Relationship between blood levels of propofol and recovery of ...

Psychiatry and Clinical Neurosciences 2014; 68: 270–274

doi:10.1111/pcn.12122

Regular Article

Relationship between blood levels of propofol and recovery of memory in electroconvulsive therapy Yasuhiko Imashuku, MD,* Kousuke Kanemoto, MD, PhD, Masanori Senda, MD, PhD and Momoyo Matsubara, MD, PhD Department of Neuropsychiatry, Aichi Medical University, Aichi, Japan

Aim: Memory impairment is a potential major adverse effect of electroconvulsive therapy (ECT). Some reports have suggested that propofol, an intravenous anesthetic widely used for general anesthesia in ECT, can minimize adverse effects on memory and cognitive function following ECT. The relation between propofol blood level during ECT and memory impairment after the procedure is unknown. We aimed to determine the relation between predicted blood level of propofol administered by targetcontrolled infusion during ECT and memory impairment after the procedure. Methods: Thirty-six patients who underwent a total of 260 series of ECT were enrolled as subjects. Anesthesia was induced with intravenous injection of propofol with a target-controlled infusion pump for predicting blood levels. Orientation and memory testing were performed after completion of ECT. In a subsequent analysis, subjects were divided into early memory recovery (n = 195) and late memory recovery (n = 65) groups. Likewise, for orientation testing,

LECTROCONVULSIVE THERAPY (ECT) has been reported to be effective in the treatment of various mental illnesses, including depression. Various adverse effects of ECT can be reduced while maintaining its effectiveness by using a pulse-wave therapeutic device in place of a conventional sine-

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*Correspondence: Yasuhiko Imashuku, MD, Department of Neuropsychiatry, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan. Email: [email protected] Received 6 August 2012; revised 26 September 2013; accepted 29 September 2013.

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subjects were divided into early recovery (n = 193) and late recovery (n = 67) groups. In both groups, predicted blood propofol levels, total propofol dose, and other variables, such as number of ECT treatments, stimulus energy volume, and spike and slow wave time, were determined for comparison.

Results: Predicted blood propofol levels and propofol total dose were significantly higher in the early memory recovery group, while no significant differences were observed for the other variables. As for orientation, there were no significant differences between the early and late orientation recovery groups. Conclusions: Our data shows that the predicted blood propofol levels and the total dose influences memory impairment after the ECT. Key words: electroconvulsive therapy, memory impairment, predicted blood level, propofol, target controlled infusion.

wave device. Furthermore, modified ECT using a muscle relaxant under general anesthesia has been recommended and shown to improve safety.1 Memory impairment is a potential major adverse effect of ECT. It has been suggested that stimulus dose and convulsion time may be involved, though that has not been fully elucidated.2 Recently, some reports have suggested that propofol, an intravenous anesthetic widely used for general anesthesia in ECT, is likely to minimize adverse effects of ECT on memory and cognitive function.3,4 However, the relation between blood levels of propofol during ECT and memory impairment after the procedure has not

© 2013 The Authors Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology


Propofol aids memory recovery after ECT 271

been examined. At our hospital, we administer propofol in a continuous manner during ECT by using target-controlled infusion (TCI). TCI allows us to predict blood levels and effective site levels by computer simulation under the supervision of an anesthesiologist. In the present study, we examined potential differences in predicted blood levels of propofol during TCI among ECT patients whose memory and orientation recovered at an early stage and those who showed late recovery.

Subjects were divided into two groups: early memory recovery (n = 195; mean recovery times ± SD = 36.7 ± 8.6 min) included those who succeeded in recalling the first memory task, and late memory recovery (n = 65; mean recovery times ± SD = 52.6 ± 13.5 min) included the ones who failed in the first memory test. In both groups, predicted blood propofol levels, total propofol dose, and other variables, such as number of ECT treatments, stimulus energy volume, and spike and slow wave time, were determined for comparison. Similarly for orientation recovery, subjects were divided into two groups: early orientation recovery (n = 193; mean recovery times ± SD = 23.6 ± 6.9 min) were those who recovered orientation immediately after completion of the ECT procedure, and late orientation recovery (n = 67; mean recovery times ± SD = 36.6 ± 9.7 min) included those who failed to succeed in answering the first orientation test. The same variables were compared between the two groups. ECT was performed as follows according to the protocol of our hospital. Administration of antiepileptic drugs and lithium carbonate was suspended prior to surgery, whereas the use of antipsychotic, antidepressant, and antianxiety agents was continued at the minimum dose necessary for treatment. A shortpulse square-wave therapeutic device (Thymatron System, Somatics, LLC, Lake Bluff, IL, USA) was used for ECT. After general anesthesia under propofol was established, 1.0–1.5 mg/kg suxamethonium was administered and an electrical stimulus was delivered. Immediately before ECT stimulation, predicted blood propofol levels were determined using a Terufusion TCI pump (Terumo, Tokyo, Japan), which is generally used for propofol anesthesia with TCI. The specific predicted levels ranged approximately between 1.5 and 2.0 μg/mL and the concentration was raised gradually until a patient would not react to a call. After we confirmed that the subject did not respond to the voice of the attending anesthesiologist, a tourniquet was attached to the unilateral femoral area and muscle relaxant was administered. Electrical stimulus was delivered when vital signs were stable, and blood levels were recorded immediately before stimulation. Stimuli were given bilaterally to the temporal regions at a frequency of 50 Hz and pulse width of 0.5 ms. The stimulus dose was set using the half-age technique and then increased by 10–15% for the next stimulation when the symmetric high-amplitude

METHODS Subjects Among patients who received ECT in the period from May 2008 to April 2009, 36 patients (22 women, 14 men; mean age ± SD = 57.4 ± 12.9 years; mean Hamilton Depression Scale scores ± SD = 23.0 ± 4.7) who underwent a total of 260 series of ECT were enrolled as subjects. The study was approved by the Ethics Committee of Aichi Medical University, and written informed consent to participate in the study was obtained from all patients prior to enrollment. Effect of electroconvulsive therapy was administered to patients with drug-resistant major depressive illness (classified based on DSM-IV).

Procedure Orientation testing was performed after completion of ECT. Orientation was rated as ‘recovered’ if a patient could correctly answer all questions regarding time, place, and name of the attending doctor; these questions were asked every about 10 min until orientation was recovered. Memory testing was started at the time of successful recovery of orientation. For memory testing, an examiner selected five words from each of three categories (marine products, vegetables/fruits, and animals), and asked the subjects to recite a set of three words from those categories (e.g. ‘squid, grape, and giraffe’), and then asked them to recall the words after 10 min. When a patient could not recall all of the words, another set of three words was read out and recollection was tested 10 min later using the same procedure as in the first trial. Trials were repeated until the subject could remember the set of three words from each of the three categories.


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Table 1. Comparison of variables between two memory recovery groups Variables

Early recovery group (n = 195)

Late recovery group (n = 65)

P

Number of ECT treatments Output energy (%) Spike and slow wave time (s) Propofol, total dose (mg) Propofol, predicted blood level (μg/mL)

6.10 ± 3.25 43.92 ± 15.95 23.21 ± 15.24 110.0 ± 52.85 1.88 ± 0.38

5.20 ± 3.17 45.92 ± 16.81 24.83 ± 16.30 86.92 ± 40.16 1.75 ± 0.34

0.051 0.421 0.507 0.001 0.004

Values presented as mean ± SD. ECT, electroconvulsive therapy.

spike and slow wave were less than 15 s. Therapy was given 2–3 times per week and repeated a total 6–12 times, depending on the therapeutic effect.

Statistical analysis For statistical analysis, after examining the normal probability distribution using a χ2-test for adequate fit, comparisons were made between the groups using the two-tailed Mann–Whitney U-test. P < 0.05 was considered significant. Data were confirmed to be outside of normal distribution and expressed as mean ± SD.

RESULTS Table 1 shows that predicted blood propofol levels and total propofol dose were significantly higher in the early memory recovery group, while no significant differences were observed for the other variables. As for orientation, Table 2 shows that there were no significant differences for any of the variables, including predicted blood propofol level and total dose, between the early and late orientation recovery groups.

DISCUSSION ECT has been reported to be effective for a variety of conditions, including depression. Furthermore, it has

been shown that the pulse-wave therapeutic device used in the present study can effectively induce convulsions with lower energy and fewer adverse effects than conventional sine-wave devices. The modified ECT protocol that is currently widely used employs a muscle relaxant under general anesthesia for safe ECT for the whole body, and it has been recommended as an improved method.1 However, orientation impairment and memory disturbance are considered to be significant adverse side-effects of ECT even in this setting. In this regard, propofol, a general anesthetic frequently used in modified ECT, has become a focus of attention by some investigators because it seemed to paradoxically alleviate post-ECT memory disturbance and cognitive dysfunction. Several short-acting anesthetics have been used for ECT. The most commonly used for the promotion of rapid recovery are the barbiturates, methohexital (not currently available in Japan) and thiopental.5 Propofol is widely known as an intravenous anesthetic that is metabolized quickly, allowing for early awakening. The acute hemodynamic response during ECT is reduced under propofol compared to thiopental, although emergence from propofol anesthesia is only marginally faster than from thiopental.6 However, several studies have demonstrated a shorter seizure duration under propofol anesthesia.5

Table 2. Comparison of variables between two orientation recovery groups Variables

Early recovery group (n = 193)

Late recovery group (n = 67)

P

Number of ECT treatments Output energy (%) Spike and slow wave time (s) Propofol, total dose (mg) Propofol, predicted blood level (μg/mL)

5.86 ± 3.21 44.38 ± 15.66 23.11 ± 15.83 117.4 ± 82.9 1.83 ± 0.38

5.91 ± 3.37 44.55 ± 17.75 25.07 ± 14.51 94.52 ± 43.17 1.87 ± 0.33

0.915 0.874 0.212 0.067 0.359

Values presented as mean ± SD. ECT, electroconvulsive therapy.



Propofol aids memory recovery after ECT 273

Propofol is a lipophilic drug that quickly crosses the blood–brain barrier and has an onset of action on the order of seconds to minutes.7 Butterfield et al. showed that cognitive impairments after ECT decreased to a greater extent with propofol than with thiopental by assessing cognitive states 45 min after each ECT applying various neuropsychological tests, including immediate and delayed verbal memory.3 The report confirmed that propofol anesthesia is less noxious to cognitive function than older anesthetic agents, such as thiopental. However, this does not lead directly to the conclusion that propofol serves as an active protector against the detrimental influence of ECT on memory. Sakamoto et al. found that performance determined by the Mini-Mental State Examination (MMSE) with propofol at a single dose of 2 mg/kg was superior to that at a dose of 1 mg/kg.8 However, the relation between blood levels of propofol during ECT and memory impairment after the procedure has not been examined. Recently, TCI has been introduced in clinical practice for anesthesia with propofol.9–11 TCI continuously regulates the dose of the anesthetic and maintains blood level at a certain effective point by predicting blood level with computer simulation. Key pharmacokinetic parameters vary widely between patients depending on age, sex, and weight. These variables can be programmed into a pharmacokinetic model describing the distribution and elimination of the drug, and the TCI system uses this information to predict the blood concentration associated with the delivery of a given amount of drug.9 In the current study, ECT was managed with propofol anesthesia through TCI under the guidance of an anesthesiologist. This enabled us to keep the blood level of anesthetic agents surprisingly stable. In this setting, we found that both predicted blood level and total dose of propofol were higher in the early memory recovery group as compared to the late memory recovery group. This provides a strong argument in favor of the protective effect of propofol anesthesia against memory derangement following ECT. In a previous experiment with rats, the level of glutamic acid in the hippocampus decreased after ECT, and this decrease was inhibited when propofol was administered before ECT.12 Luo Jie et al. found propofol reversed the change in hippocampal glutamate, γ-aminobutyric acid (GABA) level, and their ratio induced by electroconvulsive shock in depressed

rats. Furthermore, they found propofol reversed the increased expression of hippocampal glutamic acid decarboxylase 65 (GAD65) induced by electroconvulsive shock in depressed rats.13 The hippocampus is one of the essential brain regions activated in learning and memory. A balance of neuronal transmission between the excitatory neurotransmitter glutamate and the inhibitory substance GABA is required to maintain normal functions of learning and memory in the brain.14 The decrease in glutamate or increase in GABA can lead to impairment of learning and memory.15 The pathway that produces GABA in the brain used glutamate as the substrate and GAD as the catalyst. The representation of GAD is GAD 65.13 This may explain the protective effects of propofol. Furthermore, Li et al. found that propofol may also alleviate ECT-induced learning/memory impairments in depressed rats by enhancing hippocampal activation of calcium/calmodulin-dependent protein kinase IIα (CaMK IIα), a critical enzyme in the initiation and early maintenance of synaptic changes that contribute to learning and memory.16 Our study has several limitations. We did not measure memory or orientation recovery times with sub-minute accuracy and so did not perform correlation or regression analyses. Second, we examined only short-term deficits, which recovered fully using the tests administered, rather than the long-term cognitive effects of ECT. Butterfield et al. summarized previous studies investigating the influence of ECT on cognition3 and noted that most assessed memory recovery between awakening from anesthesia and discharge from the recovery room, while few tested the longer-term impact of ECT on memory under different anesthetics. Follow-up studies should thus investigate recovery over longer post-ECT periods using tests that can reveal more subtle deficits. Moreover, we classified patients into early and late memory recovery groups according to whether they answered correctly within 10 min. However, this delay tests only short-term memory and results may have differed at longer or shorter delays that engage other forms of memory. A follow-up study probing the effects of ECT under different anesthetics on recovery of other memory processes is clearly warranted. A third limitation is that we did not control for baseline cognitive function, educational background, or disease history. Finally, although there was no significant difference in the number of ECT treatments between groups, there was a trend for more treatments in the early recovery group. The


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reasons for this are unclear. Further studies involving more patients and matching baseline conditions across groups are required. Our data shows that the predicted blood propofol levels and propofol total dose influence memory impairment after ECT. When propofol is used for ECT anesthesia, we suggest that a slightly deeper anesthetic level may facilitate post-ECT recovery of verbal memory, although further studies are necessary to define the optimal dose.

5. Bauer J, Hageman I, Dam H et al. Comparison of propofol and thiopental as anesthetic agents for electroconvulsive therapy: a randomized, blinded comparison of seizure duration, stimulus charge, clinical effect, and cognitive side effects. J. ECT 2009; 25: 85–90. 6. Kumar A, Sharma DK, Mani R. A comparison of propofol and thiopentone for electroconvulsive therapy. J. Anaesthesiol. Clin. Pharmacol. 2012; 28: 353–357. 7. Patel SB, Kress JP. Sedation and analgesia in the mechanically ventilated patient. Am. J. Respir. Crit. Care Med. 2012; 185: 486–497. 8. Sakamoto A, Hoshino T, Suzuki N, Suzuki H, Kimura M, Ogawa R. Effects of propofol anesthesia on cognitive recovery of patients undergoing electroconvulsive therapy. Psychiatry Clin. Neurosci. 1999; 53: 655–660. 9. Guarracino F, Lapolla F, Cariello C et al. Target controlled infusion: TCI. Minerva Anestesiol. 2005; 71: 335–337. 10. Russel D. Intravenous anaesthesia: Manual infusion schemes versus TCI systems. Anaesthesia 1998; 53 (Suppl. 1): 42–45. 11. Gepts E. Pharmacokinetic concepts for TCI anaesthesia. Anaesthesia 1998; 53 (Suppl.): 4–12. 12. Dong J, Min S, Wei K, Li P, Cao J, Li Y. Effects of electroconvulsive therapy and propofol on spatial memory and glutamatergic system in hippocampus of depressed rats. J. ECT 2010; 26: 126–130. 13. Luo J, Min S, Wei K, Li P, Dong J, Liu Y. Propofol protects against impairment of learning-memory and imbalance of hippocampal Glu/GABA induced by electroconvulsive shock in depressed rats. J. Anesth. 2011; 25: 657–665. 14. Car H, Wis´niewski K. Similarities and interactions between GABAergic and glutaminergic systems. Rocz. Akad. Med. Bialymst. 1998; 43: 5–26. 15. Matsuyama S, Taniguchi T, Kadoyama K, Matsumoto A. Long-term potentiation-like facilitation through GABAA receptor blockade in the mouse dentate gyrus in vivo. Neuroreport 2008; 19: 1809–1813. 16. Li X, Li W, Luo J et al. Effects of propofol on the activation of hippocampal CaMK IIα in depressed rats receiving electroconvulsive therapy. J. ECT 2012; 28: 242–247.

ACKNOWLEDGMENTS The authors thank the anesthesiologists, Department of Anesthesiology, Aichi Medical University, for TCI data. The authors have no conflicts of interest to declare.

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