Blackwell Science, LtdOxford, UKPCNPsychiatry and Clinical Neurosciences1323-13162004 Blackwell Science Pty Ltd586630635Original ArticleLandiolol and mECTA. Sakamoto et al.
Psychiatry and Clinical Neurosciences (2004), 58, 630–635
Regular Article
Landiolol attenuates acute hemodynamic responses but does not reduce seizure duration during maintenance electroconvulsive therapy ATSUHIRO SAKAMOTO, md,1 RYO OGAWA, md,1 HIROKO SUZUKI, md,2 MAHITO KIMURA, md,2 YOSHIRO OKUBO, md2 AND TESTUO FUJIYA, md3 Departments of 1Anesthesiology, and 2Neuropsychiatry, Nippon Medical School and 3Department of Neurology, Medical Corporation Suzuki Hospital, Tokyo, Japan
Abstract
Maintenance electroconvulsive therapy (mECT) is an outpatient procedure that requires further consideration in terms of management of ambulatory anesthesia. Although many adjunctive drugs for stabilizing hemodynamic changes during ECT have been reported, side-effects of these drugs may delay recovery and discharge from hospital. The effects of landiolol, a novel ultra-short-acting b-adrenergic blocker, have been measured on seizure duration, hemodynamic changes, recovery from anesthesia, and cognitive function during mECT under propofol anesthesia. A total of 10 patients with depression in the remission phase, were studied in a randomized, double-blind, placebo-controlled, crossover manner. Administration of 0.1 mg/kg of landiolol immediately before anesthesia significantly blunted the increase in heart rate and blood pressure during convulsions compared with placebo; landiolol was not associated with excessive hypotension or bradycardia. Landiolol did not affect seizure duration, recovery from anesthesia, or cognitive function before or after ECT. These results suggest that landiolol can be used effectively and safely during mECT.
Key words
cognitive function, electroconvulsive therapy, hemodynamics, landiolol.
INTRODUCTION Maintenance electroconvulsive therapy (mECT) is an outpatient procedure for patients who have already exhibited satisfactory improvement with a conventional course of electroconvulsive therapy (ECT) and who have previously failed or do not tolerate maintenance drug therapy.1 Like ECT, mECT is performed under general anesthesia, however, further considerations, such as rapid recovery of psychomotor and cognitive function, need to be addressed with mECT. Many intravenous anesthetics can control the hemodynamic changes induced by ECT, however, tachycardia and hypertension can sometimes become critical,
Correspondence address: Atsuhiro Sakamoto, Department of Anesthesiology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Email:
[email protected] Received 19 February 2004; revised 26 April 2004; accepted 16 May 2004.
even in patients without apparent cardiovascular diseases,2,3 especially when a low dose of anesthetic is used to encourage rapid recovery from anesthesia and not to influence the effect of ECT. Many adjunctive drugs have been reported to reduce acute hemodynamic responses, however, problems such as a decrease in seizure duration, prolonged cardiovascular depression, and excessive hypotension prior to ECT have been reported.4–7 Esmolol has gained popularity in controlling tachycardia because of its short duration of action and high cardioselectivity. However, esmolol can be cardiodepressive and cause hypotension and congestive heart failure, thereby limiting its usefulness.8,9 Landiolol (–)-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl] methyl 3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbonylamino)ethylamino]propoxy] phenylpropionate monohydrochloride, is a recently developed ultrashort-acting b-adrenoceptor blocker created by altering the chemical structure of esmolol to produce a greater degree of cardioselectivity and more potency.10
Landiolol and mECT
The suppressive effects of landiolol on cardiovascular performance were reported to be significantly less potent than those of esmolol at equipotent b-blocking doses.11 In many reports, landiolol exhibits a predominant chronotropic effect, as compared with an inotropic effect, and, thus, causes neither excessive hypotension nor cardiac decompression.12–16 It is thought that these features make landiolol suitable for use during ambulatory anesthesia for situations that may be associated with acute hemodynamic responses. The purpose of this study is to evaluate the safety and efficacy of routine landiolol use during mECT under propofol anesthesia.
METHODS This randomized, placebo-controlled, double-blind cross-over study was approved by the review board of Suzuki Hospital, Japan and written informed consent was obtained from all subjects prior to the study. We studied 10 patients with major depression diagnosed by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, who were already undergoing mECT at an outpatient psychiatric clinic. All patients had exhibited satisfactory improvement with a conventional course of ECT at Nippon Medical School Main Hospital and had previously failed or did not tolerate drug treatment-based maintenance therapy. Patients were scheduled for 12 consecutive mECT procedures to be provided once or twice a month over 6–8 months. No change was made in any patient’s psychotherapeutic drug therapy during the study, and no premedication was given. During ECT, electrocardiographic findings, heart rate, blood pressure, end-tidal CO2, and oxygen saturation were monitored at 1-min intervals. Either landiolol (0.1 mg/kg, dissolved by normal saline 2.5 mg/mL) or placebo (normal saline 0.04 mL/kg) was administered intravenously (IV) over 30 s just before induction of anesthesia. This was done in a doubleblind manner using a within-patient randomized block design, consisting of six two-treatment blocks. Anesthesia was induced by IV propofol 1.5 mg/kg administered over 30 s. After loss of consciousness, a tourniquet applied to the upper arm was inflated to isolate the circulation to the arm and permit an accurate assessment of the motor seizure. Then, 1.0 mg/kg of IV succinylcholine was administered in the opposite arm. Ventilation was assisted using a facemask with 100% oxygen, and the patients maintained normocapnia. An electrical sign curve stimulus was delivered via bitemporal electrodes using a SAKAI CS-1 device (Sakai Medical Instruments, Tokyo, Japan) at 110 v setting for 7 s. Motor seizure duration was evaluated according to
631
the time from the start of ECT stimulus to cessation of tonic-clonic motor activity in the ‘isolated’ arm. Duration of time to recover from anesthesia was determined by asking the patient to open his or her eyes at 1-min intervals and recording the time from the start of injecting the induction agent until a response was first obtained. The Folstein Mini-Mental Status Examination (MMSE)17 was used to assess cognitive function before and 2 h after ECT. A score of less than 20 was considered to represent cognitive impairment.17,18 The standard discharge criteria after general anesthesia19 were adapted for each patient. In addition, all patients received psychomotor and cognitive examinations by the attending psychiatrists. At 3 h after the ECT procedure, the patient could be discharged from the hospital accompanied by a responsible adult. All data are expressed as mean ± SD. Statistical evaluation in each session (placebo or landiolol) on seizure duration, cardiac parameters, recovery times, and MMSE score were performed by one-way anova. Statistical evaluations between sessions were performed with the c2 test and one-way factorial anova using Bonferroni’s correction to perform multiple comparisons. A P-value < 0.05 was considered statistically significant.
RESULTS All 10 patients (9 women, 1 man) were able to complete the study and received placebo and landiolol six times each. No patient experienced a depressive episode, considered to be a recurrence, during the study. Mean age, weight, and height of the 10 patients enrolled in the study were 67 ± 8 years (range 56–80 years), 54 ± 7 kg (range 42–86 kg), and 153 ± 7 cm (range 142–175 cm), respectively. A total of 120 treatments (60 placebo and 60 landiolol) were studied. Table 1 shows the patient characteristics including mainly prescribed antidepressants for each patient. No patient was medicated with other psychotropic drugs, which may influence the cardiovascular system. The mean motor seizure duration during the placebo session and landiolol session were 24.8 ± 5.8 s and 24.2 ± 6.2 s, respectively, with no significant difference between groups. Table 2 shows the motor seizure duration of each patient. There were no differences in motor seizure duration between placebo and landiolol sessions in any patient. The results of systolic blood pressure (SBP) and heart rate (HR) following each session are shown in Figs 1 and 2. During the placebo session, the patients showed maximum SBP and HR changes 1–3 min after ECT, and those changes returned to baseline values 5– 15 min after ECT. In contrast, administration of landiolol prevented the increase in SBP at 1–3 min after
632
A. Sakamoto et al.
Table 1. Patient characteristics Patient 1 2 3 4 5 6 7 8 9 10
Sex
Age (years)
Weight (kg)
Height (cm)
F F F F F F F F F M
68 69 56 80 68 73 62 73 58 57
42 48 58 61 63 58 47 55 56 86
142 152 156 148 158 154 148 155 160 175
Complications
HT
HT DM
Antidepressant (mg/day) M (60) N (75) F (50) A (75) F (50) C (75) M (40) F (50) M (60) C (150)
A, amitriptyline; C, clomipramine; DM, diabetes mellitus; F, fluvoxamine; HT, hypertension; M, minaserin; N, nortriptyline.
Table 2. Motor seizure duration time in two treatment sessions
Patient 1 2 3 4 5 6 7 8 9 10
Placebo (n = 6, each) 18.7 ± 2.1 25.3 ± 4.0 20.7 ± 3.1 23.7 ± 5.7 27.3 ± 3.1 28.3 ± 5.2 30.7 ± 4.7 24.7 ± 6.4 21.3 ± 3.7 26.8 ± 3.1
Seizure duration (s) Landiolol Total (n = 6, each) (n = 12, each) 17.8 ± 2.2 24.5 ± 4.6 19.5 ± 2.9 21.7 ± 7.6 28.7 ± 2.7 28.0 ± 5.7 30.8 ± 5.0 23.8 ± 6.1 22.0 ± 4.3 25.2 ± 7.5
18.3 ± 2.1 24.9 ± 4.1 20.1 ± 2.9 22.7 ± 6.5 28.0 ± 2.9 28.2 ± 5.2 30.8 ± 4.6 24.3 ± 5.9 21.7 ± 3.9 26.0 ± 5.5
electrical stimulus. HR tended to decrease, but not significantly, after landiolol administration, and was maintained lower than the value in the placebo session until 3 min after ECT. Recovery time from anesthesia in the placebo session and the landiolol session were 8.6 ± 1.5 min (range 6–12 min) and 8.8 ± 1.7 min (6–15 min), respectively, with no significant differences between groups. Table 3 shows the recovery time from anesthesia in each patient. There were no differences of time to recovery between placebo and landiolol sessions in any patient. MMSE scores before and after ECT in the placebo session were 27.5 ± 2.5 (range 23–30) and 27.5 ± 2.5 (23–30), respectively, and those scores in the landiolol session were 27.5 ± 2.5 (range 23–30) and 27.5 ± 2.5 (23–30), respectively. No patients showed an MMSE score under 20 before or after ECT. There were no differences in scores between placebo and landiolol sessions in any patient.
Figure 1. Changes in systolic blood pressure during electroconvulsive therapy. Values are mean ± SD. B, baseline; A, just after anesthesia; D, discharge from hospital. () placebo treatment session; () landiolol treatment session. *P < 0.05 compared with placebo. #P < 0.05 compared with the baseline value.
DISCUSSION The goal of mECT is to maintain the patient in remission by administering additional ECT to prevent relapse or recurrence of illness.1 Furthermore, prevention of severe hemodynamic changes during ECT, rapid recovery from anesthesia, and prevention of prolonged psychomotor and cognitive impairment are necessary to carry out mECT safely. Landiolol is thought to be one of the useful drugs for this purpose, because this study demonstrated that administration of landiolol just before induction of anesthesia,1 attenuated hemodynamic changes effectively,2 did not reduce seizure duration,3 did not affect early cognitive recovery,4 and did not prolong recovery time from anesthesia.
Landiolol and mECT
633
Figure 2. Changes in heart rate during electroconvulsive therapy. Values are mean ± SD. B, baseline; A, just after anesthesia; D, discharge from hospital. () Placebo treatment session; () landiolol treatment session. *P < 0.05 compared with placebo. #P < 0.05 compared with the baseline value.
Table 3. Recovery time from anesthesia in two treatment sessions
Patient 1 2 3 4 5 6 7 8 9 10
Recovery time from anesthesia (min) Placebo Landiolol Total (n = 6, each) (n = 6, each) (n = 12, each) 7.8 ± 0.8 8.3 ± 1.5 8.3 ± 1.4 9.0 ± 1.4 8.3 ± 2.3 9.3 ± 1.8 9.5 ± 1.6 7.8 ± 1.3 9.3 ± 1.0 8.5 ± 1.4
8.0 ± 0.6 8.8 ± 2.1 8.0 ± 1.8 9.3 ± 1.5 8.5 ± 3.3 9.5 ± 1.2 9.2 ± 1.5 8.3 ± 1.8 9.3 ± 1.0 8.7 ± 1.7
7.9 ± 0.7 8.6 ± 1.8 8.2 ± 1.5 9.2 ± 1.4 8.4 ± 2.7 9.4 ± 1.4 9.3 ± 1.5 8.1 ± 1.5 9.3 ± 1.0 8.6 ± 1.5
We have routinely used 1.5 mg/kg of propofol as an induction anesthetic for mECT based on the results of our previous study for severely depressed in-patients undergoing ECT with propofol anesthesia.20 The lower dose (1.0 mg/kg) of propofol was shown not to control hemodynamic changes adequately and to prevent the early recovery of cognitive function. The higher dose (2.0 mg/kg) was shown to shorten the convulsion time extremely. Thus, we used 1.5 mg/kg of propofol in this study. We did not use the anticholinergic drug, atropine, as premedication in the present study, because the usual dose of atropine as premedication cannot inhibit the vagal activity adequately.21 There are several studies that the routine use of atropine could compro-
mise cardiac stability,22 and the intravenous injection of atropine at the time of necessity is recommended.21 Current guidelines from the Royal College of Psychiatry recommend avoiding atropine during ECT,23 and the randomized-controlled studies supported this recommendation.24 From the results of maintaining remission during the study, mean recovery time of 8.7 min, and no difference of cognitive function during mECT, the propofol dose we used is thought to be suitable for ambulatory ECT. However, the preventive effects against acute hemodynamic responses with propofol are not adequate, with some patients showing an increase in blood pressure exceeding 180 mmHg, or tachycardia exceeding 120 bpm. Thus, adjunctive drugs for preventing those hemodynamic changes are desired in high-risk patients, such as patients with cardiovascular diseases, patients who presented critical tachycardia or hypertension during previous ECT, and patients who are expected to show severe hemodynamic changes. Many adjunctive drugs such as b-blockers, calcium antagonists, and narcotics have been used to prevent excessive hemodynamic changes induced by ECT, however, some of these drugs reduce seizure duration and may, thus, interfere with the treatment efficacy of ECT.4,6 Esmolol, a theoretically suitable drug for attenuating cardiovascular responses because it is a bblocker with a short half-life, was reported to reduce seizure duration even with low doses.5,7 Interestingly, another b-blocker, labetalol, was reported not to affect seizure duration.25 In this study, landiolol had no effect on seizure duration. The reason for the differences among b-blockers is unknown. Early studies showed that landiolol is a novel ultrashort-acting b-blocker that has a shorter elimination time (half-life 3–4 min) and higher b-selectivity than esmolol.10,11,16 Landiolol was also reported to have less cardiodepressant effects than esmolol; these features seem to be suitable for mECT. The present study showed that 0.1 mg/kg of landiolol significantly attenuated the increase in HR and SBP until 3 min after the electric stimulus. Landiolol showed the tendency to decrease HR from its administration to 3 min after the electrical stimulus and maintained HR at the pre-ECT level during the observation period. However, neither severe bradycardia (HR < 50 bpm) nor hypotension (SBP < 80 mmHg) occurred. The predominance of chronotropic effects seen in this study was in agreement with the results of other studies that examined the effect of landiolol during tracheal intubation.12,13 In those studies, landiolol was found to significantly blunt the increase in HR, however, it significantly attenuated the increase in SBP only at the time of the maximum increase in SBP.
634
In this study, significant differences were not shown between placebo and landiolol treatment sessions in terms of recovery time after anesthesia and MMSE scores before and after ECT. These results suggest that landiolol does not prevent the early recovery from ECT treatment-induced psychomotor and cognitive impairments. Considering that landiolol does not reduce seizure duration and adequately prevents acute hemodynamic responses, this agent is thought to be suitable for the prophylactic use during mECT in patients at risk of cardiovascular complications. Because the present study evaluated only one dose of landiolol at a single time, dose-dependent and timingdependent effects on observed parameters are unknown. Further study is necessary to elucidate this issue for the safer and wider use of landiolol.
CONCLUSIONS In conclusion, bolus dose of 0.1 mg/kg landiolol administered immediately before anesthesia prevented the increase in HR and SBP during convulsions and did not lead to hypotension or bradycardia. Landiolol did not interfere with seizure duration or affect early recovery from psychomotor and cognitive impairments. These results indicate that landiolol can be one of the useful adjunctive drugs for hemodynamic stability during mECT.
REFERENCES 1. Abrams R. Electroconvulsive Therapy. Oxford University Press, New York, 2002. 2. Knos GB, Sung YF, Cooper RC, Stoudemire A. Electroconvulsive therapy – induced hemodynamic changes unmask unsuspected coronary artery disease. J. Clin. Anesth. 1990; 2: 37–41. 3. Ding Z, White PF. Anesthesia for electroconvulsive therapy. Anesth. Analg. 2002; 94: 1351–1364. 4. 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: 556–562. 5. Kovac AL, Goto H, Pardo MP, Arakawa K. Comparison of two esmolol bolus doses on the haemodynamic response and seizure duration during electroconvulsive therapy. Can. J. Anaesth. 1991; 38: 204–209. 6. Avramov MN, Stool LA, White PF, Husain MM. Effects of nicardipine and labetalol on the acute hemodynamic response to electroconvulsive therapy. J. Clin. Anesth. 1998; 10: 394–400. 7. van den Broek WW, Leentjens AF, Mulder PG, Kusuma A, Bruijn JA. Low-dose esmolol bolus reduces seizure duration during electroconvulsive therapy: a double-
A. Sakamoto et al.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19. 20.
21.
blind, placebo-controlled study. Br. J. Anaesth. 1999; 83: 271–274. 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: 873–880. Reilly CS, Wood M, Koshakji RP, Wood AJ. Ultrashort-acting beta-blockade: a comparison with conventional beta-blockade. Clin. Pharmacol. Ther. 1985; 38: 579–585. Iguchi S, Iwamura H, Nishizaki M et al. Development of a highly cardioselective ultra short-acting beta-blocker, ONO-1101. Chem. Pharm. Bull. (Tokyo) 1992; 40: 1462– 1469. Sugiyama A, Takahara A, Hashimoto K. Electrophysiologic, cardiohemodynamic and beta-blocking actions of a new ultra-short-acting beta-blocker, ONO-1101, assessed by the in vivo canine model in comparison with esmolol. J. Cardiovasc. Pharmacol. 1999; 34: 70–77. Kitamura A, Sakamoto A, Inoue T, Ogawa R. Efficacy of an ultrashort-acting beta-adrenoceptor blocker (ONO1101) in attenuating cardiovascular responses to endotracheal intubation. Eur. J. Clin. Pharmacol. 1997; 51: 467–471. Hasuo H. Effect of ONO-1101, a novel short-acting bblocker, on hemodynamic responses to isoflurane inhalation and tracheal intubation. J. Anesth. 1998; 12: 115– 118. Ahmet I, Fukushima N, Sawa Y et al. The effects of a new ultra-short-acting beta-adrenergic blocker, ONO-1101, on cardiac function during and after cardiopulmonary bypass. Surg. Today 1999; 29: 248–254. Atarashi H, Kuruma A, Yashima M et al. Pharmacokinetics of landiolol hydrochloride, a new ultra-shortacting beta-blocker, in patients with cardiac arrhythmias. Clin. Pharmacol. Ther. 2000; 68: 143–150. Sasao J, Tarver SD, Kindscher JD, Taneyama C, Benson KT, Goto H. In rabbits, landiolol, a new ultra-shortacting beta-blocker, exerts a more potent negative chronotropic effect and less effect on blood pressure than esmolol. Can. J. Anaesth. 2001; 48: 985–989. Folstein MF, Folstein SE, McHugh PR. ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 1975; 12: 189–198. Ross CA, Peyser CE, Shapiro I, Folstein MF. Delirium: phenomenologic and etiologic subtypes. Int. Psychogeriatr. 1991; 3: 135–147. Korttila K. Recovery from outpatient anaesthesia. Factors affecting outcome. Anaesthesia 1995; 50: 22–28. 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. Parnis SJ, van der Walt JH. A national survey of atropine use by Australian anaesthetists. Anaesth. Intensive Care 1994; 22: 61–65.
Landiolol and mECT
22. Kelway B, Simpson KH, Smith RJ, Halsall PJ. Effects of atropine and glycopyrrolate on cognitive function following anaesthesia and electroconvulsive therapy (ECT). Int. Clin. Psychopharmacol. 1986; 1: 296–302. 23. Royal College of Psychiatrists. The ECT Handbook: The second report of the Royal College of Psychiatrist’s Special Committee on ECT CR39. Royal College of Psychiatrists, London, 1995.
635
24. Mayur PM, Shree RS, Gangadhar BN, Subbakrishna DK, Janakiramaiah N, Rao GS. Atropine premedication and the cardiovascular response to electroconvulsive therapy. Br. J. Anaesth. 1998; 81: 466–467. 25. McCall WV, Shelp FE, Weiner RD, Austin S, Harrill A. Effects of Labetalol on Hemodynamics and Seizure Duration During ECT. Convuls. Ther. 1991; 7: 5– 14.
