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* From the Departments of Anesthesiology and
Psychiatry, Gunma University School of Medicine, Maebashi, Japan.
Address correspondence to: Dr. Shigeru Saito, Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22, Showamachi, Maebashi, 371-8511, Japan. Phone: +81-27-220-8454; Fax: +81-27-220-8473; E-mail: shigerus{at}showa.gunma-u.ac.jp
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Methods: In the first study (n = 15), dose-dependent hemodynamic changes were studied when landiolol was administered immediately after induction of anesthesia. In the second study (n = 12), effects of esmolol and landiolol on systemic and cerebral circulation were compared. Patients in Study 1 received three doses of landiolol, and patients in Study 2 received two types of ß-adrenergic-blocking drugs, in a randomized cross-over design in a series of ECT trials.
Results: In the first study, 0.25 to 0.5 mg·kg–1 landiolol induced a lower heart rate after the electrical stimulation compared to vehicle (P < 0.01). Landiolol did not have significant effects on blood pressure. In the second study, heart rate was stabilized by 1.0 mg·kg–1 esmolol iv or 0.5 mg·kg–1 landiolol iv. Increase in mean blood pressure was ameliorated by esmolol (P < 0.01), but not by landiolol. Mean cerebral blood flow velocity in the middle cerebral artery increased at one to two minutes after the electrical stimulation regardless of the use of ß-adrenergic-blocking drugs (P < 0.01). Muscular and electroencephalographic seizure durations were not significantly altered by the ß-adrenergic-blocking drugs.
Conclusion: Landiolol suppresses heart rate elevation during ECT without affecting blood pressure. Cerebral blood flow velocity in the middle cerebral artery is not affected by the use of either esmolol or landiolol.
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Introduction |
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In order to moderate the systemic hemodynamic fluctuations, recent guidelines have recommended use of anti-chronotropic drugs and/or anti-hypertensive medications to reduce the cardiovascular risks of ECT.2 An ultra-short acting ß-adrenergic-blocking drug, esmolol, can be used as an anti-chronotropic drug.3
During the sympathetic stimulation phase of ECT, cerebral blood flow is also augmented. Studies with transcranial Doppler ultrasonography demonstrate an increase in cerebral blood flow velocity in a real-time manner.4,5 In one study, alprenolol partially attenuated cerebral blood flow elevation at a dose which prevents blood pressure (BP) elevation.6 Although esmolol is often used during ECT, there has been no report describing the effect of the ultra-short acting ß-adrenergic-blocking drugs on cerebral blood flow during ECT.
Recently, a new ultra-short acting ß-adrenergic-blocking drug, landiolol, became clinically available. This drug is a more specific anti-chronotropic drug than esmolol, with minimal effect on BP.7 It is possible that landiolol is effective in ameliorating systemic and cerebral hemodynamic changes during ECT. Until now, there has been one report that demonstrated anti-chronotropic and hypotensive properties of landiolol in patients who received maintenance ECT with 1.5 mg·kg–1 propofol and a sine-wave stimulator.8
The hypothesis examined in the present studies was that ultra-short acting ß-adrenergic-blocking drugs ameliorate systemic and cerebral hemodynamics immediately after the electrical stimulation. In addition, we compared the effects of two ultra-short acting ß-adrenergic-blocking drugs, esmolol and landiolol, on systemic and cerebral circulation during ECT. In the first study, dose-dependent effects of landiolol on heart rate (HR) and BP were identified during ECT. In a second study, the effects of esmolol and landiolol on systemic and cerebral circulation were compared at equipotency.7
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These patients were suffering from endogenous depression, and were in good physical health. No patient had cardiovascular or cerebrovascular complications, such as ischemic heart disease, hypertension, arrhythmia, cerebral infarction, intracranial aneurysm, arteriovenous malformation, or drug allergies. Patients under anti-hypertensive medication including ß-adrenergic-blocking drugs were excluded from the study subjects. Also, patients who had obstructive pulmonary disease such as bronchial asthma were excluded from the study. All patients were treated more than six times (three times per week at two-day intervals). The number of ECT sessions for each patient was determined by psychiatrists according to psychiatric symptoms, age, previous history of therapeutics, and the response to ECT. The data were obtained in the second to fifth ECT sessions in Study 1, and the second to fourth sessions in Study 2 in each case, after confirming that no adverse effects were reported in the previous ECT sessions. The selection of dosing (0, 0.125, 0.25, or 0.5 mg·kg–1) or drugs (saline vehicle, esmolol 1.0 mg·kg–1, or landiolol 0.5 mg·kg–1) was determined using a random table. Except for the use of beta-blocking agents, anesthesia and electrical stimulation were identical in the ECT sessions where data were obtained.
Anesthesia management and electrical stimulation
To avoid an unfavourable parasympathetic reflex, atropine 0.01 mg·kg–1 im was given as premedication. Arterial BP was measured continuously at the right radial artery using a tonometric BP monitor (CBM-7000; Colin Co. Ltd., Komaki, Japan). Oxygen saturation was continuously monitored by a pulse oximeter (N-395; NELLCOR Puritan Bennett Inc. Lake Bluff, IL, USA). General anesthesia was induced with propofol 1 mg·kg–1 iv. Propofol was administered over 15 sec through an indwelling iv catheter. After loss of consciousness, succinylcholine chloride 1 mg·kg–1 iv was administered and the patient was ventilated at a rate of 15 breath·min–1 by a trained anesthesiologist using a facemask with 100% oxygen, and the end-tidal carbon dioxide measured at nostril was maintained between 35 to 40 mmHg. One minute after the succinylcholine injection, vehicle or one of the ultra-short acting ß-adrenergic-blocking drugs dissolved in 10 mL of saline was injected over 30 sec. The syringe containing ß-adrenergic-blocking drugs or vehicle was labelled with a sequential number, so that the physicians could not identify the contents of the syringe. Three minutes after the succinylcholine injection, an electrical current was applied bilaterally. The dose of the electrical stimulation was determined during the first ECT session by stepwise increases in stimulus intensity to determine seizure threshold. The electrical stimulus was delivered by trained psychiatrists using an ECT-stimulator (THYMATRONTM DGx; Somatics Inc. Pleasanton, CA, USA). The efficacy of electrical stimulation was determined by the so-called tourniquet technique - that is by observation of convulsive movements of the distal leg, around which an inflated tourniquet was set to block the distribution of muscle relaxant. Electroencephalogram seizure duration was also measured by an electroencephalogram monitor set in the electrical stimulator.
Measurement of cerebral blood flow velocity
A transcranial-Doppler (TC2-64; EME Co. Ltd., Uberlingen, Germany) probe was adjusted to detect middle cerebral artery (MCA) flow from the right temporal side. The flow velocity at the MCA was measured using a 2-MHz ultrasonic wave. The Doppler signals were obtained through the right temporal window at a depth of 45 to 55 mm from the surface. The signal quality was determined from both its characteristic high pitch sound and the waveform of the displayed sonogram. The velocity was calculated automatically by tracing the wave forms every five seconds.
Data analysis
The data are expressed as mean and the corresponding standard deviation. Data were compared by analysis of variance for repeated measures with a P value < 0.05 considered statistically significant. For comparison of each mean value, two-way analysis of variance was applied, and post-hoc testing was performed using Sheffe’s method (StatView 5.0, SAS Institute Inc., NC, USA).
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. The patients ranged from 54 to 81 yr of age in the first study, and from 40 to 80 yr in the second study. Patients had been prescribed multiple psychiatric medications at various doses during their treatment, but were considered non-responsive to drug therapies. The medications were interrupted at least one day before the start of the ECT sessions. In both the first and second studies, there was no abortive electrical stimulation, and muscular and electroencephalographic seizure durations were not significantly different between groups (Table B). All patients in this study completed their scheduled ECT sessions (6–12 times) without any complication.
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). No change in HR was observed in the patients who received landiolol 0.125 to 0.5 mg·kg–1. There were significant differences between the vehicle treated group and the 0.25 mg·kg–1 landiolol treated group (P < 0.05), and between the vehicle treated group and the 0.5 mg·kg–1 landiolol-treated group (P < 0.01). Patients who received 0.25 to 0.5 mg·kg–1 landiolol had a lower HR after electrical stimulation when compared to the patients who received vehicle (P < 0.01 at one to five minutes after the electrical stimulation in the patients who received 0.5 mg·–1; P < 0.01 at one and three minutes and P < 0.05 at four and five minutes after the stimulation in the patients who received 0.25 mg·kg–1). Blood pressure increased one minute after the stimulation in all groups, with no significant difference between the groups (Figure 2). No adverse effects, such as arrhythmia or severe bradycardia, were observed in association with the use of landiolol.
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). There were no changes in HR compared to baseline values in either the esmolol or landiolol treated groups. Patients who received esmolol had a significantly lower HR one minute after stimulation, compared to patients who received vehicle (P < 0.05). Patients who received landiolol had a lower HR at one to four minutes after the stimulation, compared to the patients who received vehicle (P < 0.01). Mean BP increased one minute after the stimulation in the patients who received vehicle or landiolol (P < 0.01), (Figure 4). Mean BP in the patients who received esmolol did not change after the stimulation, and the value at one minute after the stimulation was lower than the corresponding value in the vehicle treated patients (P < 0.01).
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). The value in the esmolol or landiolol treated groups increased one to three minutes after the stimulation (P < 0.01 at 1–2 min after the stimulation, P < 0.05 at 3 min after the stimulation), with no significant differences between groups.
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Discussion |
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Heart rate and mean BP of the vehicle treated groups in the present study were compatible with our previous results.9–11 An increase in the cerebral blood flow velocity at one to three minutes after electrical stimulation was prolonged in this study compared to our previous study, where the increase subsided within two minutes.9 The relatively greater age of patients, and possible cerebral atherosclerotic changes may have had been contributing factors in the present study.
During ECT, a parasympathetic discharge is stimulated at the beginning of seizure, thereafter sympathetic tones are elevated for five to ten minutes.1,12 In the sympathetic dominant phase, HR and BP are increased and cardiac oxygen demand is elevated. Both we13 and Bergsholm et al.14 reported that the rate pressure product (HR x SBP), an index of myocardial oxygen demand, is elevated by 50 to 400% immediately after the electrically induced seizure. When propofol is used as the induction drug, hemodynamic changes are minor compared to the effects observed with methohexital or thiopental.2,12 In some cases, temporary tachycardia is solely observed without hypertension.
In order to moderate systemic hemodynamic fluctuations, recent guidelines have recommended use of anti-chronotropic drugs and/or anti-hypertensive medications to reduce the cardiovascular risks of ECT.2 The indication for these drugs may be greater when either methohexital or thiopental are used. An ultra-short acting ß-adrenergic-blocking drug, esmolol, can be used as an anti-chronotropic agent.3 In some cases, however, BP elevation is not effectively prevented by esmolol. Several investigators recommend the combined use of two ß-adrenergic-blocking drugs, labetalol, which has combined 
- and ß- blocking properties, and esmolol, to prevent both tachycardia and hypertension in patients with cardiovascular disease.15
Landiolol is a more specific anti-chronotropic ß-adrenergic-blocking drug than esmolol, with minimal effects on BP.7 The carboxyl side branches contribute to its specific anti-chronotropism.16 Sasao et al. demonstrated that landiolol decreased HR more rapidly than esmolol without affecting BP in a rabbit model.7 In the present study, the effect on HR after the electrical stimulation was similar when comparing esmolol and landiolol. In contrast, a moderating effect on BP was observed only with esmolol. Kitamura et al. also reported that the action of landiolol was mostly anti-chronotropic, without anti-inotropic action in their study during tracheal intubation.17 These phenomena may imply that the action of landiolol is purely anti-chronotropic. Recently, however, Sakamoto et al. demonstrated hypotensive properties of landiolol in patients who received maintenance ECT with 1.5 mg·kg–1 propofol and a sine-wave stimulator.8 It is possible that landiolol has some hypotensive action when administered with higher anesthetic doses.
In a clinical study examining the hemodynamic effects of landiolol during tracheal intubation, 0.25 to 0.5 mg·kg–1 landiolol effectively prevented tachycardia during intubation.17 Based upon the results of this study, we examined the systemic hemodynamic effects of landiolol over a dose range of 0.125 to 0.5 mg·kg–1. The results of the present study demonstrate that landiolol can be used safely and effectively in attenuating tachycardia in response to ECT under propofol anesthesia. According to reports by Sasao et al., the anti-chronotropic potency of landiolol was approximately double that of esmolol in an in vivo rabbit model.7 The recommended dose of esmolol for ECT is approximately 1 mg·kg–1,2,12 suggesting an effective dose of 0.25 to 0.5 mg·kg–1 landiolol for this indication. We observed that 0.25 to 0.5 mg·kg–1 landiolol and 1.0 mg·kg–1 esmolol exhibit a similar anti-chronotropic response one minute after the electrical stimulation.
The anti-chronotropic action of landiolol is slightly longer than that of esmolol in the canine isolated heart preparation.18 In our study, HR in the landiolol treated group was lower than that of the vehicle treated group for four minutes, while the HR in the esmolol treated group was lower than that of the vehicle group for one minute. This difference might imply that the anti-chronotropic action of landiolol is longer than that of esmolol.
There have been several reports describing ischemic cardiac complications during ECT.19,20 Usually, both anti-chronotropic and anti-inotropic actions are required for hemodynamic stabilization during ECT under barbiturate anesthesia. However, in the patients with ischemic heart disease and compromised cardiac function, pure anti-chronotropic action without anti-inotropic action may be required.21 Landiolol might be suitable when ECT is scheduled for patients with low cardiac output syndrome accompanied by ischemic heart disease, to whom pure anti-chronotropic action without anti-inotropic effect is advantageous. Also, when tachycardia is an isolated hemodynamic manifestation during ECT, landiolol might be superior to other ß-adrenergic-blocking drugs. Since this study was designed to identify the effects of landiolol and esmolol in patients without cardiovascular complications, further studies and more clinical experience are required to determine what types of patients are most suitable to these ß-adrenergic-blocking drugs.
Although catastrophic cerebral complications in association with ECT are rare, careful management is recommended when patients have an intracranial mass or aneurysm.2 Previously, we reported that the use of anti-hypertensive drugs influences cerebral blood flow, and that the effect on cerebral blood flow varies amongst the anti-hypertensive drugs. Effects of ultra-short acting ß-adrenergic-blocking drugs on cerebral blood flow during ECT have not been examined. However, there are several reports that examined effects of esmolol on cerebral blood flow in other clinical settings. Strebel et al. demonstrated that an increase in cerebral blood flow velocity induced by ketamine administration could not be blocked by esmolol.22 Heinke et al. reported that esmolol does not affect a cerebral blood flow increase after ß-adrenergic stimulation.23 In accordance with these reports, in our present study, both esmolol and landiolol had minimal effects on cerebral blood flow velocity during ECT. In contrast, Grillo et al. demonstrated that an increase in cerebral blood flow during emergence from neurosurgical anesthesia was blunted by continuous esmolol infusion.24 The effect of ultra-short acting ß-adrenergic-blocking drugs on cerebral blood flow might vary depending on the clinical setting.
In the present study, neither esmolol nor landiolol had a significant effect on seizure duration. Sakamoto et al. also demonstrated that landiolol at 0.1 mg·kg–1 did not affect seizure duration in ECT.8 These results were compatible with the report by Weinger et al. that demonstrated a minimal effect of esmolol on seizure duration.25 However, van den Broek et al.26 reported relatively short seizures when esmolol was used during ECT. Differences with respect to patient characteristics, use of opioids, and the dose and type of anesthetics might explain the varying results in these clinical studies.
In conclusion, the new ultra-short acting ß-adrenergic-blocking drug, landiolol, effectively suppressed HR elevation after the electrical stimulation of ECT. The effect on BP was minimal and less than that of esmolol. Cerebral blood flow velocity in the MCA was not affected by the use of either esmolol or landiolol.
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Accepted for publication June 6, 2005. Revision accepted July 6, 2005.
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2 Weiner RD, Coffey CE, Fochtmann LJ, et al. The Practice of Electroconvulsive Therapy: Recommendations for Treatment, Training, and Privileging, 2nd ed. A Task Force Report of the American Psychiatric Association. Washington DC: American Psychiatric Association; 2001.
3 Howie MB, Hiestand DC, Zvara DA, Kim PY, McSweeney TD, Coffman JA. Defining the dose range for esmolol used in electroconvulsive therapy hemodynamic attenuation. Anesth Analg 1992; 75: 805–10.
4 Saito S, Yoshikawa D, Nishihara F, et al. The cerebral hemodynamic response to electrically induced seizures in man. Brain Res 1995; 673: 93–100.[Medline]
5 Vollmer-Haase J, Folkerts HW, Haase CG, Deppe M, Ringelstein EB. Cerebral hemodynamics during electrically induced seizures. Neuroreport 1998; 9: 407–10.[Medline]
6 Saito S, Kadoi Y, Iriuchijima N, et al. Reduction of cerebral hyperemia with anti-hypertensive medication after electroconvulsive therapy. Can J Anesth 2000; 47: 767–74.
7 Sasao J, Tarver SD, Kindscher JD, Taneyama C, Benson KT, Goto H. In rabbits, landiolol, a new ultra-short acting beta-blocker, exerts a more potent negative chronotropic effect and less effect on blood pressure than esmolol. Can J Anesth 2001; 48: 985–9.
8 Sakamoto A, Ogawa R, Suzuki H, Kimura M, Okubo Y, Fujiya T. Landiolol attenuates acute hemodynamic responses but does not reduce seizure duration during maintenance elelctroconvulsive therapy. Psychiatry Clin Neurosci 2004; 58: 630–5.[Medline]
9 Saito S, Kadoi Y, Nara T, et al. The comparative effects of propofol versus thiopental on middle cerebral artery blood flow velocity during electroconvulsive therapy. Anesth Analg 2000; 91: 1531–6.
10 Kadoi Y, Saito S, Seki S, Ide M, Morita T, Goto F. Electroconvulsive therapy impairs systolic performance of the left ventricle. Can J Anesth 2001; 48: 405–8.
11 Saito S, Kadoi Y, Nihishara F, Aso C, Goto F. End-tidal carbon dioxide monitoring stabilized hemodynamic changes during ECT. J ECT 2003; 19: 26–30.[Medline]
12 Ding Z, White PF. Anesthesia for electroconvulsive therapy. Anesth Analg 2002; 94: 1351–64.
13 Nishihara F, Saito S, Tobe M, Harada N, Kadoi Y, Goto F. Hemodynamic changes during electroconvulsive therapy under propofol anesthesia. J Anesth 2002; 16: 332–5.[Medline]
14 Bergsholm P, Bleie H, Gran L, d’Elia G. Cardiovascular response and seizure duration as determined by electroencephalography during unilateral electroconvulsive therapy. Acta Psychiatr Scand 1993; 88: 25–8.[Medline]
15 Weinger MB, Partridge BL, Hauger R, Mirow A, Brown M. Prevention of the cardiovascular and neuroendocrine response to electroconvulsive therapy: II. Effects of pretreatment regimens on catecholamines, ACTH, vasopressin, and cortisol. Anesth Analg 1991; 73: 563–9.
16 Iguchi S, Iwamura H, Nishizaki M, et al. Development of a highly cardioselective ultra short-acting beta-blocker, ONO-1101. Chem Pharm Bull 1992; 40: 1462–9.
17 Kitamura A, Sakamoto A, Inoue T, Ogawa R. Efficacy of an ultrashort-acting beta-adrenoceptor blocker (ONO-1101) in attenuating cardiovascular responses to endotracheal intubation. Eur J Clin Pharmacol 1997; 51: 467–71.[Medline]
18 Motomura S, Hagihara A, Narumi Y, Hashimoto K. Time course of a new ultrashort-acting beta-adrenoceptor-blocking drug, ONO-1101: comparison with those of esmolol and propranolol by using the canine isolated, blood-perfused heart preparations. J Cardiovasc Pharmacol 1998; 31: 431–40.[Medline]
19 Lopez-Gomez D, Sanchez-Corral MA, Cobo JV, Jara F, Esplugas E. Myocardial infarction after electroconvulsive therapy (Spanish). Rev Esp Cardiol 1999; 52: 536–8.[Medline]
20 Ali PB, Tidmarsh MD. Cardiac rupture during electroconvulsive therapy. Anaesthesia 1997; 52: 884–6.[Medline]
21 Kirshenbaum JM, Kloner RA, Antman EM, Braunwald E. Use of an ultra short-acting beta-blocker in patients with acute myocardial ischemia. Circulation 1985; 72: 873–80.
22 Strebel S, Kaufmann M, Maitre L, Schaefer HG. Effects of ketamine on cerebral blood flow velocity in humans. Influence of pretreatment with midazolam or esmolol. Anaesthesia 1995; 50: 223–8.[Medline]
23 Heinke W, Zysset S, Hund-Georgiadis M, Olthoff D, von Cramon DY. The effect of esmolol on cerebral blood flow, cerebral vasoreactivity, and cognitive performance: a functional magnetic resonance imaging study. Anesthesiology 2005; 102: 41–50.[Medline]
24 Grillo P, Bruder N, Auquier P, Pellissier D, Gouin F. Esmolol blunts the cerebral blood flow velocity increase during emergence from anesthesia in neurosurgical patients. Anesth Analg 2003; 96: 1145–9.
25 Weinger MB, Partridge BL, Hauger R, Mirow A. Prevention of the cardiovascular and neuroendocrine response to electroconvulsive therapy: I. Effectiveness of pretreatment regimens on hemodynamics. Anesth Analg 1991; 73: 556–62.
26 van den Broek WW, Leentjens AF, Mulder PG, Kusuma A, Bruijn JA. Low-dose esmolol bolus reduces seizure duration during electroconvulsive therapy: a double-blind, placebo-controlled study. Br J Anaesth 1999; 83: 271–4.
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