind to treatment order, as necessitated by the study design. ECT & Anaesthetic procedures. Participants received the type of ECT clinically prescribed by their treating psychiatrist. As such, study patients received a variety of forms of ECT administered in the clinical service e these included right unilateral (RUL) 1.0 ms, RUL 0.3 ms, bitemporal (BT) 1.0 ms and bifrontal (BF) 1.0 ms. ECT was given using a Mecta device (MECTA Spectrum 5000Q, maximum output 1152 mC, Mecta Corp, Lake Oswego, OR). Anaesthesia given was thiopentone (2e4 mg/kg), with succinylcholine administered (0.5e1 mg/kg) for muscle relaxation. For all patients, thiopentone was administered over 4e6 s, in a standardised fashion. If additional thiopentone was administered (after initial bolus) prior to stimulation, due to clinical concerns over patient awareness, these sessions were excluded from analysis. The patient’s airway was managed with a facemask. End-tidal carbon dioxide (ETCO2) levels were sampled via a nasopharyngeal catheter (40 cm oxygen catheter, OC-7010, Pennine healthcare, Derby, UK), inserted after the patient was anaesthetised, and measured using a monitoring device (B40 Patient Monitor, GE Health, Shanghai). Seizure threshold was established by the titration method at the first treatment session. Subsequent treatment was delivered at 1.5 times seizure threshold (for BT & BF 1.0 ms treatments), 3e6 times seizure threshold (for RUL 1.0 ms treatments) and 6 times seizure threshold (for RUL 0.3 ms treatments), according to the service’s clinical dosing protocols. All participants were free of benzodiazepine use for at least 12 h prior to each ECT treatment session, as per the clinical service protocol. For all sessions, the anaesthetic-ECT time interval (in minutes and seconds) was measured from the commencement of thiopentone bolus administration to the start of the delivery of the ECT stimulus, in a standardised manner. ECT nursing staff recorded the anaesthetic-ECT time interval for each ECT treatment session, to the nearest second, using a stopwatch. This information was recorded in the clinical file by the treating psychiatrist for each session, consistent with the routine clinical practice in the ECT service. For sessions in which participants were randomised to a “short” anaesthetic-ECT time interval, the anaesthetist and psychiatrist aimed to ensure delivery of the ECT stimulus as close to 1 min and 30 s after anaesthetic administration as possible. For sessions requiring a “long” anaesthetic-ECT time interval, the anaesthetist and psychiatrist aimed to ensure delivery of the ECT stimulus as close to 2 min and 30 s after anaesthetic administration as possible. In all sessions, if there were concerns regarding the delivery of the stimulus at the time designated by the randomisation allocation, the clinical safety of the patient was deemed paramount and the ECT stimulus was only administered when this was clinically appropriate. For those sessions in which participants were randomised to receive a “normal” ventilation approach, the anaesthetist ventilated the patient at a rate of approximately 8e10 breaths per minute (from the cessation of spontaneous respiration until just prior to ECT stimulus administration). For those sessions requiring a “hyperventilation” approach, the anaesthetist ventilated the patient at a rate of approximately 25 breaths per minute. The end-tidal CO2 values were recorded for all sessions, immediately following the last breath administered by the anaesthetist (before ECT stimulus administration). The 10-Item Orientation Questionnaire score, assessed 30 min after ECT, was also recorded at every treatment session [30]. Scores of 0, indicating that the participant was too sedated to complete the assessment, were excluded from analysis. EEG Ratings e At each session, two channel EEG recordings were made (left and right fronto-mastoid), after recording sites had been cleaned with normal saline. For all treatments the gain setting
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remained at 0.02 mV/mm. EEG data recorded from the Mecta device was converted into PDF format for blinded ratings. Using the procedures described in Taylor et al. [11], seizure quality indices (peak mid-ictal amplitude (mm), regularity (0e6 scale), post-ictal suppression (0e3 scale), and general seizure quality (1e5 scale)) were rated utilising a quantitative-qualitative scale [10,31]. Of these indices, post ictal suppression was utilised for power analysis, on the basis of research findings indicating its clinical significance, and GSQ was included as an overall measure of ictal quality that can be easily used by clinicians [21,27,28,32]. Seizure duration was also recorded for each session. All seizure quality ratings were performed by a single trained rater, an experienced ECT psychiatrist (RT); good inter-rater reliability had previously been established with a second trained rater in a retrospective sample [11]. All ratings were performed blind to the anaesthetic-ECT time interval and ventilation data, as well as other ECT and clinical data. Data & Statistical Analysis. All statistical analyses were conducted using SPSS software (IBM SPSS Statistics 25 for Windows; SPSS Inc.). Data collected included: the anaesthetic-ECT time interval (sec), end-tidal CO2 (mmHg), ECT electrode placement (RUL/ BT/BF) and pulse width (ms), ECT stimulus charge (mC), initial seizure threshold (mC), ECT treatment number, motor seizure duration, EEG seizure duration, concurrent medication use during ECT [antidepressants (yes/no), lamotrigine (yes/no), lithium (yes/ no) and antipsychotics (yes/no)], and recovery of orientation score post-treatment (0-10). The effect of the anaesthetic-ECT time interval, and ventilation rate, on seizure quality indices was analysed through the use of Linear mixed effects models, with subject as a random effect (covariance structure AR1). For each dependent variable (amplitude, regularity, postictal suppression, and general seizure quality) a separate mixed effect model was produced, controlling for variables that could potentially affect seizure expression: anaesthesia dose (thiopentone mg), ECT treatment number, age (years) and ECT type (electrode placement and pulse width). ECT charge (mC), initial seizure threshold (mC) and concurrent medication [antidepressants (yes/no), lamotrigine (yes/no), lithium (yes/no) and antipsychotics (yes/no)] were considered but not included in the final models, as they did not significantly improve the performance of the models. Separate mixed effects models were also run for seizure duration and for recovery of orientation score, using the same covariates. Primary analyses were conducted in the intentionto-treat sample, with anaesthetic-ECT time interval and ventilation rate as dichotomous variables. Secondary analyses repeated the primary analyses using continuous data for the actual anaestheticECT time interval (seconds) and end-tidal CO2 (mmHg) achieved at each session. Statistical tests were two-tailed and significance was set at p < 0.05 For the primary outcome (ictal seizure quality) the significance level was adjusted to 0.0125 to correct for multiple testing for each of the four ictal quality measures. Results Table 1 displays the basic demographic and clinical data for the sample. A total of 211 ECT sessions from 54 participants were available for analysis (see Fig. 1). Two sessions were subsequently omitted from the analysis as additional thiopentone was administered prior to ECT stimulus administration (due to clinical concerns regarding potential patient awareness) leaving 209 total sessions. The anaesthetic-ECT time interval had a significant impact on ictal seizure quality, with longer time intervals producing higher quality seizures on all measures (amplitude, postictal suppression, regularity and general seizure quality e see Table 2; p < 0.01). Ventilation approach did not significantly influence ictal seizure
Please cite this article as: Taylor R et al., Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.12.012
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Table 1 Demographic & clinical data. Age, years (mean, SD)
49.8 (16.0)
Gender (no. female, %)
35/54 (64.8%)
Diagnosis (no., %) MDE, unipolar MDE, bipolar I MDE, bipolar II MDE, schizoaffective
35/54 (64.8%) 6/54 (11.1%) 10/54 (18.5%) 3/54 (5.6%)
Concurrent medications (no., %) Antidepressants Antipsychotics Lithium Lamotrigine
45/54 (83.3%) 38/54 (70.4%) 14/54 (25.9%) 8/54 (14.8%)
ECT type (no., %) RUL 1.0 ms RUL 0.3 ms BT 1.0 ms BF 1.0 ms
135/211 (64.0%) 58/211 (27.5%) 6/211 (2.8%) 12/211 (5.7%)
Charge, mC (mean, SD)
306.4 (164.2)
Initial ST, mC (mean, SD)
72.1 (51.7)
Thiopentone dose, mg (mean, SD)
275.0 (36.1)
Succinylcholine dose, mg (mean, SD)
71.0 (11.6)
Anaesthetic-ECT time interval, sec (mean, SD) - short time interval sessions - long time interval sessions
128.6 (30.5) 99.7 (10.1) 157.3 (9.7)
End-tidal CO2, mmHg (mean, SD) - normal ventilation rate sessions - hyperventilation rate sessions
29.8 (9.0) 35.6 (7.1) 24.2 (6.9)
quality for any of the quality indices used in this study. Consistent with prior research, patient age also significantly influenced seizure quality for all indices (amplitude, regularity, postictal suppression and general seizure quality), with older age associated with lower quality seizures (p < 0.01)10,23,32. Thiopentone dose and ECT type did not significantly influence seizure quality. The anaesthetic-ECT time interval also had a significant effect on seizure duration, with longer time intervals being associated with longer seizures (p < 0.01). No other variables had a significant influence on seizure duration. Similarly, none of the variables studied had a significant effect on recovery of orientation scores posttreatment. Results from the secondary analyses (using continuous data for the actual anaesthetic-ECT time interval (seconds) and end-tidal CO2 (mmHg) achieved at each session) were similar to the primary analyses (see Table 3). That is, the anaesthetic-ECT time interval had a significant impact on all ictal quality measures (amplitude, postictal suppression, regularity and general seizure quality; p < 0.01) and also seizure duration (longer time intervals producing higher quality seizures and longer seizures; p < 0.01). Age had a significant effect on all ictal quality measures (p < 0.01), while end tidal CO2 (mmHg) and ECT type did not have a significant effect on any quality measures. Thiopentone dose had a significant effect on seizure amplitude (higher doses associated with lower amplitude), though the magnitude of this effect was small. The distribution of end tidal CO2 (mmHg) and anaesthetic-ECT time interval (sec) values achieved is shown in Fig. 2.
Discussion This prospective randomised trial provides the most compelling and definitive evidence yet for the impact of the anaesthetic-ECT time interval on ictal seizure quality. Consistent with results from
previous retrospective studies with large samples, the anaestheticECT time interval had a significant impact on ictal seizure quality, with longer times leading to higher quality seizures. This effect appears to be due to lengthening the time interval itself (and the diminished anticonvulsant properties at the time of stimulus), rather than the specific ventilation approach used during the time between anaesthetic induction and ECT stimulus administration. That is, there was no significant difference between normal ventilation and hyperventilation approaches for seizure quality, independent of the effect of the time interval. In terms of clinical implications, these results argue strongly for the routine clinical measurement and recording of the anaestheticECT time interval. Given the ease with which this variable is measured, and the strength of the impact observed on seizure quality, this can be easily incorporated into standard practice for any ECT service. Importantly, without monitoring this variable there is a risk that changes in ictal quality observed between sessions may erroneously be thought due to changes in seizure threshold. As previously suggested, this could lead to unnecessary dose increases during an ECT course, when in fact there may have just been different anaesthetic-ECT time intervals between sessions [10]. Importantly, the anaesthetic-ECT time interval and absolute dose of anaesthetic utilised are likely inextricably linked. Therefore, in clinical practice, it will be important to monitor and control both of these variables, as they cannot be considered in isolation. The tolerability of longer time intervals, with the target long time interval chosen in this study (ECT stimulus delivery aimed at 2 min and 30 s from the administration of thiopentone), was good e additional administration of anaesthetic was only required on two occasions due to clinical concerns of potential awareness. Extending the time interval beyond this limit may alter the risk-benefit ratio, as excessively long anaesthetic-ECT time intervals will necessarily increase the risks of patient awareness and inadequate muscle relaxation e the anaesthetic agent used, absolute anaesthetic dose administered, and individual patient pharmacokinetics, will also influence the point at which this occurs. As such, the preferred time interval (to optimise ictal quality) will necessarily be contingent upon a combination of these factors. While the manner of recording ETCO2 was imperfect, the hyperventilation and normal ventilation approaches were applied accurately as required by the study design. Measurement of ETCO2 via nasal catheter was selected as a practical and relatively noninvasive approach. While some prior studies have suggested hyperventilation may influence seizure duration and orientation scores, we did not observe any significant effects of ventilation rate on these variables or the primary outcome measures (of seizure quality). As previously mentioned, prior studies in this area have been limited by small sample sizes, heterogeneity in ventilation techniques (and measurement approaches), and heterogeneity in ECT and anaesthetic factors [33]. Further, the anaesthetic-ECT time interval has generally not been considered in such studies, and may play a role in explaining the results previously observed. This concern may also be raised for previous studies examining the influence of a variety of different variables on ictal seizure quality. Consistent with previous studies examining ictal seizure quality, age had a significant effect for all quality measures examined, with older age being associated with generally poorer quality seizures [10,23,32]. Comparatively, anaesthetic dose (mg) and ECT type did not significantly influence ictal seizure quality. This result is not unexpected for anaesthetic dose, which is tailored for individual patients by weight and other factors, and for which there was very little variation in dosing between the four treatment sessions for each patient. With respect to the influence of ECT type, our sample included only a very small number of sessions with bitemporal or bifrontal treatments (minimising the potential to adequately
Please cite this article as: Taylor R et al., Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.12.012
R. Taylor et al. / Brain Stimulation xxx (xxxx) xxx
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Fig. 1. Participant Flow Diagram. * Note 2 sessions not analysed due to administration of additional anaesthetic (thiopentone) prior to stimulation.
Table 2 Primary intention to treat analysis e mixed effects models examining impact of treatment and patient factors on ictal seizure quality. Covariate/Dependent
Amplitude (mm) Est
Anaesthetic-ECT time interval (Short/Long) Ventilation approach (Norm/Hyper) Age (years) Thiopentone (mg) ECT type - BT brief - BF brief - RUL ultra-brief - RUL brief
SE
p
Post-ictal suppression (0e3)
Regularity (0e6)
Est
Est
SE
p
SE
GSQ (1e5) p
Est
SE
Duration (sec) p
Est
SE
Orientation score (010) p
Est
SE
p
2.214 0.478 0.000 0.316 0.075 0.000 0.274 0.072 0.000 0.327 0.072 0.000 7.923 1.543
0.000 0.214
0.219 0.330
0.301
0.479 0.530 0.135
1.550
0.371 0.364
0.222 0.103
0.237 0.025 e 5.018 0.463 2.818 e
0.034 0.013 e 3.819 2.217 1.156 e
0.132 0.047 e 15.038 8.731 4.554 e
0.398 0.192 0.104 0.267 0.860 0.025 e
0.000 0.054 0.082 0.196 0.836 0.019 e
0.023 0.000 e 0.325 0.109 0.277 e
0.075 0.072 0.062 0.005 0.002 e 0.553 0.321 0.168 e
0.000 0.793 0.359 0.560 0.737 0.106 e
0.027 0.000 e 0.671 0.034 0.157 e
0.072 0.385 0.066 0.005 0.002 e 0.524 0.304 0.159 e
0.000 0.954 0.485 0.207 0.913 0.326 e
0.030 0.001 e 0.128 0.041 0.052 e
0.072 0.354 1.393 0.004 0.001 e 0.465 0.270 0.141 e
0.000 0.438 0.964 0.784 0.879 0.713 e
0.113 0.061 e 16.940 1.551 10.629 e
0.035 0.002 e 2.764 1.250 0.023 e
0.019 0.007 e 2.142 1.239 0.651 e
0.077 0.734 0.433 0.204 0.319 0.972 e
Est (estimate); SE (standard error); GSQ (general seizure quality); ECT (electroconvulsive therapy); BT (bitemporal); BF (bifrontal); RUL (right unilateral); mm (millimetres); sec (seconds); mg (milligrams). * Note: for ECT type, RUL brief used as reference type.
Please cite this article as: Taylor R et al., Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.12.012
6
R. Taylor et al. / Brain Stimulation xxx (xxxx) xxx
Table 3 Secondary analysis e mixed effects models examining impact of treatment and patient factors on ictal seizure quality. Covariate/Dependent
Anaesthetic-ECT time interval (min) ETCO2 (mmHg) Age (years) Thiopentone (mg) ECT type - BT brief - BF brief - RUL ultrabrief - RUL brief
Amplitude (mm) p
Post-ictal suppression (0e3)
Regularity (0e6)
Est
Est
Est
SE
2.094
0.480 0.000 0.266
0.081 0.001 0.242
0.075 0.002 0.278
0.053 0.234 0.026 e 4.973 0.537 3.026 e
0.032 0.034 0.013 e 3.838 2.235 1.176 e
0.005 0.005 0.002 e 0.568 0.331 0.175 e
0.005 0.005 0.002 e 0.534 0.311 0.164 e
0.100 0.000 0.046 0.066 0.202 0.811 0.014 e
0.005 0.022 0.000 e 0.350 0.110 0.287 e
SE
p
0.315 0.000 0.958 0.358 0.541 0.742 0.108 e
0.007 0.027 0.000 e 0.660 0.055 0.153 e
SE
GSQ (1e5) p
Est
0.193 0.000 0.908 0.516 0.224 0.859 0.357 e
0.008 0.030 0.001 e 0.110 0.034 0.049 e
SE
Duration (sec) p
SE
p
0.076 0.000 7.918
1.554
0.000 0.101 0.238 0.673
0.005 0.004 0.002 e 0.471 0.274 0.145 e
0.104 0.131 0.046 e 14.527 8.463 4.463 e
0.979 0.364 0.072 0.056 0.217 0.945 0.011 e
0.099 0.000 0.466 0.975 0.816 0.903 0.738 e
Est
Orientation score (010)
0.003 0.120 0.084 e 18.264 0.588 11.906 e
Est
0.011 0.035 0.004 e 2.667 1.132 0.001 e
SE
0.016 0.021 0.007 e 2.232 1.293 0.684 e
p
0.507 0.093 0.543 0.522 0.239 0.387 0.998 e
Est (estimate); SE (standard error); GSQ (general seizure quality); ECT (electroconvulsive therapy); mm (millimetres); sec (seconds); min (minutes); ETCO2 (end tidal CO2); mmHg (millimetres of mercury); mg (milligrams); BT (bitemporal); BF (bifrontal); RUL (right unilateral). * Note: for ECT type, RUL brief used as reference type.
Fig. 2. End tidal CO2 values (mmHg) by ventilation approach and time interval (secs).
investigate the difference between bilateral and unilateral montages). Post ECT Orientation scores were also examined to see if the anaesthetic-ECT time interval or ventilation approach had any effect on post ECT recovery of orientation, given this has been shown to predict retrograde amnesia following ECT [26,34]. No effects were found for either variable, suggesting that any effects, if present, were not marked. Alternatively, it is possible that the post ECT orientation measure used was not sufficiently sensitive to capture differences, or that there are effects on other cognitive domains not examined in this study. One limitation of the current study is the inability to draw clear conclusions regarding the effect of the anaesthetic-ECT time interval on overall clinical outcome in this cohort (in terms of reduction of depressive symptoms). Due to the study design, where each patient acted as their own control and received all four combinations of the intervention (that is, long and short time interval and normoventilation and hyperventilation), we could not assess whether prolonging the time interval over an entire ECT course improves mood or cognitive outcomes. This may be an area for further study, though such a design may potentially put patients at risk of receiving lower efficacy treatment (if randomised to an entire course of shorter time interval treatments). One alternative may be to randomise patients to a course of longer anaesthetic-ECT time intervals or a course with treatment as usual (i.e. clinician determined time interval). Despite this, these findings enhance ECT practitioner knowledge about factors influencing the ictal EEG (and thereby may improve dosing decisions made while considering ictal EEG changes). As previously mentioned, the optimal or preferred anaesthetic-ECT time interval is likely to vary between individuals, and will also be influenced by the anaesthetic agent
used and absolute anaesthetic dose administered. Additionally, the use of thiopentone as the primary anaesthetic agent in this study raises the question of the generalisability of results observed. Prior retrospective findings with propofol in this regard support the importance of the anaesthetic-ECT time interval, though alternative agents with different pharmacological profiles may yield different results [10]. Finally, RUL ECT comprised >90% of treatment sessions analysed in this study, with minimal BF and BT treatments available for analysis. Strengths of the study include the prospective twofactor design, with randomisation of both time interval and ventilation rate, and evaluation of potential confounding factors, which were included in the analysis models. In conclusion, this trial is the first prospective randomised study to examine the influence of the anaesthetic-ECT time interval and ventilation approach on ictal seizure quality. Longer anaestheticECT time intervals were found to produce higher quality seizures for all quality measures examined, while ventilation rate pretreatment showed no significant effect on ictal seizure quality. These results support the routine measurement and recording of the anaesthetic-ECT time interval in clinical practice and suggest the possibility of optimisation on an individual patient basis. Author contributions R.T. prepared the manuscript for publication, coordinated the study & data collection, and contributed to the study design & analysis. H.W, J.L, B.S, J.M and H.K contributed to the data collection & study design. D.H. contributed to the statistical analysis & study design. S.N contributed to the statistical analysis & preparation of figures. C.L and D.M contributed to the study design & analysis. All authors revised and approved the final manuscript. Declaration of competing interest None. Acknowledgements Dr Taylor was supported by a fellowship from the Health Education & Training Institute, NSW, Australia. Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.jretconser.2019.102002.
Please cite this article as: Taylor R et al., Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.12.012
R. Taylor et al. / Brain Stimulation xxx (xxxx) xxx
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Please cite this article as: Taylor R et al., Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.12.012