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Anesthetic Considerations for Magnetic Seizure Therapy: A Novel Therapy for Severe Depression

White, Paul F., PhD, MD, FANZCA*; Amos, Quinlan, MD*; Zhang, Yunan, MD*; Stool, Louis, MD*; Husain, Mustafa M., MD; Thornton, Larry, MD; Downing, Michael, MD; McClintock, Shawn, PhD*; Lisanby, Sarah H., MD

doi: 10.1213/01.ane.0000221182.71648.a3
Ambulatory Anesthesia: Research Report
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Electroconvulsive therapy (ECT) is a highly effective treatment for severe depression. However, its use is associated with significant posttreatment cognitive impairment. Magnetic seizure therapy (MST) was developed as an alternative therapy that could reduce postseizure side effects through the induction of more “focal” seizure activity. Using an open-parallel study design, we compared 20 case-matched patients undergoing a series of either ECT or MST procedures with respect to their anesthetic, muscle relaxant, and cardiovascular drug requirements, effects on cardiovascular and electroencephalographic bispectral index (BIS) values, and early recovery times. We found that MST was associated with a reduced time to orientation (4 ± 1 versus 18 ± 5 min; P < 0.01) compared with ECT. To minimize residual muscle paralysis after MST, a reduction in the succinylcholine dosage (38 ± 17 versus 97 ± 2 mg; P < 0.01) was required. The BIS values were higher before, and lower immediately after, the stimulus was applied in the MST (versus ECT) group. The Hamilton depression rating scale score was significantly reduced from the baseline value in both treatment groups; however, the posttreatment score was lower after the series of ECT treatments (6 ± 6 versus 14 ± 10; P < 0.05). We conclude that MST was associated with a decreased requirement for muscle relaxants, reduced variability in the BIS values after seizure induction, and a more rapid recovery of cognitive function compared with ECT. Further studies are required to evaluate the antidepressant efficacy of MST versus ECT when they are administered at comparable levels of cerebral stimulation.

IMPLICATIONS: Magnetic seizure therapy (MST) is a novel therapy for depression. It is associated with a more rapid recovery of cognitive function compared with conventional electroconvulsive therapy (ECT). To minimize residual paralysis after MST treatments, a reduced dose of succinylcholine should be administered. Of importance, these preliminary data suggest that MST may produce less effective seizure activity than ECT.

From the Departments of *Anesthesiology and Pain Management and †Psychiatry, University of Texas Southwestern Medical Center, Dallas; and ‡Department of Neuroscience, New York State Psychiatric Institute, Columbia University Medical Center, New York, New York.

Supported, in part, by endowment funds from the Margaret Milam McDermott Distinguished Chair in Anesthesiology, and the UT Southwestern Medical Student Summer Research Program and the Stanley Medical Research Institute, Bethesda, MD.

Accepted for publication March 7, 2006.

Address correspondence and reprint requests to Paul F. White, PhD, MD, Department of Anesthesiology and Pain Management, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9068. Address e-mail to paul.white@utsouthwestern.edu.

In an effort to find safer and more effective alternatives to antidepressant drugs for treating severe depression, investigators have recently examined a variety of nonpharmacologic modalities (e.g., modified electroconvulsive therapy [ECT], repetitive transcranial magnetic stimulation [rTMS], and magnetic seizure therapy [MST]) (1). Although ECT is highly effective, its use is limited by adverse cognitive sequelae (e.g., short-term memory loss) and frequent relapse (up to 80%) after discontinuation of the therapy. rTMS was introduced as an alternative to ECT, which was associated with less impairment of cognitive function because the brain is stimulated with magnetic fields that do not induce seizure activity (2,3). Unfortunately, investigators have found rTMS to be of limited efficacy in relieving depressive symptoms (4,5).

MST is a more potent form of magnetic stimulation than rTMS, using rapidly alternating magnetic fields to induce generalized seizures (6). Because magnetic fields pass through tissue without impedance, MST can stimulate more localized regions of the cerebral cortex than conventional ECT (7). It has been suggested that minimizing disturbances of the medial temporal regions of the brain would reduce cognitive side effects. Because MST uses higher intensity, more frequent, and longer durations of stimulation than rTMS, this larger dose of magnetic stimulation can produce generalized tonic-clonic seizures resembling ECT (8). Preliminary studies involving a small number of patients have suggested that MST possesses antidepressant efficacy with minimal cognitive side effects (9,10).

We examined the anesthetic drug requirements, bispectral index (BIS) values, and early recovery times with MST and ECT using a case-control study design in which each patient undergoing a series of MST treatments was matched to a patient of similar age, weight, and sex undergoing a series of ECT treatments.

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METHODS

Ten adult patients with major depression were consented to participate in an initial evaluation of MST at the University of Texas Southwestern Medical Center at Dallas according to an IRB approved study protocol between January and December 2003. After obtaining IRB approval, an additional 10 age-, weight-, and sex-matched patients undergoing standard ECT treatments during the same time period were used as a reference population for purposes of comparing the anesthetic drug requirements for these two nonpharmacologic treatment modalities. The Hamilton depression (Ham-D) rating scale (11), a 17-item scoring system that has been validated as a reliable measure of the severity of depressive symptoms (12), was used to assess the baseline level of depression in both treatment groups.

All patients underwent a series of 10–12 treatments during 3–4 weeks with either ECT or MST using a standardized protocol. Upon entering the treatment room, an IV catheter was placed, and the electrocardiogram, heart rate (HR), noninvasive arterial blood pressure, capnography, and pulse oximetry were monitored using a Medical Systems Dash 4000 (Milwaukee, WI). In addition to the cutaneous MST or ECT gel electrodes, an electroencephalographic (EEG) BIS monitoring strip was applied to the forehead (Aspect Medical Systems, Newton, MA). The baseline hemodynamic variables (e.g., mean arterial blood pressure [MAP] and HR) and BIS values were recorded before the administration of any anesthetic drugs. These variables were reassessed at 1- to 2-min intervals before, during, and immediately after the stimulus was applied. Supplemental oxygen was administered using a facemask delivery system with inline carbon dioxide monitoring. In the MST patients, earplugs were inserted to protect against the high-frequency clicking noise produced by the vibrating copper wires within the stimulating coil. In all patients, a rubber bite block was inserted after induction of anesthesia to prevent dental damage due to masseter muscle stimulation. None of the patients required tracheal intubation.

All patients were administered an antisialagogue, glycopyrrolate 2.5 μg/kg IV, and ketorolac 0.4 mg/kg IV 2–3 min before induction of anesthesia. The induction of anesthesia was achieved with etomidate 0.15–0.2 mg/kg IV. If the initial dose was inadequate, a supplemental bolus dose (0.025–0.05 mg/kg IV) was administered. For muscle relaxation, succinylcholine 0.5–1.0 mg/kg IV was administered to provide muscle relaxation. At subsequent treatment sessions, the dosage of succinylcholine was increased (to minimize movements) or decreased (to minimize residual paralysis on awakening) in increments of 25% of the original dose. Patients' lungs were manually ventilated using a facemask to achieve end-expiration CO2 values of 30–34 mm Hg before application of the stimulus.

The ECT stimulus was delivered using a Spectrum 5000Q ECT device (MECTA Corp, Lake Oswego, OR) via bifrontal leads using a pulse width of 0.5 ms at 2.5 times the seizure threshold (as determined at the first treatment session before initiating the study treatments). MST was administered using a custom modified Magstim device (Magstim Co. LTD, Wales, United Kingdom) consisting of 16 booster modules. The MST stimulus consisted of a peak magnetic field of 2 Tesla at the coil surface, and the pulse had a dampened cosine waveform with a width of 500 μs. The MST patients were treated with the maximal output (50 Hz for 8 s) of the stimulator (1.3 times the seizure threshold). The EEG electrodes were slotted to reduce the risk of burns from the heat generated by the magnetic stimulus.

Poststimulation increases in HR and MAP were treated with bolus doses of labetalol (0.075 mg/kg IV) or nicardipine (4 μg/kg IV), respectively. The criteria for administering supplemental boluses of labetalol was a HR >100 bpm for more than 1 min and nicardipine MAP >120 mm Hg for more than 1 min. If both the HR and MAP were increased, labetalol was administered before nicardipine. When the monitor failed to report a MAP value (e.g., during movement of the upper extremities), it was immediately reactivated.

The duration of motor and EEG seizure activity was recorded using the standard lower-limb isolation technique (for motor seizure activity) and bilateral frontal-mastoid EEG channel (for EEG seizure activity). The length of the motor seizure was assessed in the isolated lower extremity by a nurse observer. The time from application of the stimulus until the patient was able to respond appropriately to simple commands (e.g., name, place, and day of the week) was used to assess initial recovery time by a blinded observer in the postanesthesia recovery area. When patients were discharged from the recovery area they were asked if they recalled any residual muscle weakness upon regaining consciousness.

Statistical analysis of demographic, drug dosage, and Ham-D data consisted of Student's t-test with a Bonferroni correction for multiple comparisons. In analyzing the relative effects of the two treatments, data were analyzed after calculating the mean values across all treatments for each individual patient. Changes in hemodynamic variables and BIS values over time were analyzed using repeated-measures analysis of variance with P values <0.05 considered to be statistically significant.

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RESULTS

Patient demographic data, Ham-D scores, and anesthetic dosage requirements for the MST and ECT groups are summarized in Table 1. All patients tolerated the MST and ECT treatments without any clinically significant complications. Typical EEG tracings obtained during MST and ECT treatments revealed a lesser degree of post-ictal suppression after MST (Fig. 1). The etomidate anesthetic requirement was similar in the two age, weight, and sex-matched patient populations. However, the average dosage of succinylcholine had to be reduced in the MST (versus ECT) group to minimize residual muscle paralysis upon return of cognitive functioning (P < 0.01). Although patients in the MST and ECT groups received similar dosages of glycopyrrolate and labetalol, the average dose of nicardipine was significantly larger in the ECT (versus MST).

Table 1

Table 1

Figure 1.

Figure 1.

The initial recovery time to orientation was reduced in the MST (versus ECT) group (4 ± 1 versus 18 ± 5 min; P < 0.01). The smaller dose of nicardipine in the MST group (and the more rapid awakening) contributed to larger MAP values at the 2-min and 3-min time intervals after application of the stimulus (Fig. 2). Although the Ham-D scores were significantly reduced at the end of both the ECT and MST treatments, posttreatment Ham-D values were significantly smaller in the ECT group (Table 1).

Figure 2.

Figure 2.

The durations of motor and EEG seizure activity did not differ in the two treatment groups (Table 1). However, the pattern of changes in the EEG BIS values differed immediately before and after application of the stimulus (Fig. 2). Specifically, the BIS values were higher 1 min before the stimulus and reduced 1 min after the stimulus was applied in the MST (versus ECT) group. In contrast to the ECT treatments, a post-ictal decrease in the BIS was not observed after the MST-induced seizures (Fig. 2).

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DISCUSSION

Depression is the world's most common mental health problem (13). Analogous to ECT, MST produced a significant antidepressant effect after a series of 10–12 treatments. However, MST was associated with a faster recovery of cognition than ECT after each treatment session. Kosel et al. (10) initially described the successful use of MST to treat a woman with refractory major depression without any clinically significant cognitive side effects. MST treatments produce an increase in cerebral blood flow to the fronto-parietal and the basal ganglia, regions of the brain associated with depressive symptoms (14). Both MST and ECT induce motor and EEG seizures through electrical stimulation of the brain. However, the electrical field induced by MST is more localized, reducing spread to the medial temporal regions of the brain implicated in the cognitive side effects of ECT (6).

A preliminary study (9) involving 10 patients suggested that MST might be associated with less severe muscle aches, fewer subjective memory complaints, and headaches than ECT. In this initial randomized comparison with ECT using methohexital anesthesia (9), MST-induced motor and EEG seizures were reported to be of shorter duration and lower-ictal EEG amplitude compared with ECT. Not surprisingly, the MST-treated patients performed better on tests measuring attention, retrograde amnesia, and category fluency than those receiving ECT. Because patients regain orientation more rapidly after MST (versus ECT), use of smaller doses of succinylcholine would be expected to reduce the uncomfortable symptoms associated with residual muscle paralysis upon return of consciousness.

Although anesthesia for ECT has recently been reviewed in the peer-reviewed anesthesia literature (15), the anesthetic considerations for MST have not been previously discussed. In the initial study at Columbia University (7,9), atropine 0.4 mg IV was given before the induction of anesthesia with methohexital 0.75 mg/kg IV. Succinylcholine 0.75 mg/kg IV was used for muscle relaxation. To prolong the duration of seizure activity in the current MST study, etomidate was used in place of methohexital to induce anesthesia (16). In contrast to the preliminary comparative study (9), use of etomidate was associated with similar durations of motor and EEG seizure activity for both MST and ECT treatments.

The rapid early recovery of orientation after MST required the use of the smallest effective dose of succinylcholine to avoid return of consciousness before full recovery from the residual muscle paralysis. As a result of the reduced dose of succinylcholine, there was a higher degree of electromyographic activity in the MST group, contributing to the higher prestimulus BIS values in the MST (versus ECT) group. This observation is consistent with previous reports in both volunteers (17) and patients (18). The changes in BIS values during ECT treatments under etomidate anesthesia were similar to the pattern reported in an earlier ECT study using methohexital for anesthesia (19). Of note, the BIS values were significantly higher at 1 min and lower at 2 min poststimulus in the ECT (versus MST) group.

In contrast to the ECT group, post-ictal depression of the BIS value was not observed in the MST group (Figs. 1 and 2). Given the similar seizure durations in the MST and ECT groups, these EEG-based data suggest that the amplitude of the induced seizure activity may have been reduced with MST (versus ECT), contributing to less post-ictal depression. It should be noted that the maximal magnetic stimulation was 1.3 times the magnetic seizure threshold for the MST treatments compared with 2.5 times the electrical stimulus threshold for the ECT treatments. The BIS values at 4 min after application of the stimuli were similar in both treatment groups (Fig. 2), suggesting that recovery from etomidate anesthesia was similar in both groups. Consistent with our earlier ECT-BIS study (19), MST-treated patients were awake and oriented with a mean (± sd) BIS value of 72 (±20), significantly lower than their baseline BIS value.

Analogous to ECT (15), MST was associated with an acute hyperdynamic response after application of the magnetic stimulus. The magnitude of the acute hemodynamic response after application of the magnetic stimulus was greater than the hyperdynamic response after the electrical stimulus. However, the differences in the poststimulus MAP values were probably related to the use of smaller doses of the calcium-channel blocker nicardipine and the more rapid recovery of cognitive functioning in the MST (versus ECT) group. Future clinical studies with MST should attempt to identify optimal stimulation parameters, antihypertensive dosage requirements, and predictors of a favorable response to the treatment (20).

There are several important limitations to this preliminary analysis of the anesthetic requirements for MST (versus ECT). First, there was no prospective randomization of the patients to the MST and ECT treatment groups. Second, it was not possible to blind the anesthesiologist administering the drugs to the type of brain stimulation being applied. Therefore, the significant differences with respect to the medication requirements may reflect, in part, operator bias. Third, the magnitude of the electromyogram activity was not objectively quantified. The failure to aggressively treat the acute hyperdynamic response to the MST stimulus is another deficiency of this analysis. Because the magnitude of the hemodynamic response to MST had not been previously described, we were less proactive in administering the calcium channel blocker to patients in this group. Given the differences in the amplitude of the magnetic-induced (versus electrical) seizure activity and posttreatment Ham-D scores, future studies with MST should use a higher magnetic output device (e.g., one capable of delivering outputs equal to 2.5 times the magnetic seizure threshold). Finally, more careful neurophysiological assessment of patient outcome with respect to depressive symptoms and cognitive functioning will be important in understanding the future role of MST for treating symptoms of severe depression.

In conclusion, anesthesia for MST requires modification in the standard technique used for ECT because of the patient's more rapid recovery of consciousness after the procedure. Further clinical studies are required to determine if MST will be a useful alternative to ECT for the treatment of severe depression.

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