Anesth Analg 2004;98:1030-1035
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000105874.50605.3C
TECHNOLOGY, COMPUTING, AND SIMULATION
Bispectral Index as an Indicator of Seizure Inducibility in Electroconvulsive Therapy Under Thiopental Anesthesia
Ryoichi Ochiai, MD, PhD,
Tatsuya Yamada, MD, PhD,
Shunya Kiyama, MD, PhD,
Takako Nakaoji, MD, PhD, and
Junzo Takeda, MD, PhD Section Editor
Department of Anesthesiology, School of Medicine, Keio University, Tokyo, Japan
Address correspondence and reprint requests to Ryoichi Ochiai, Department of Anesthesiology, School of Medicine, Keio University, 35, Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan. Address e-mail to ochiai{at}sc.itc.keio.ac.jp
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Abstract
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The prediction of seizure thresholds in electroconvulsive therapy (ECT) remains problematic. We examined the relationship between bispectral index (BIS) score and seizure duration in ECT performed under thiopental anesthesia in patients receiving their usual regimen of antidepressant medication for its potential as a predictor of seizure inducibility. One-hundred ECT treatments were evaluated in 16 adult patients diagnosed with depression. BIS scores were recorded at the preanesthetic and preictal periods and at recovery from ECT. Seizure duration was defined as the duration of the electroencephalogram seizure pattern. The relationships between preanesthetic and preictal BIS scores and seizure duration were evaluated. Effective seizure threshold was determined by receiver operator characteristic analysis, and the area under the curve (AUC) was calculated for seizure durations of more than 10 s, more than 20 s, and more than 30 s. The relationship between seizure duration and thiopental estimated effect-site and plasma concentrations was analyzed as well. Preictal BIS scores for seizures lasting longer than 30 s were significantly higher than those for seizures lasting <30 s. A preictal BIS score of 55 or more represents a strongly determinant condition for achieving seizures that last longer than 30 s (AUC, 0.937; receiver operator characteristic), as well as for briefer seizures that last more than 20 or 10 s (AUC: 0.938 and 0.959, respectively). There was no significant correlation between seizure duration and the estimated thiopental effect-site or plasma concentration. We conclude that during thiopental anesthesia, the minimum threshold for inducing seizures of any duration correlates with a preictal BIS score of 55. This threshold was independent of antidepressant regimen and thiopental dosage. We suggest that the preictal BIS score is useful in predicting the ictogenic threshold in ECT.
IMPLICATIONS: We found that the bispectral index (BIS) score serves as an indicator of seizure inducibility in electroconvulsive therapy (ECT) under thiopental anesthesia and that the relationship between BIS score and seizure duration was not linear, suggesting that the pharmacological mechanisms by which thiopental and propofol suppress ECT seizure activity are different.
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Introduction
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Electroconvulsive therapy (ECT) is used to treat a number of major affective disorders, including depression (1). Drugs used in the anesthetic management of ECT can affect the induced seizures because of their depressive effects on the central nervous system (CNS). Among the IV anesthetics, propofol has been recommended for ECT anesthesia for its more stable systemic and better cerebral hemodynamics in comparison to barbiturates, although seizure duration under propofol anesthesia tends to be shorter than under barbiturate or etomidate anesthesia (2–4). Propofol also acts to reduce the duration of electrically induced seizures in a dose-dependent manner, and the bispectral index score (BIS) may represent the degree of propofol-induced CNS depression (5)
Although the mechanisms underlying general anesthesia are not well understood, it is possible that an anesthetic state can be achieved by enhancing neuronal inhibition, by decreasing neuronal excitation, or by a combination of both. It has been suggested that general anesthetics enhance inhibitory synaptic transmission, and 
-aminobutyric acid (GABA)-mediated synaptic inhibition has been investigated as the mode of action of these drugs. Several studies have shown that a number of IV anesthetics do indeed modulate GABA-mediated inhibition (6–8). It has also been suggested that propofol augments the activity of excitatory and glycinergic receptors and/or pathways (9), an effect that may be at least partly responsible for the motor manifestations that have been reported to occur after the administration of propofol. The effects of propofol on excitatory synaptic transmission remain controversial; in any case, such augmentation has not been reported as an effect of thiopental anesthesia. Given these reports of differing modes and activity, it is conceivable that the overall effects of different IV anesthetics on the CNS during ECT may vary (10).
As mentioned above, a previous study has shown that propofol anesthesia induces a linearly dose-dependent reduction in ECT seizure duration (5). We hypothesized that, as noted in that study, the correlation between BIS score and seizure duration might vary when other drugs are used to induce anesthesia in ECT, because of their different pharmacokinetic and pharmacodynamic profiles. This study was conducted to assess whether the BIS score provides a predictor of seizure duration in ECT performed under thiopental anesthesia.
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Methods
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This clinical study was performed with the approval of the IRB and Human Rights Committee and with written consent from the patient or next of kin, as appropriate. Sixteen adult patients diagnosed with depression requiring repeated ECT treatments were involved in the study, and 100 ECT sessions were evaluated. At the time of the study, the patients were receiving various regimens of benzodiazepines, antidepressants, or both, including diazepam, imipramines (imipramine or clomipramine), amoxapine, amitriptyline, trazodone, fluvoxamine, paroxetine, and milnacipran, which were continued until the morning of ECT.
Arterial blood pressure (by cuff), electrocardiogram, SpO2, and BIS (BIS A2000 with Rev. 3.0.0) were monitored before the induction and for the duration of the anesthesia. Anesthesia was induced with IV thiopental (3–6 mg/kg) and suxamethonium (1 mg/kg) after the administration of oxygen by face mask for at least 3 min. A staff anesthesiologist who was unaware of the purpose of the study determined the dosage of thiopental and the timing of the ECT stimuli. Ventilation was assisted manually with 100% oxygen by face mask. After the induction of hypnosis and muscle relaxation, an electrical stimulus was delivered via bitemporal electrodes by using a Sakai CS-1 apparatus (Sakai Medical Instruments, Tokyo, Japan) set at 110 V and maintained for 5–7 s. The duration of each induced seizure was determined by monitoring the electroencephalogram seizure pattern and recorded. A tourniquet applied to the upper arm was inflated to isolate the circulation to the arm and permit the assessment of motor seizure activity. Patients were discharged from the recovery room when they met discharge criteria.
The plasma and effect-site concentrations of thiopental at the time of ECT stimulation were modeled with pharmacokinetic modeling software (STANPUMP, copyright S. Shafer). Modeled concentrations were corrected for age, sex, height, and weight.
Patient demographic data are stated as mean ± SD. The results of the ECT sessions were grouped by seizure duration: <30 s and >30 s. BIS score and estimated thiopental concentration were compared between the two groups with one-way analysis of variance and the Scheffé post hoc test. P < 0.05 was considered statistically significant. The correlation between seizure duration and thiopental effect-site and plasma concentration was evaluated by using the least-squares method.
The relationship between BIS score and seizure duration was analyzed by receiver operator characteristics curves (ROC), in which the area under the curve (AUC) was calculated as described elsewhere (11). Analyses were performed for the >30-s group and, to facilitate comparison with the propofol study cited previously, for seizures of >10 and >20 s as well. Preanesthetic and preictal BIS scores were analyzed for correlations with seizure duration.
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Results
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One-hundred ECT stimuli in 16 patients (age, 20–84 yr) were administered without any adverse events. Demographic data for the patients are shown in Table 1. The average bolus dosage of thiopental was 4.1 mg/kg. The average dosage in the >30-s group was significantly larger than that in the <30-s group (Table 2). There were, however, no significant differences between groups in the estimated plasma or effect-site concentrations of thiopental at the time of ECT stimulation.
The correlations between seizure duration and plasma and effect-site concentrations are illustrated in Figure 1. The correlation coefficients were 0.0244 and 0.0052, respectively.
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Figure 1. Relationship between electroconvulsive therapy-induced seizure duration and estimated thiopental concentration in plasma ( and at the effect site (•). There was no significant correlation.
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BIS scores before the induction of anesthesia (preanesthetic) and immediately before the ECT stimulation (preictal) were significantly higher in the >30-s group than in the <30-s group, but there were no significant differences in BIS scores at the recovery of spontaneous breathing or at discharge from the recovery room (Table 2).
The correlations between seizure duration and preictal and preanesthetic BIS scores are shown in Figure 2, A and B, respectively. There was no significant correlation between seizure duration and either preanesthetic or preictal BIS scores. The dotted line in Figure 2A indicates the correlation between preictal BIS score and seizure duration during propofol anesthesia, as reported elsewhere (5).
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Figure 2. Relationship between electroconvulsive therapy-induced seizure duration and preictal bispectral index (BIS) score (A) or preanesthetic BIS score (B). The dotted line in (A) shows the relationship between preictal BIS score and seizure duration during propofol anesthesia (5).
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ROC curves derived for seizures of >10, >20, and >30 s are shown in Figure 3. Seizures were successfully induced at preictal BIS scores of 55 or more for each duration group (AUC: 0.959, 0.938, and 0.941, respectively; Fig. 3A). However, there was no significant correlation between preanesthetic BIS score and seizures for any of the three duration groups (AUC: 0.653, 0.644, and 0.612 for >10, >20, and >30 s, respectively; Fig. 3B).
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Figure 3. Electroconvulsive therapy adequacy evaluated by a receiver operator characteristic curve on the basis of seizure durations of more than 10, 20, and 30 s. A, Preictal bispectral index (BIS) scores; B, preanesthetic BIS scores. AUC = area under the curve.
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Discussion
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This study clearly demonstrated that, under thiopental anesthesia for ECT, only electrical stimuli administered at BIS scores of 55 or higher produce seizures of more than 10 seconds in duration. The pharmacodynamic effects of anesthetics and their interactions with other psychoactive drugs may play an important role in determining ECT seizure inducibility, and we suggest that the BIS score is an effective indicator in the anesthetic management of ECT.
Preictal BIS scores correlate linearly with seizure duration during propofol anesthesia for ECT (5). This linear correlation was confirmed at BIS scores between 30 and 80, although the correlation coefficient was relatively low (R2 = 0.527). This finding of a linear dose-response relationship across a wide range of BIS scores suggests that propofol has a potent anticonvulsant effect and counters previous suggestions of a proconvulsant effect for propofol (12,13). However, in this study, we did not find a linear relationship between BIS and seizure duration in ECT under thiopental anesthesia. In Figure 2A, the dotted line indicates the relationship between seizure duration and BIS scores during propofol anesthesia (from the previous study) and highlights the absence of a linear dose-response relationship in thiopental anesthesia, particularly at BIS scores of <55. Furthermore, when seizure induction was evaluated in relation to the preictal BIS score by using ROC curves for the three seizure duration groups (Fig. 3A), it was found that a BIS score of 55 was the lower limit for seizure inducibility, with an AUC of more than 0.9 for all groups. These findings support the notion that the anticonvulsant effects of propofol and thiopental have different pharmacological bases (14).
The findings from our study do not allow us to speculate on the causes for the differences in seizure inducibility between thiopental and propofol. However, several in vivo and in vitro studies have indicated that different IV anesthetics have different effects on the CNS. The GABAergic system seems to be the common target site that mediates the depressive effects of these anesthetics, but the effects on excitatory systems, such as N-methyl-D-aspartate, kainate, and 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, appear to be drug specific. Thiopental is reported to activate the GABA pathway and thus to suppress the excitatory pathway (15). The effects of propofol, however, seem to be divergent. Some studies reveal propofol-induced enhancement of GABAergic transmission and facilitation of excitatory amino acid receptor-mediated responses, including AMPA and kainic acid receptor subtypes (9). However, in vitro data from other studies suggest that propofol inhibits excitatory amino acid agonist-mediated effects on the neuronal channel currents and calcium entry into synaptosomes (16,17). The mechanisms that affect seizure inducibility during the anesthetic management of ECT should become clearer after the mechanism of effect for various drugs has been determined.
Preanesthetic BIS scores show no correlation with seizure duration (Fig. 2B). The ROC findings also suggest little association of preanesthetic BIS score with seizure duration (AUC, 0.6). No studies have been conducted to assess awake BIS scores in clinically depressed patients receiving various regimens of antidepressant medications. Previous studies that examined the relationship between seizure threshold and demographic factors, such as disease state, revealed that such factors do not serve as accurate predictors of seizure threshold. Thus, it seems unlikely that the preanesthetic BIS score, which may reflect the disease state as well as the pharmacologic effect of concomitant medication, will serve as an effective predictor of seizure duration (18,19).
Unilateral ECT is becoming more common than bilateral stimulation; however, bilateral stimulation was used in this study, because it is standard practice at the institution where the study was conducted. Choice of site is generally made to minimize post-ECT side effects, such as cognitive effects. However, regardless of the shorter distance between the electrodes in unilateral stimulation, seizure thresholds are parallel to those in bifrontal or bilateral stimulation (20). The induction of seizures by unilateral stimulation seems to be similar to that of bilateral stimulation, and a similar relationship between preictal BIS score and seizure duration can be expected (21–24).
If the effect-site concentration of thiopental is linearly correlated with its anticonvulsant effect, an inverse correlation between its concentration and seizure duration would be expected. However, as mentioned previously, no such inverse correlation was observed. Our data suggest that the preictal BIS score indicates what might be called the overall degree of CNS depression, or the "seizure inducibility," as determined by the anticonvulsant effects of thiopental and the underlying disease state. The duration of seizures induced in this context is dependent on a number of factors. The wide range of estimated plasma and effect-site concentrations in Figure 1 suggests that the timing of electrical stimulation after anesthetic administration is crucial to the induction of seizures. The drugs most often used in the anesthetic management of ECT include methohexital, etomidate, propofol, and thiopental, all of which are highly lipid soluble (25). The plasma and effect-site concentrations of thiopental, for instance, vary progressively within 10 minutes after administration. Pharmacokinetic simulations indicate that, after the administration of thiopental 5 mg/kg in adults, plasma concentration peaks (>80 µg/mL) within 1 minute and decreases to <10 µg/mL within 10 minutes. Effect-site concentration is also estimated to reach its peak (>25 µg/mL) within 3 minutes and decrease to <10 µg/mL by 10 minutes after administration. Likewise, propofol reaches its peak effect-site concentration within 3 minutes and decreases to 30% in 10 minutes. It is most likely that the varying concentration of anesthetics would significantly affect the effect of electrical stimulation by ECT in terms of when the stimulation should be delivered after the loss of consciousness. Because it is suggested that the BIS score represents the effect-site concentration, it provides an excellent variable for timing ECT stimulation (26,27). The BIS score may also be helpful in assessing whether it is possible to induce a seizure, because it may provide a gauge of overall CNS responsivity, as determined by the combined pharmacologic effects of anesthetics and concomitant antidepressant drugs.
Methohexital is not available in Japan, and thiopental has been widely adopted as the drug of choice for the anesthetic management of ECT. However, there have been few clinical studies regarding the effects of thiopental on ECT seizure duration. One reason that methohexital has been chosen as an anesthetic for ECT in other countries is for its proconvulsant effect, which facilitates seizure induction. However, the proconvulsant effect of thiopental in clinical anesthesia has not been clearly demonstrated. Our data suggest that thiopental has a weak proconvulsant effect at smaller effect-site concentrations. The question of whether seizure duration determines ECT treatment outcome and efficacy remains controversial (28,29), and further studies need to be performed to clarify the relationships between seizure duration, choice of anesthetic, and ECT treatment outcome.
The interaction of thiopental with concomitantly used antidepressants may also affect seizure threshold in a clinically significant way. In this study, the patients received their usual dosages of antidepressants on the morning of the procedure. The significant differences in preanesthetic BIS scores may be attributed to the combined effects of those drugs and the disease state itself. There was furthermore no significant difference between groups in the estimated plasma and effect-site concentrations of thiopental. Although these findings may indicate decreased responsivity due to the combined effect of thiopental and antidepressants, the BIS score reflects the overall degree of CNS depression and makes it possible to time the delivery of ECT stimulation accordingly.
In conclusion, thiopental showed no linear dose-response relationship in regard to ECT seizure duration. The BIS score is a useful predictor of the inducibility of seizures, independent of thiopental dosage and the concomitant use of antidepressant medications, and a BIS of 55 would appear to represent an effective lower limit on the ability to induce seizures of any duration.
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Accepted for publication October 23, 2003.
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Abstract
Introduction
