Circulatory Effects of Atracurium in Patients with Cardiovascular Disease

Br. J. Anaesth. (1986), 58, 83S-88S

CIRCULATORY EFFECTS OF ATRACURIUM IN PATIENTS WITH CARDIOVASCULAR DISEASE J. R. MOYERS, J. G. CARTER, B. L. FEHR, C. C. LINEBERRY, M. D. SOKOLL AND S. SHIMOSATO

PATIENTS AND METHODS

Forty patients with severe cardiovascular disease (ASA class III and IV) were studied. Written consent was obtained from each subject and the study was approved by our Human Studies Review Committee. Beta-blocking drugs, if previously prescribed, were continued until the morning of surgery. All patients were premedicated with morphine, hyoscine and diazepam and, on their arrival in the operating room, a catheter was placed in a hand vein under local anaesthesia. Five hundred millilitre of Ringer's lactate with 5% dextrose solution was given over 15 min. The radial and pulmonary arteries were cannulated before induction of anaesthesia. The patients were anaesthetized with i.v. diazepam 0.1-0.3 mg kg"1 and fentanyl 50-100 ug and the lungs ventilated from a mask with 50 % nitrous oxide in oxygen to maintain normal arterial P&cot an<^ P^The patients were divided into four groups (A-D) of 10. All received the same total dose of atracurium (0.4 mg kg"1) according to the following regimens, which was sufficient to produce J. R. MOVERS, M.D. ; J. G. CARTER, M.D. ; M. D . SOKOLL, MJ). ;

S. SHIMOSATO,

University

M.D., PH.D.;

Department

of

Anesthesia,

of Iowa, Iowa City, Iowa 52242,

U.S.A.

B. L. FEHR, M.P.H.; CHARLES C. LINEBERRY, PHJ).; Anesthe-

siology Section, Burroughs Wellcome Co., 3030, Cornwallis Road, Research Triangle Park, N C 27709, U.S.A.

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This study was designed to examine the circulatory effects of administration of atracurium in divided bolus doses to patients with severe cardiovascular disease undergoing surgery for an abdominal aortic aneurysm or coronary artery bypass grafting. A dose was chosen (0.4 mg kg"1) which was sufficient to produce adequate neuromuscular blockade for intubation and is in excess of the ED96 for twitch depression.

SUMMARY Atracurium 0.4 mg kg-1, which was sufficient to produce neuromuscular blockade sufficient for intubation, was administered as divided bolus doses to 40 patients with severe cardiovascular disease. Little haemodynamic change occurred. A transient reduction in arterial pressure was noted in one patient. Atracurium was found to be safe and effective, and administration in small bolus doses separated by 30 s may reduce the likelihood of significant circulatory changes.

adequate neuromuscular blockade for intubation and was in excess of the EDBB for twitch depression (Gergis et al., 1983; Hughes and Payne, 1983). Groups A and B were undergoing abdominal aortic aneurysm resection; group A received atracurium in four bolus doses of 0.1 mg kg"1 30 s apart and group B received two doses of 0.2 mg kg"1 30 s apart. The patients in groups C and D were undergoing coronary artery bypass graft surgery. Ejection fractions of patients in group C were greater than or equal to 0.5 and those of groups D were less than 0.5. Group C received atracurium in two 0.2-mg kg"1 doses 30 s apart. Two patients in group D received two 0.2-mg kg"1 doses 30 s apart and the remaining eight patients received atracurium in four 0.1 -mg kg"1 doses 30 s apart. Heart rate, systemic arterial, pulmonary arterial and right atrial pressures were recorded continuously. Pulmonary capillary wedge pressure was recorded intermittently. Cardiac output was measured by thermodilution and was standarized as cardiac index. Stroke volume, total peripheral resistance, pulmonary vascular resistance, stroke work and left ventricular work index were derived using conventional formulae. The above measurements were made before induction of anaesthesia, following induction of

BRITISH JOURNAL OF ANAESTHESIA

84S 80

60

3-

I 40

2Group A Group B

Dose Dose

\ Awake

Asleep

2.5

5.0

L

10.0

Time (mln) after atracurtum FIG. 1. Heart rate (mean ± SEM) before and after injection of atracurium. *Group B: heart rate significantly (P < 0.05) slower at 2.5, 5 and 10 min compared with asleep.

Awake

Asleep

5.0

2.5

10.0

Time (min) after atracurtum

FIG. 3. Cardiac index (mean ± SEM) before and after injection of atracurium. *Group C: significantly (P < 0.05) greater at 2.5 min after atracurium compared with asleep.

1300-1

120-i

i

100

1200

J

80

110060100040-

Group A Group B Group C

20-

L Awake

Asleep

900

Group D

Dose

Dose 800

2.5

5.0

10.0

I-

Tkne(min) alter atracurtum FIG. 2. Mean arterial pressure (mean ± SEM) before and after injection of atracurium.

anaesthesia after arterial pressure and heart rate were stable for at least 2 min, and 2.5,5 and 10 min following the injection of the first bolus dose of atracurium. The values obtained in the stable, anaesthetized patient were used as the control for evaluating the cardiovascular effects after administration of atracurium. Statistical evaluation was performed using analysis of variance and P less than or equal to 0.05 was considered significant.

Awake

Asleep

2.5

5.0

10.0

h

Tbne(mln) after atracurtum

FIG. 4. Total peripheral resistance (mean ± SEM) before and after injection of atracurium. *Group B: significantly (P < 0.05) greater at 10 min after atracurium compared with asleep.

RESULTS

There were no statistically significant changes in mean values in groups A and D for heart rate (fig. 1), mean arterial pressure (fig. 2), cardiac index (fig. 3), total peripheral (fig. 4), and pulmonary vascular (fig. 5) resistance, stroke volume (fig. 6), stroke work (fig. 7) and left ventricular work index (fig. 8) at either the 2.5-, or 5- or 10-min measurement periods compared with control. In

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GroupA Group B Group C Group D

Group C Group D

20

85 S

ATRACURIUM AND CARDIOVASCULAR DISEASE 140-1

120

Group A Group B Group C Group D

120-

100-

-? 100 80

J

80-

Dose

L

60

Awake Asleep

2.5

5.0

60 40 Awake

10.0

Asleep

H

Time (min) after atracurium FIG. 5. Pulmonary vascular resistance (mean±SEM) before and after injection of atracurium.

00-.

Group A

-i-

I

90-

2.5

5.0

10.0

Time (min) after atracurtum FIG. 7. Stroke work (mean±SEM) before and after injection of atracurium.

6-1

Group A Group B

Group C Group D

/ y\
±

70-

'

] I Dose

Dose nn Awake

1

Asleep

Awake Asleep 2.5

5.0

10.0

H

Tlme(min) after atracurtum FIG. 6. Stroke volume (mean±SEM) before and after injection of atracurium. *Group C: significantly (P < 0.05) greater at 2.5 min after atracurium compared with asleep.

addition, for groups A and D, there were no statistically significant changes in mean pulmonary arterial, right atrial and pulmonary capillary wedge pressures. In group B there were no statistically significant changes in mean arterial pressure, cardiac index, pulmonary vascular resistance, stroke volume, stroke work, left ventricular work index (see figures) and pulmonary capillary wedge pressure. However, the mean heart rates were significantly slower (approximately 5 %) compared with control

2.5

t

5.0

10.0

H

Tbne(mtn) after atracurtum FIG. 8. Left ventricular work index (mean ±SEM) before and after injection of atracurium.

at 2.5, 5 and 10 min after injection of atracurium (fig. 1). At 10 min, right atrial pressure and mean pulmonary artery pressure were lower (14% and 9%, respectively) and total peripheral resistance was higher (11%). In group C heart rate, mean arterial pressure, total peripheral and pulmonary vascular resistances, stroke work, left ventricular work index (see figures) and pulmonary capillary wedge pressure did not change significantly after administration of atracurium. Mean values for cardiac index (fig. 3) and stroke volume (fig. 6) were significantly higher (12% and 15%, respectively) compared with

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Group A Group B Group C Group D

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TABLE I. Heart rate (beat min'1) (mean ± SEAT) of patients receiving atracurium and P-blockers before operation compared with no fi-blockers. *P < 0.05 compared with subsequent values. +P < 0.05 compared tm'th the group not taking P-blockers at the same measurement period After atracurium

P-blockers before op. (n - 15)

Anaesthesia

2 min

5 min

10 min

59±3*t

50±2f

51±2t

51±2f

49±2t

73 ±3*

61±2

59±2

59±2

59±2

control at 2.5 min, but not at either 5 or 10 min after administration of atracurium. Right a trial pressure was lower at 2.5 (18%) and 10 min (20%), but not at 5 min. The mean pulmonary artery pressure was lower at 2.5 (8 %), 5 (6 %) and 10 min (12%). The pulmonary capillary wedge pressure was lower at 2.5 (10%), 5 (11%) and 10 min (14%). One patient in group C had a transient (60 s) but marked reduction in mean arterial pressure (26 mm Hg) which occurred shortly after injection of atracurium and before the 2-min measurement period, but which required no treatment. Heart rates of patients from all four groups who were taking P-blocking drugs before operation were compared with the heart rates of those not taking P-blockers (table I). The administration of atracurium was not associated with any statistically significant change in heart rate within either of these groups at any measurement period compared with the heart rate measured during a steady state of anaesthesia (P > 0.05). The mean heart rates of the patients taking p-blocking drugs were slower at all measurement periods compared with patients not receiving P-blockers. DISCUSSION

Both tubocurarine and metocurine can produce arterial hypotension when administered i.v. (Savarese, Ali and Antonio, 1977; Harrison, 1972; Savarese, 1979). In addition, metocurine has produced tachycardia in at least one study (Savarese, Ali and Antonio, 1977). Pancuronium and gallamine produce tachycardia and an accompanying increase in systemic arterial pressure (Kennedy and Farman, 1968; Stoelting, 1972; Miller et al., 1975). More recently, vecuronium has been shown to have a minimal effect on the circulation of patients anaesthetized with halothane

and nitrous oxide for coronary artery bypass surgery (Morris et al., 1983). Atracurium given in divided i.v. bolus doses to patients with severe cardiovascular disease was associated with little change in haemodynamic values in 39 of 40 patients. Using mean values, statistically significant haemodynamic changes did occur in groups B and C, the groups with the more rapid administration, but these were not clinically significant. One patient experienced a substantial (31 %), but transient, decrease in systemic arterial pressure. Hughes and Chappie (1981) produced hypotension in dogs with i.v. atracurium, only after administering more than eight times the effective neuromuscular blocking dose. In healthy patients, several investigators found no significant changes in arterial pressure or heart rate after giving up to 0.6 mg kg"1 of atracurium in single or divided doses during fentanyl, nitrous oxide and oxygen anaesthesia (Payne and Hughes, 1981; Katz et al., 1982; Foldes et al., 1983). Similarly, atracurium has not been associated with circulatory changes in healthy patients anaesthetized with halothane, enflurane or isoflurane (Payne and Hughes, 1981; Hilgenberg, Stoelting and Harris, 1983; Rupp, Fahey and Miller, 1983; Sokoll et al., 1983). Others have found transient reductions in arterial pressure after administering large single bolus doses (0.5-0.6 mg kg"1) of atracurium to healthy patients (Basta et al., 1982; Barnes et al., 1983). Basta and colleagues (1982) reported decreases in arterial pressure of 13 and 20% after 0.5-mg kg"1 and 0.6-mg kg"1 bolus doses of atracurium, respectively, during fentanyl, nitrous oxide and oxygen anaesthesia. The hypotension peaked 60-90 s after administration and resolved in 5 min. However, they found no arterial pressure changes with bolus doses of 0.4 mg kg"1 or smaller. Barnes and colleagues (1983) gave

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No P-blockers (n = 25)

Awake

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ATRACURIUM AND CARDIOVASCULAR DISEASE

In contrast to changes reported after pancuronium and gallamine, we found no significant increase in heart rate associated with atracurium, in keeping with the findings of most other investigators (Payne and Hughes, 1981; Katz et al., 1982; Barnes et al., 1983; Foldes et al., 1983; Hilgenberg, Stoelting and Harris, 1983; Philbin et al., 1983; Pokar and Brandt, 1983; Rupp, Fahey and Miller, 1983; Sokoll et al., 1983). Basta and colleagues (1982) did find small increases (5-8%) in heart rate after doses of atracurium 0.5-0.6 mg kg"1. Four cases of severe bradycardia associated with atracurium have been described (Carter, 1983). However, surgical manoeuvres, such as traction on the peritoneum, may explain the changes. In our study, potential changes in heart rate may have been obscured by preoperative administration of P-blocking drugs. However, analysis of the subgroup of patients not taking P-blockers revealed no effect on heart rate by atracurium. In this study atracurium was found to be effective and safe when administered to patients with severe cardiovascular disease. Rapid administration of large doses may occasionally produce transient hypotension in these patients. It appears from the results of this study that administration of atracurium as small bolus doses separated by 30 s may reduce the likelihood of eliciting significant changes in the haemodynamic state. ACKNOWLEDGEMENT This study was supported by a grant from Burroughs Wellcome and grant No. 2R01 GM33137-02A1 from the National Institutes of Health. REFERENCES Barnes, P. K., Thomas, V. J. E., Boyd, I., and Holloway, T. (1983). Comparison of the effects of atracurium and tubocurarine on heart rate and arterial pressure in anaesthetized man. flr. J. Anaesth., 55, 91S. Basta, S. J., Ali, H. H., Savarese, J. J., Sunder, N., Gionfriddo, M., Cloutier, G., Lineberry, C , and Cato, A. E. (1982). Clinical pharmacology of atracurium besylate (BW33A): a new non-depolarising muscle relaxant. Arusth. Analg., 61, 723. Savarese, J. J., Ali, H. H., Moss, J., and Gionfriddo, M. (1983). Histamine-releasing potencies of atracurium, dimethyl tubocurarine and tubocurarine. flr. J. Anaesth., 55, 105S. Carter, M. L. (1983). Bradycardia after the use of atracurium. flr. Med. J., 287, 247. Foldes, F. F., Nagashima, H., Boros, M., Tassonyi, E., Fitzal, S., and Agoston, S. (1983). Muscular relaxation with atracurium, vecuronium and Duador under balanced anaesthesia, flr. J. Anaesth., 55, 97S.

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0.6 mg kg"1 as a bolus to healthy patients anaesthetized with thiopentone, nitrous oxide and oxygen. Five of the 18 patients studied developed a 7-24 % decrease in mean arterial pressure within 90 s after administration of atracurium, and skin flushing was noted in one patient. Four minutes after giving atracurium, arterial pressures had returned to the control value in each of these five patients. Philbin and others (1983) studied 16 patients with coronary artery disease receiving bolus doses of atracurium either 0.3 mg kg"1 or 0.4 mg kg"1 after fentanyl, lorazepam, nitrous oxide and oxygen anaesthesia. One patient had arterial pressure changes similar to the patient in our study who experienced transient hypotension. Philbin reported that, in one of the patients receiving the 0.3-mg kg"1 dose, mean arterial pressure immediately decreased from 70 to 50 mm Hg. This was accompanied by an increase in cardiac output, decrease in systemic vascular resistance and flushing of the skin. No therapy was instituted and circulatory values returned to control within 5 min. There were no significant haemodynamic changes in the other patients receiving atracurium 0.3 mg kg"1 or in the group receiving 0.4 mg kg"1. Pokar and Brandt (1983) injected atracurium 0.6-1.0 mg kg"1 to a right atrial catheter in patients 1-2 h after cardiac surgery. Two minutes after injection, four of nine patients had decreases of greater than 10% ( — 17% maximum) in mean arterial pressure. The decrease in arterial pressure persisted in three of the nine patients for 5 min, but had resolved in all patients by the 10-min measurement period. The occasional episodes of hypotension with atracurium are probably attributable, at least partially, to the release of histamine. Decreases in arterial pressure after large doses of atracurium have been partially prevented by prior administration of H t and H t blockers in dogs (Hughes and Chappie, 1981). Basta and colleagues (1983) have shown the propensity of atracurium to release histamine to be approximately one-half that of metocurine and less than one-third that of tubocurarine, relative to neuromuscular blocking as equipotent doses. The degree of hypotension after administration of neuromuscular blocking agents has been related to the resultant concentration of plasma histamine (Moss et al., 1981). Hypotension after atracurium should occur less frequently than after either tubocurarine or metocurine.

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Moss, J., Rosow, C. E., Savarese, J. J., Philbin, D. M., and Kniffen, K. J. (1981). Role of histamine in the hypotensive action of d-tubocurarine in humans. Anesthesiology, 55, 19. Payne, J. P., and Hughes, R. (1981). Evaluation of atracurium in anaesthetized man. Br. J. Anaesth., 53, 45. Philbin, D. M., Machaj, V. R., Tomickek, R. C , Schneider, R. C , Allan, J. C , Lowenstein, E., and Lineberry, C. C. (1983). Haemodynamic effects of bolus injection of atracurium in patients with coronary artery disease. Br. J. Anaesth., 55, 131S. Pokar, H., and Brandt, L. (1983). Haemodynamic effects of atracurium in patients after cardiac surgery. Br. J. Anaesth., SS, 139S. Rupp, S. M., Fahey, M. R., and Miller, R. D. (1983). Neuromuscular and cardiovascular effects of atracurium during nitrous oxide-fentanyl and nitrous oxide-isoflurane anaesthesia. Br. J. Anaesth., 55, 67S. Savarese, J. J. (1979). The autonomic margin of safety of metocurine and d-tubocurarine in the cat. Anesthesiology, 50, 40. Ah', H. H., and Antonio, R. P. (1977). The clinical pharmacology of metocurine: dimethyltubocurarine revisited. Anesthesiology, 47, 277. Sokoll, M. D., Gergis, S. D., Mehta, M., Kemmotsu, O., and Rudd, D. (1983). Haemodynamic effects of atracurium in surgical patients under nitrous oxide, oxygen and isoflurane anaesthesia. Br. J. Anaesth., 55, 77S. Stoelting, R. K. (1972). The hemodynamic effects of pancuronium and d-tubocurarine in anesthetised patients. Anesthesiology, 36, 612.

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Gergis, S., Sokoll, M. D., Mehta, M., Kemmotsu, O., and Rudd, G. D. (1983). Intubation conditions after atracurium and suxamethonium. Br. J. Aiuusth., 55, 83S. Harrison, G. A. (1972). The cardiovascular effects of some relaxant properties of four relaxants in patients about to undergo cardiac surgery. Br. J. Anaesth., 44, 485. Hilgenberg, J. C , Stocking, R. K., and Harris, W. A. (1983). Haemodynamic effects of atracurium during enfluranenitrous oxide anaesthesia. Br. J. Anaesth., 55, 81S. Hughes, R., and Chappie, D. J. (1981). The pharmacology of arxacurium—a new competitive neuromuscular blocking agent. Br. J. Anaesth., 53, 31. Payne, J. P. (1983). Clinical assessment of atracurium using the single twitch and tetanic responses of the adductor pollicis muscle. Br. J. Anaesth., 55, 47S. Katz, R. L., Stirt, J., Murray, A. L., and Lee, C. (1982). Neuromuscular effects of atracurium in man. Anesth. Analg., 61, 730. Kennedy, B. R., and Farman, J. V. (1968). Cardiovascular effects of gallamine triethiodide in man. Br.J. Anaesth., 40, 773. Miller, R. D., Eger, E. I. u, Stevens, W. C , and Gibbons, R. (1975). Pancuronium induced tachycardia in relation to alveolar halothane, dose of pancuronium, and prior atropine. Anesthesiology, 42, 352. Morris, R. B., Cahalan, M. K., Miller, R. D., Wilkinson, P. L., Quasha, A. L., and Robinson, S. L. (1983). The cardiovascular effects of vecuronium (Org NC 45) 8nd pancuronium in patients undergoing coronary artery bypass grafting. Anesthesiology, 58, 438.

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