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Prevention by acebutolol of rhythm disorders following coronary bypass surgery
International Journal Elsevier
ofCardiology,8 (1985)
275
275-283
IJC 00265
Prevention by acebutolol of rhythm disorders following coronary bypass surgery Pierre
Materne
‘, Robert
Larbuisson
2, Pierre
and Henri
Collignon
Kuibertus
‘, Raymond
Limet
’
’
’ Institute of Medrcine. Sectron of Cardrologv: “Department -’ Department (Received
oj,fAnesthesmloR)’ and Intensive Care; of Surgeyr. L’niuersitv of Li>ge. Belgium
3 September
1984: revision accepted
12 December
1984)
Materne P, Larbuisson R, Collignon P. Limet R, Kulbertus H. Prevention by acebutolol of rhythm disorders following coronary bypass surgery. Int J Cardiol 1985;8:275-283. Seventy-one patients submitted routinely to coronary artery bypass surgery were randomized into 2 groups. Group A (32 patients) received 24 hr after initiation of surgery an intravenous perfusion of 100 mg of acebutolol given over 24 hr (22 cases) or 600 mg administered orally (10 cases). On subsequent days, they received 1200 mg of acebutoloI/day orally. Group B (39 patients) was used as control. The groups were comparable in terms of age, sex, severity of coronary disease, preoperative therapy, duration of extracorporeal circulation, aortic clamping time, and immediate postoperative haemodynamic findings. No patient received digitalis. During hospital stay (10 days), 1 group A patient (3%) and 13 group B patients (33%; P -c 0.001) developed a sustained episode of atrial arrhythmia (fibrillation, flutter or at&d ectopic tachycardia). Tbe majority of these rhythm disorders developed between days 2 and 4. On Holter monitoring on days 7-10, malignant ventricular extrasystoles (grades IV and V of Lown’s classification) were more frequent in group B (65.2%) than in group A (19.3%; P < 0.001). Haemodynamic measurements taken at rest were performed in 27 patients on days 7-10 (16 patients of group A; 11 of group B). No difference was observed between the two groups. Acebutolol is a safe and efficacious drug for the prevention of arrhythmias following coronary surgery. (Key words: coronary
artery disease;
Correspondence to: H.E. Kulbertus, Hospital, 66 Bvd de la Constitution,
0167-5273/85/$03.30
cardiac
surgery)
MD, FACC, Institute of Medicine. 4020 Likge. Belgium.
0 1985 Elsevier Science Publishers
Section of Cardiology,
B.V. (Biomedical
Division)
University
276
Introduction Supraventricular tachyarrhythmias are particularly frequent in the postoperative period following coronary artery bypass surgery (18 to 40%) [l-8]. Various aetiologies have been considered such as adrenergic hyperactivity, interruption of therapy with betablockers, peroperative myocardial infarction, pericardial effusion, etc.. . [9]. The rhythm disorders most frequently occur within 72 hr of the operation. With a view to decrease the incidence of these arrhythmias, the use of digitalis in the early postoperative period has been recommended. However, randomized trials using this therapy yielded deceiving results [5,10,11]. It is only recently that betablockers have been utilized in this indication and several studies have indicated a clearcut reduction of supraventricular tachycardia in patients submitted to betablockade in the early postoperative period [l-8]. The purpose of the present investigation was to assess the value of acebutolol for the prevention of supraventricular and ventricular arrhythmias following coronary surgery and to investigate the haemodynamic tolerance to this treatment shortly after operation. Methods
and Patient
Selection
One hundred and five consecutive patients undergoing routine coronary bypass procedure were considered for inclusion into the study. Fifteen patients were excluded before operation, 12 because of a left ventricular ejection fraction below 40% and 3 because of previous treatment by amiodarone. Nineteen patients were excluded immediately after operation either because of a major perioperative complication (myocardial infarction: 6 cases, cardiac tamponade: 1 case) or because of the inopportune prescription of another antiarrhythmic drug (12 patients). Thus, 71 patients were finally included in the prospective randomized trial: none of them received digitalis before operation and during hospitalization. Surgical Procedure All patients were put on extracorporeal circulation and bypass surgery was performed during aortic clamping under myocardial protection by moderate hypothermia and single dose cold potassium cardioplegia. For all grafts, the saphenous vein was utilized. Acebutolol Treatment after Surgery Thirty-two patients (group A) were randomized to acebutolol which they received 24 hr after initiation of surgery at the dose of either 100 mg intravenously (22 cases) or 600 mg orally during the first day (10 cases) and of 1200 mg/24 hr orally, afterwards. Thirty-nine patients constituted the control group (group B). Arrhythmia Detection All patients were monitored for 4 days. Afterwards, a routine electrocardiogram was taken daily. Finally, a Holter ambulatory 24-hr electrocardiographic recording
217
was performed between days 7 and 10, postoperatively. All the patients who developed a sustained arrhythmia and had to be treated were not submitted to the rest of the protocol. Haemodynamic
Data
Haemodynamic measurements were taken approximately 24 hr after initiation of bypass grafting and before acebutolol therapy. A catheter was introduced into the radial artery and a Swan-Ganz catheter positioned into the pulmonary artery. A repeated haemodynamic investigation was performed in 27 consecutive patients between days 7 and 10. Cardiac output was measured by thermodilution, left ventricular stroke work index expressed in g/m’ (LVSWI) was calculated according to the following formula: LVSWI = SVI x (MAP - PWP) x 0.0136. where SVI = stroke volume index (ml/m2), MAP = mean arterial pressure (mm Hg) and PWP = pulmonary wedge pressure (mm Hg). During the second haemodynamic investigation, an effort test was performed in the first 17 of the 27 patients. It consisted of an isometric exercise (manual compression of hand manometer at half the maximal developed pressure for 2 min). In the last 10 patients, a liquid overload by 500 ml of Gentran@ perfused over 30 min was achieved. Statistical Analysis Standard Student’s t-test and x2 test were used for statistical < 0.05 were considered as indicative of a significant difference.
analysis.
P values
Results Pre-treatment
Data
As indicated in Tables 1 and 2, the treated and control groups were comparable in terms of sex distribution, age and severity of coronary heart disease. The proportion of patients under betablockade before surgery was the same in the two groups of patients. In addition, as usual in this institution, betablockers were interrupted at the time of admission i.e. a minimum of 2 days before the surgical procedure. Operative data were similar in both groups and there was no difference in terms of duration of extracorporeal circulation, aortic clamping time or amount of cardioplegic solution. Hemodynamic data obtained after surgery and before initiation of treatment were also identical in terms of heart rate, pulmonary wedge pressure, mean systemic arterial pressure, cardiac index and left ventricular stroke work index. In the postoperative immediate period serum potassium was maintained in the usual normal range (3.8 to 5.1 mg/l) in all cases. In this institution,
278 TABLE
1
Comparison
between
group A (acebutolol)
Total number Sex Mean age (years) Severity of coronary
ECC = extracorporeal
39 patients 32 males 7 females 57.9 + 6.9
15.7 43.1 40.6
20.5 41 .o 38.5
NS NS NS
65.6
58.9
NS
136.1 f 35.5 40.6+ 16.1 538 k245
126.7 + 40.1 35.95 13.2 482 +189
NS NS NS
B
NS NS
circulation;
NS = not significant.
2
Haemodynamic
HR PWP MAP CI LVSWI
Group
32 patients 28 males 4 female5 55.1 _+7.6
characteristics
Duration of ECC (min) Aortic clamping time (min) Cardioplegic solution (ml)
TABLE
Group A
therap.v with betablockers
(%) Surgical
B (controls)
vessel disease
Mono-vessel disease (48) Double-vessel disease (S) Triple-vessel disease (5%) Preoperatioe
and group
findings
immediately
after coronary
(beats/min) (mm Hg) (mm Hg) (I per min/m’) (g/m’
)
surgery
Group
A
89.9? 9.2* 84.7+ 2.6_+ 31.3i
14.3 3.8 0.5 0.6 8.4
(24 hr after initiation Group
of surgical
procedure).
B
92.7 f 12.8 10.2* 4.4 85.0+11.8 2.9_+ 0.6 32.6 k 10.6
NS NS NS NS NS
CI = cardiac index; HR = heart rate; LVSWl = left ventricular stroke work index; MAP = mean arterial pressure; NS = not significant; PWP = pulmonary wedge pressure.
postoperative patients systematically receive a potassium the first 2 hr and another 40 mg over the next 24 hr.
infusion
of 40 mEq over
Postoperative Arrhythmias (Table 3) An arrhythmia required treatment.
was considered
sustained
when
it lasted
for
> 1 hr and/or
Sustained Supraventricular Arrhythmia. In group A, 1 patient developed sustained atria1 fibrillation on the second day (3.1%). In group B, 13 cases of sustained atria1 arrhythmias were observed (33.3%) (P < 0.01) (atria1 fibrillation 6 cases, atria1 flutter 4 cases, atria1 tachycardia 1 case, combined atria1 flutter and fibrillation 2 cases). In addition, 2 patients (group B) presented a sinus tachycardia with a heart rate faster than 130/min which required treatment. At the 24-hr ambulatory electrocardiogram
279
TABLE Frequency
3 of postoperative
arrhythmias
Supraventricular tachyarrhythmias at monitoring atrial fibrillatmn atria1 flutter atrral tachycardia combined flutter and fibrillation
P
Group A (32 patients)
Group B (39 patienta)
No.
No.
F,
13
33.3
6 4 1 2 2 2
5.1 5.1
1
& 3.1
1 _.
-__ < 0.01
NS NS
Paroxysmal atria1 fibrillation on Holter Sinus tachycardia > 130/min All supraventricular
1
3.1
tachyarrhythmias Frequent ( 3 5%) supraventrtcular
2
6.2
17
43.6
< 0.001
extrasystoles Ventricular extrasystoles
3
9.7
3
14.3
NS
6
19.3
15
65.2
< 0.001
grade IV or V of Lawn’s classification NS = not significant,
performed between days 7 and 10, paroxysmal atria1 fibrillation was detected in 1 case of group A and in 2 cases of group B. Altogether, significant supraventricular tachyarrhythmias were noted in 6.2% of group A patients (2/32) and in 17 cases (43.6%) of the 39 patients of group B (P < 0.001). The arrhythmias appeared most often between the 3rd and the 4th day after operation (11 instances). Only 2 cases were seen during the first postoperative day. Supraventricular &topic Beats. In patients without sustained supraventricular tachyarrhythmia, supraventricular ectopic beats were carefully searched for on the Holter tape. They were considered frequent when they occurred at a rate higher than S/l000 beats. This was the case in 3 patients of group A (9.7%) and in 3 patients of group B (14.3%) (not significant). Ventricular &topic Beats. Ventricular ectopic beats seen on the Holter tape were classified according to Lown’s gradation system. Only classes IV and V were taken into consideration; thus severe ventricular extrasystoles were detected in 6 patients of group A (19.35%) and in 15 patients of group B (65.2%) (P -c0.001). Arrhythmias in Relation with Operative Characteristics. In this study, there was no correlation between the occurrence of sustained tachyarrhythmias and preoperative therapy, duration of intervention, or postoperative haemodynamic findings, In particular, sustained supraventricular arrhythmias were not more frequent in group B patients who received betablockers prior to surgery (34.8%) than in those who did not receive such therapy (56.2%) (not significant).
280 TABLE
4
Haemodynamic
findings
HR (beats/min) MAP (mm Hg) PWP (mm Hg) CI (I per min/m’) LVSWI (g/m2)
at rest on days 7-10. Group A (16 patients)
Group B (11 patients)
P
76.1 & 8.5 92 +15 8.0+ 3.1 3.1 + 0.5 9.6 47.8*
96.4* 11.0 98 *lo 7.6i 4.0 3.3* 0.5 44.7 f 10.9
< 0.001 NS NS NS NS
CI = cardiac index: HR = heart rate; LWSWI = left ventricular stroke work index; MAP = mean arterial pressure; NS = not significant; PWP = pulmonary wedge pressure
TABLE Changes
5 in pulmonary
PWP (mm Hg) LVSWI (g/m’) LVSWI = left ventricular
Haemodynamic
wedge pressure
and left ventricular
stroke work index between
Group A
Group
-1.4+ 5.0 +16.8+11.9
-2.o* 3.3 +9.9+11.7
stroke work index: NS = not significant;
days 1 and 7-10.
B
PWP = pulmonary
NS NS wedge pressure.
Findings on Days 7 to 10
Data Obtained at Rest. These data are summarized in Table 4 which shows that the only significant difference between the 2 groups was the resting heart rate which was 76.1 f 8.5 in group A, as compared to 96.4 f 11.0 in group B (P < 0.001). The other parameters showed no difference between the 2 groups. Interestingly (Table 5) when the haemodynamic findings of day 1 were compared with those of days 7 to 10, the changes in pulmonary wedge pressure and left ventricular stroke work index were similar in both groups. Isometric Exercise. Moderate isometric exercise testing was performed in 10 patients of group A and 7 patients of group B. The changes in haemodynamic parameters as compared to rest values were very similar. The pulmonary wedge pressure raised by 3.5 + 2.5 mm Hg in group A, as opposed to 1.3 f 1.7 in group B (not significant). The only difference was noted for stroke work index which decreased by 0.84 f 4.8 mg/m’ in group A whereas it increased by 5.7 & 6.2 in group B (P < 0.05). Overload by a Macromolecular Solution. Five hundred ml of Gentran”” were administered over a 30-min period to 6 patients of group A and 4 patients of group B. The pulmonary wedge pressure increased by 2.8 f 2.6 mm Hg in group A, versus 3.0 f 1.5 in group B. The stroke work index increased by 6.6 f 6.5 mg/m’ in group A as compared to 4.0 f 6.2 in group B. There were no significant differences between the 2 groups.
281
Side-effects During the hospital stay (average 10 days), no unwanted side-effect related to acebutolol therapy was noted. The dose of 1200 mg/day was maintained throughout hospitalization and without excessive bradycardia. The average heart rate in group A at day 9 was 76.1 &-8.6 beats/min.
Discussion Supraventricular and ventricular arrhythmias are frequent after coronary artery bypass surgery as well as after all types of cardiac operation or thoracotomy [12]. After coronary surgery, the frequency of atria1 flutter and fibrillation is particularly high (18 to 40%). These atria1 arrhythmias most frequently develop in the early postoperative phase and are associated with a fast ventricular response which may compromise the haemodynamic equilibrium or produce myocardial ischaemia [l-8]. Digoxin has been reported to decrease the incidence of those postoperative atria1 tachyarrhythmias [lo-131. However, 2 recent randomized studies have failed to confirm this finding [5-111. In addition, prophylactic administration of digoxin in this indication may be hazardous. Indeed, digitalis intoxication may develop more easily aftei cardiac surgery because of hypocalcemia, hypomagnesemia and reduction of creatinin clearance [14,15]. Finally, the postoperative hyperadrenergic state may in some way counteract the depressing effect of digoxin on the auriculoventricular junction [7,16]. Several recent studies indicated that the prophylactic administration of propranolol clearly decreases the frequency of supraventricular arrhythmias after coronary bypass surgery [l-7]. Timolol has also been utilized in the same indication with success [8]. Stephenson et al. [3] in a randomized study of 223 patients showed that the frequency of supraventricular arrhythmias was decreased from 23 to 8% by small doses of propranolol. Boudoulas and coworkers [l] in an open study of 80 patients reported 30% of supraventricular arrhythmias in the control group as opposed to 5% in the group treated by propranolol. Silverman and his group [6] using small doses of propranolol (4 X 10 mg) obtained the same results, i.e. decrease of the frequency of supraventricular arrhythmia from 28 to 6%. They stressed the fact that, in their series, there was no finding in the pre- or perioperative period which might predict the later occurrence of postoperative arrhythmias. Acebutolol is a cardioselective betablocker with quinidine-like effect and moderate intrinsic sympathetic activity. It has already been used in cardiac surgery. Thorns et al. have studied its mode of administration and plasma levels during the perioperative period [17]. In the present study, the early use of acebutolol reduced from 43.6 to 6.2% the incidence of supraventricular tachyarrhythmias after coronary surgery. Some authors have proposed to use a combination of digoxin and propranolol for the prevention of postoperative tachyarrhythmias [5,12]. Thus, Roffman and Fieldman [5] studied 172 patients 63 of whom served as controls, 59 received digoxin only and 50 a combination of digoxin and propranolol. The frequency of supra-
282
ventricular arrhythmias was 28.2, 28.9, and 2.2%, respectively. A second investigation by Mills et al. [18] noted a frequency of 30% of supraventricular arrhythmias in patients without treatment as opposed to 3.4% in patients receiving digoxin with propranolol. There is, however, no clearcut evidence that the adjunction of digoxin is beneficial. Boudoulas et al. [l], using measurements of systolic intervals, described a good haemodynamic tolerance to betablockers throughout the postoperative period. In the present study, we confirm the good tolerance to acebutolol even at high doses (1200 mg/24 hr). We should, however, stress the fact that all patients with a preoperative ejection fraction lower than 40% were: excluded from this study. Ventricular arrhythmias following coronary artery bypass surgery have received less attention [3,7]; sustained ventricular tachycardia is rare in this situation and ventricular ectopic beats, even if frequent and of high grade probably have little clinical significance. It is worthy of note however that in the present study we demonstrated that acebutolol reduced the frequency of high grade ventricular ectopic beats from 65.2 to 19.3%, as shown by Holter monitoring. The clinical and prognostic implications of these results deserve further studies. Several authors have attributed the high frequency of arrhythmias following cardiac surgery to the interruption of betablockers before intervention [2,4,19]. In the present work, we observed no difference in the frequency of supraventricular arrhythmias between the patients who received or did not receive betablockers prior to surgery. In conclusion, prophylactic administration of acebutolol starting 24 hr after coronary artery bypass surgery dramatically decreases the incidence of supraventricular rhythm disturbances and of ventricular ectopic beats. No deleterious haemodynamic effect was noted.
Acknowledgments We wish to acknowledge the assistance of Mr. A. Goddet, B. Vervier in the preparation of this manuscript.
Ms. S. Smeets and Mrs.
References 1 Boudoulas H, Lewis RP, Karayannacos P, Vasko JS. Beneficial effect of continuation of propranolol through coronary bypass surgery. Clin Cardiol 1979;2:87-91. 2 Salazar C, Frishman W, Friedman S. Beta-blockade therapy for supraventricular tachyarrhythmias after coronary surgery: a propranolol withdrawal syndrome. Angiology 1979;30:816-919. 3 Stephenson LW. MacVaugh H. Tomasello DN, Josephson ME. Propranolol for prevention of postoperative cardiac arrhythmias: a randomized study. Ann Thorac Surg 1980;29:113-116. 4 Mohr R, Smohnsky A, Goor DA. Prevention of supraventricular tachyarrhythmias with low-dose propranolol after coronary bypass. J Thorac Cardiovasc Surg 1981;81:840-845. S Roffman JA, Fieldman A. Digoxin and propranolol in the prophylaxis of supraventricular tachydysrhythmias after coronary artery bypass surgery. Ann Thorac Surg 1981:31:496-501. 6 Silverman NA, Wright R, Levitsky S. Efficacy of low-dose propranolol in preventing postoperative supraventricular tachyarrhythmias: a prospective randomized study. Ann Surg 1982;196:194-197.
283 7 Williams OB, Stephenson LW, Holford FD, Langer T, Dunkman WB. Josephson ME. Arrhythmia prophylaxis using propranolol after coronary artery surgery. Ann Thorac Surg 1982;34:435-438. 8 Vecht RJ, Ikweuke J, Nicolaides FP. Liassides C, Cleary J. Timolol prophylaxis of supraventricular arrhythmias after coronary artery bypass graft: a randomized study. Em Heart J 1983:4(suppl F):28. 9 Angelini P, Feldman Ml, Lufschanowski R. Cardiac arrhythmias during and after heart surgery: diagnosis and management, Prog Cardiovasc Dis 1974;16:469-492. 10 Johnson LW. Dickstein RA, Frueman CT. Prophylactic digitalization for coronary artery bypass surgery. Circulation 1976;53:819-822, 11 Tyrus DH, Stohert JC, Kaiser GC. Supraventricular tachyarrhythmias after myocardial revascularization: a randomized trial of prophylactic digitalization. J Thorac Cardiovasc Surg 1979;77:310-314. 12 Ghosh P. Pakrashi BC. Cardiac dysrhythmias after thoracotomy. Br Heart J 1972;34:384. 13 O’Kane H. Geha A, Baue A. Prophylactic digitalization in aortocoronary bypass patients. Circulation 1972;46-II:199. 14 Morrison J. Tallip PT. Serum digitalis and arrhythmia in patients undergoing cardiopulmonary bypass. Circulation 1973;47:341-346. 15 Bose M, Glassman E, Spencer FC. Arrhythmia following cardiac surgery: relation to serum digoxin levels. Am Heart J 1975;89:288-293. 16 Boudoulas H, Snyder CL, Lewis RP, Kates RE, Karayannacos PE. Vasko JS. Safety and rationale for continuation of propranolol therapy during coronary bypass operation. Ann Thorac Surg 1978;26:222-226. 17 Thorns GM, Reece IJ, Odeom ND, Kaye CM, Sankey MG. Acebutolol and coronary artery surgery. Plasma levels following preoperative treatment. Anaesthesia 1982;37:1078-1083. 18 Mills SA, Poole CV. Breyer RH et al. Digoxin and propranolol in the prophylaxis of dysrhythmias after coronary artery bypass grafting. Circulation 1983;68-II:222-225. 19 Oka Y, Frishman W, Decker RM et al. Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 10. Beta-adrenoceptor blockade and coronary artery surgery. Am Heart J 1980;99:255-269.
ofCardiology,8 (1985)
275
275-283
IJC 00265
Prevention by acebutolol of rhythm disorders following coronary bypass surgery Pierre
Materne
‘, Robert
Larbuisson
2, Pierre
and Henri
Collignon
Kuibertus
‘, Raymond
Limet
’
’
’ Institute of Medrcine. Sectron of Cardrologv: “Department -’ Department (Received
oj,fAnesthesmloR)’ and Intensive Care; of Surgeyr. L’niuersitv of Li>ge. Belgium
3 September
1984: revision accepted
12 December
1984)
Materne P, Larbuisson R, Collignon P. Limet R, Kulbertus H. Prevention by acebutolol of rhythm disorders following coronary bypass surgery. Int J Cardiol 1985;8:275-283. Seventy-one patients submitted routinely to coronary artery bypass surgery were randomized into 2 groups. Group A (32 patients) received 24 hr after initiation of surgery an intravenous perfusion of 100 mg of acebutolol given over 24 hr (22 cases) or 600 mg administered orally (10 cases). On subsequent days, they received 1200 mg of acebutoloI/day orally. Group B (39 patients) was used as control. The groups were comparable in terms of age, sex, severity of coronary disease, preoperative therapy, duration of extracorporeal circulation, aortic clamping time, and immediate postoperative haemodynamic findings. No patient received digitalis. During hospital stay (10 days), 1 group A patient (3%) and 13 group B patients (33%; P -c 0.001) developed a sustained episode of atrial arrhythmia (fibrillation, flutter or at&d ectopic tachycardia). Tbe majority of these rhythm disorders developed between days 2 and 4. On Holter monitoring on days 7-10, malignant ventricular extrasystoles (grades IV and V of Lown’s classification) were more frequent in group B (65.2%) than in group A (19.3%; P < 0.001). Haemodynamic measurements taken at rest were performed in 27 patients on days 7-10 (16 patients of group A; 11 of group B). No difference was observed between the two groups. Acebutolol is a safe and efficacious drug for the prevention of arrhythmias following coronary surgery. (Key words: coronary
artery disease;
Correspondence to: H.E. Kulbertus, Hospital, 66 Bvd de la Constitution,
0167-5273/85/$03.30
cardiac
surgery)
MD, FACC, Institute of Medicine. 4020 Likge. Belgium.
0 1985 Elsevier Science Publishers
Section of Cardiology,
B.V. (Biomedical
Division)
University
276
Introduction Supraventricular tachyarrhythmias are particularly frequent in the postoperative period following coronary artery bypass surgery (18 to 40%) [l-8]. Various aetiologies have been considered such as adrenergic hyperactivity, interruption of therapy with betablockers, peroperative myocardial infarction, pericardial effusion, etc.. . [9]. The rhythm disorders most frequently occur within 72 hr of the operation. With a view to decrease the incidence of these arrhythmias, the use of digitalis in the early postoperative period has been recommended. However, randomized trials using this therapy yielded deceiving results [5,10,11]. It is only recently that betablockers have been utilized in this indication and several studies have indicated a clearcut reduction of supraventricular tachycardia in patients submitted to betablockade in the early postoperative period [l-8]. The purpose of the present investigation was to assess the value of acebutolol for the prevention of supraventricular and ventricular arrhythmias following coronary surgery and to investigate the haemodynamic tolerance to this treatment shortly after operation. Methods
and Patient
Selection
One hundred and five consecutive patients undergoing routine coronary bypass procedure were considered for inclusion into the study. Fifteen patients were excluded before operation, 12 because of a left ventricular ejection fraction below 40% and 3 because of previous treatment by amiodarone. Nineteen patients were excluded immediately after operation either because of a major perioperative complication (myocardial infarction: 6 cases, cardiac tamponade: 1 case) or because of the inopportune prescription of another antiarrhythmic drug (12 patients). Thus, 71 patients were finally included in the prospective randomized trial: none of them received digitalis before operation and during hospitalization. Surgical Procedure All patients were put on extracorporeal circulation and bypass surgery was performed during aortic clamping under myocardial protection by moderate hypothermia and single dose cold potassium cardioplegia. For all grafts, the saphenous vein was utilized. Acebutolol Treatment after Surgery Thirty-two patients (group A) were randomized to acebutolol which they received 24 hr after initiation of surgery at the dose of either 100 mg intravenously (22 cases) or 600 mg orally during the first day (10 cases) and of 1200 mg/24 hr orally, afterwards. Thirty-nine patients constituted the control group (group B). Arrhythmia Detection All patients were monitored for 4 days. Afterwards, a routine electrocardiogram was taken daily. Finally, a Holter ambulatory 24-hr electrocardiographic recording
217
was performed between days 7 and 10, postoperatively. All the patients who developed a sustained arrhythmia and had to be treated were not submitted to the rest of the protocol. Haemodynamic
Data
Haemodynamic measurements were taken approximately 24 hr after initiation of bypass grafting and before acebutolol therapy. A catheter was introduced into the radial artery and a Swan-Ganz catheter positioned into the pulmonary artery. A repeated haemodynamic investigation was performed in 27 consecutive patients between days 7 and 10. Cardiac output was measured by thermodilution, left ventricular stroke work index expressed in g/m’ (LVSWI) was calculated according to the following formula: LVSWI = SVI x (MAP - PWP) x 0.0136. where SVI = stroke volume index (ml/m2), MAP = mean arterial pressure (mm Hg) and PWP = pulmonary wedge pressure (mm Hg). During the second haemodynamic investigation, an effort test was performed in the first 17 of the 27 patients. It consisted of an isometric exercise (manual compression of hand manometer at half the maximal developed pressure for 2 min). In the last 10 patients, a liquid overload by 500 ml of Gentran@ perfused over 30 min was achieved. Statistical Analysis Standard Student’s t-test and x2 test were used for statistical < 0.05 were considered as indicative of a significant difference.
analysis.
P values
Results Pre-treatment
Data
As indicated in Tables 1 and 2, the treated and control groups were comparable in terms of sex distribution, age and severity of coronary heart disease. The proportion of patients under betablockade before surgery was the same in the two groups of patients. In addition, as usual in this institution, betablockers were interrupted at the time of admission i.e. a minimum of 2 days before the surgical procedure. Operative data were similar in both groups and there was no difference in terms of duration of extracorporeal circulation, aortic clamping time or amount of cardioplegic solution. Hemodynamic data obtained after surgery and before initiation of treatment were also identical in terms of heart rate, pulmonary wedge pressure, mean systemic arterial pressure, cardiac index and left ventricular stroke work index. In the postoperative immediate period serum potassium was maintained in the usual normal range (3.8 to 5.1 mg/l) in all cases. In this institution,
278 TABLE
1
Comparison
between
group A (acebutolol)
Total number Sex Mean age (years) Severity of coronary
ECC = extracorporeal
39 patients 32 males 7 females 57.9 + 6.9
15.7 43.1 40.6
20.5 41 .o 38.5
NS NS NS
65.6
58.9
NS
136.1 f 35.5 40.6+ 16.1 538 k245
126.7 + 40.1 35.95 13.2 482 +189
NS NS NS
B
NS NS
circulation;
NS = not significant.
2
Haemodynamic
HR PWP MAP CI LVSWI
Group
32 patients 28 males 4 female5 55.1 _+7.6
characteristics
Duration of ECC (min) Aortic clamping time (min) Cardioplegic solution (ml)
TABLE
Group A
therap.v with betablockers
(%) Surgical
B (controls)
vessel disease
Mono-vessel disease (48) Double-vessel disease (S) Triple-vessel disease (5%) Preoperatioe
and group
findings
immediately
after coronary
(beats/min) (mm Hg) (mm Hg) (I per min/m’) (g/m’
)
surgery
Group
A
89.9? 9.2* 84.7+ 2.6_+ 31.3i
14.3 3.8 0.5 0.6 8.4
(24 hr after initiation Group
of surgical
procedure).
B
92.7 f 12.8 10.2* 4.4 85.0+11.8 2.9_+ 0.6 32.6 k 10.6
NS NS NS NS NS
CI = cardiac index; HR = heart rate; LVSWl = left ventricular stroke work index; MAP = mean arterial pressure; NS = not significant; PWP = pulmonary wedge pressure.
postoperative patients systematically receive a potassium the first 2 hr and another 40 mg over the next 24 hr.
infusion
of 40 mEq over
Postoperative Arrhythmias (Table 3) An arrhythmia required treatment.
was considered
sustained
when
it lasted
for
> 1 hr and/or
Sustained Supraventricular Arrhythmia. In group A, 1 patient developed sustained atria1 fibrillation on the second day (3.1%). In group B, 13 cases of sustained atria1 arrhythmias were observed (33.3%) (P < 0.01) (atria1 fibrillation 6 cases, atria1 flutter 4 cases, atria1 tachycardia 1 case, combined atria1 flutter and fibrillation 2 cases). In addition, 2 patients (group B) presented a sinus tachycardia with a heart rate faster than 130/min which required treatment. At the 24-hr ambulatory electrocardiogram
279
TABLE Frequency
3 of postoperative
arrhythmias
Supraventricular tachyarrhythmias at monitoring atrial fibrillatmn atria1 flutter atrral tachycardia combined flutter and fibrillation
P
Group A (32 patients)
Group B (39 patienta)
No.
No.
F,
13
33.3
6 4 1 2 2 2
5.1 5.1
1
& 3.1
1 _.
-__ < 0.01
NS NS
Paroxysmal atria1 fibrillation on Holter Sinus tachycardia > 130/min All supraventricular
1
3.1
tachyarrhythmias Frequent ( 3 5%) supraventrtcular
2
6.2
17
43.6
< 0.001
extrasystoles Ventricular extrasystoles
3
9.7
3
14.3
NS
6
19.3
15
65.2
< 0.001
grade IV or V of Lawn’s classification NS = not significant,
performed between days 7 and 10, paroxysmal atria1 fibrillation was detected in 1 case of group A and in 2 cases of group B. Altogether, significant supraventricular tachyarrhythmias were noted in 6.2% of group A patients (2/32) and in 17 cases (43.6%) of the 39 patients of group B (P < 0.001). The arrhythmias appeared most often between the 3rd and the 4th day after operation (11 instances). Only 2 cases were seen during the first postoperative day. Supraventricular &topic Beats. In patients without sustained supraventricular tachyarrhythmia, supraventricular ectopic beats were carefully searched for on the Holter tape. They were considered frequent when they occurred at a rate higher than S/l000 beats. This was the case in 3 patients of group A (9.7%) and in 3 patients of group B (14.3%) (not significant). Ventricular &topic Beats. Ventricular ectopic beats seen on the Holter tape were classified according to Lown’s gradation system. Only classes IV and V were taken into consideration; thus severe ventricular extrasystoles were detected in 6 patients of group A (19.35%) and in 15 patients of group B (65.2%) (P -c0.001). Arrhythmias in Relation with Operative Characteristics. In this study, there was no correlation between the occurrence of sustained tachyarrhythmias and preoperative therapy, duration of intervention, or postoperative haemodynamic findings, In particular, sustained supraventricular arrhythmias were not more frequent in group B patients who received betablockers prior to surgery (34.8%) than in those who did not receive such therapy (56.2%) (not significant).
280 TABLE
4
Haemodynamic
findings
HR (beats/min) MAP (mm Hg) PWP (mm Hg) CI (I per min/m’) LVSWI (g/m2)
at rest on days 7-10. Group A (16 patients)
Group B (11 patients)
P
76.1 & 8.5 92 +15 8.0+ 3.1 3.1 + 0.5 9.6 47.8*
96.4* 11.0 98 *lo 7.6i 4.0 3.3* 0.5 44.7 f 10.9
< 0.001 NS NS NS NS
CI = cardiac index: HR = heart rate; LWSWI = left ventricular stroke work index; MAP = mean arterial pressure; NS = not significant; PWP = pulmonary wedge pressure
TABLE Changes
5 in pulmonary
PWP (mm Hg) LVSWI (g/m’) LVSWI = left ventricular
Haemodynamic
wedge pressure
and left ventricular
stroke work index between
Group A
Group
-1.4+ 5.0 +16.8+11.9
-2.o* 3.3 +9.9+11.7
stroke work index: NS = not significant;
days 1 and 7-10.
B
PWP = pulmonary
NS NS wedge pressure.
Findings on Days 7 to 10
Data Obtained at Rest. These data are summarized in Table 4 which shows that the only significant difference between the 2 groups was the resting heart rate which was 76.1 f 8.5 in group A, as compared to 96.4 f 11.0 in group B (P < 0.001). The other parameters showed no difference between the 2 groups. Interestingly (Table 5) when the haemodynamic findings of day 1 were compared with those of days 7 to 10, the changes in pulmonary wedge pressure and left ventricular stroke work index were similar in both groups. Isometric Exercise. Moderate isometric exercise testing was performed in 10 patients of group A and 7 patients of group B. The changes in haemodynamic parameters as compared to rest values were very similar. The pulmonary wedge pressure raised by 3.5 + 2.5 mm Hg in group A, as opposed to 1.3 f 1.7 in group B (not significant). The only difference was noted for stroke work index which decreased by 0.84 f 4.8 mg/m’ in group A whereas it increased by 5.7 & 6.2 in group B (P < 0.05). Overload by a Macromolecular Solution. Five hundred ml of Gentran”” were administered over a 30-min period to 6 patients of group A and 4 patients of group B. The pulmonary wedge pressure increased by 2.8 f 2.6 mm Hg in group A, versus 3.0 f 1.5 in group B. The stroke work index increased by 6.6 f 6.5 mg/m’ in group A as compared to 4.0 f 6.2 in group B. There were no significant differences between the 2 groups.
281
Side-effects During the hospital stay (average 10 days), no unwanted side-effect related to acebutolol therapy was noted. The dose of 1200 mg/day was maintained throughout hospitalization and without excessive bradycardia. The average heart rate in group A at day 9 was 76.1 &-8.6 beats/min.
Discussion Supraventricular and ventricular arrhythmias are frequent after coronary artery bypass surgery as well as after all types of cardiac operation or thoracotomy [12]. After coronary surgery, the frequency of atria1 flutter and fibrillation is particularly high (18 to 40%). These atria1 arrhythmias most frequently develop in the early postoperative phase and are associated with a fast ventricular response which may compromise the haemodynamic equilibrium or produce myocardial ischaemia [l-8]. Digoxin has been reported to decrease the incidence of those postoperative atria1 tachyarrhythmias [lo-131. However, 2 recent randomized studies have failed to confirm this finding [5-111. In addition, prophylactic administration of digoxin in this indication may be hazardous. Indeed, digitalis intoxication may develop more easily aftei cardiac surgery because of hypocalcemia, hypomagnesemia and reduction of creatinin clearance [14,15]. Finally, the postoperative hyperadrenergic state may in some way counteract the depressing effect of digoxin on the auriculoventricular junction [7,16]. Several recent studies indicated that the prophylactic administration of propranolol clearly decreases the frequency of supraventricular arrhythmias after coronary bypass surgery [l-7]. Timolol has also been utilized in the same indication with success [8]. Stephenson et al. [3] in a randomized study of 223 patients showed that the frequency of supraventricular arrhythmias was decreased from 23 to 8% by small doses of propranolol. Boudoulas and coworkers [l] in an open study of 80 patients reported 30% of supraventricular arrhythmias in the control group as opposed to 5% in the group treated by propranolol. Silverman and his group [6] using small doses of propranolol (4 X 10 mg) obtained the same results, i.e. decrease of the frequency of supraventricular arrhythmia from 28 to 6%. They stressed the fact that, in their series, there was no finding in the pre- or perioperative period which might predict the later occurrence of postoperative arrhythmias. Acebutolol is a cardioselective betablocker with quinidine-like effect and moderate intrinsic sympathetic activity. It has already been used in cardiac surgery. Thorns et al. have studied its mode of administration and plasma levels during the perioperative period [17]. In the present study, the early use of acebutolol reduced from 43.6 to 6.2% the incidence of supraventricular tachyarrhythmias after coronary surgery. Some authors have proposed to use a combination of digoxin and propranolol for the prevention of postoperative tachyarrhythmias [5,12]. Thus, Roffman and Fieldman [5] studied 172 patients 63 of whom served as controls, 59 received digoxin only and 50 a combination of digoxin and propranolol. The frequency of supra-
282
ventricular arrhythmias was 28.2, 28.9, and 2.2%, respectively. A second investigation by Mills et al. [18] noted a frequency of 30% of supraventricular arrhythmias in patients without treatment as opposed to 3.4% in patients receiving digoxin with propranolol. There is, however, no clearcut evidence that the adjunction of digoxin is beneficial. Boudoulas et al. [l], using measurements of systolic intervals, described a good haemodynamic tolerance to betablockers throughout the postoperative period. In the present study, we confirm the good tolerance to acebutolol even at high doses (1200 mg/24 hr). We should, however, stress the fact that all patients with a preoperative ejection fraction lower than 40% were: excluded from this study. Ventricular arrhythmias following coronary artery bypass surgery have received less attention [3,7]; sustained ventricular tachycardia is rare in this situation and ventricular ectopic beats, even if frequent and of high grade probably have little clinical significance. It is worthy of note however that in the present study we demonstrated that acebutolol reduced the frequency of high grade ventricular ectopic beats from 65.2 to 19.3%, as shown by Holter monitoring. The clinical and prognostic implications of these results deserve further studies. Several authors have attributed the high frequency of arrhythmias following cardiac surgery to the interruption of betablockers before intervention [2,4,19]. In the present work, we observed no difference in the frequency of supraventricular arrhythmias between the patients who received or did not receive betablockers prior to surgery. In conclusion, prophylactic administration of acebutolol starting 24 hr after coronary artery bypass surgery dramatically decreases the incidence of supraventricular rhythm disturbances and of ventricular ectopic beats. No deleterious haemodynamic effect was noted.
Acknowledgments We wish to acknowledge the assistance of Mr. A. Goddet, B. Vervier in the preparation of this manuscript.
Ms. S. Smeets and Mrs.
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