British Journal of Anaesthesia 1990; 64: 611-616
HAEMODYNAMIC EFFECTS OF THE PHOSPHODIESTERASE INHIBITOR ENOXIMONE IN COMPARISON WITH DOBUTAMINE IN ESMOLOL-TREATED CARDIAC SURGERY PATIENTS
SUMMARY In a randomized study, the haemodynamic effects of the new phosphodiesterase-lllinhibitor, enoximone, were compared with dobutamine in acutely (3-adrenoceptor blocked patients. Twenty patients scheduled for aortocoronary bypass grafting suffering from tachycardia (heart rate (HR) > 100 beat min-') were treated by infusion of esmolol, an ultra-short acting, selective fi,-b/ocker. Twenty minutes after the start of esmolol, either enoximone 0.5 mg kg-1 as a bolus (n = 10) or dobutamine 5 ng kg-1 min~1 was administered. Haemodynamic effects were monitored for 40 min, including measurement of left ventricular haemodynamics. Esmolol reduced HR (—27%) and d?ldxmtx (-38%) significantly in both groups. Cardiac index (Cl) was decreased also. Enoximone increased Cl (+35%) and dP/dx^ (+39%) significantly, while no change in dobutamine-treated patients was observed. Systemic vascular resistance increased only in the dobutamine group (+44%). KEY WORDS Heart: enoximone, dobutamine, esmolol. artery.
global cardiac performance [1,2]. However, block of adrenergic receptors may reduce myocardial contractility which is associated often with a decrease in cardiac output [3, 4]. Positive inotropes are sometimes necessary to reduce these cardiodepressant side effects of P-blockers. Traditionally, catecholamines such as dobutamine are used widely to increase myocardial performance and improve haemodynamic state [5—7]. Their action is based on (3-adrenoceptor stimulation, which may be associated with severe side-effects or be ineffective because of down-regulation in severe heart failure or iatrogenic pharmacological block [8,9]. Phosphodiesterase-III-inhibitors such as enoximone are a new class of drug with positive inotropic properties, offering an alternative for the treatment of depressed myocardial performance [10-13]. The aim of this study was to investigate how the haemodynamic profile of enoximone and dobutamine may be modified by P-adrenoceptor block during cardiac surgery.
PATIENTS AND METHODS
We studied 20 patients undergoing elective aortocoronary bypass surgery. Informed consent was obtained from each patient and the study was Surgery: coronary approved by the Institutional Human Ethics Committee of the hospital. All patients were premedicated with fluni-
The use of P-adrenergic blockers is established in the management of various cardiovascular disorders, such as angina pectoris, hypertension, tachycardia or arrhythmia [1]. Particularly in patients with coronary artery disease, tachycardiainduced ischaemia may compromise myocardial oxygen balance, followed by deterioration of
J. BOLDT, M.D., D . KLING, M.D.,
B. ZlCKMANN,
M.D.,
G.
HEMPELMANN, M.D. (Department of Anaesthesiology and Intensive Care Medicine); F. DAPPER, M.D. (Department of Cardiovascular Surgery); Klinikstr. 29, Justus-LiebigUniversity Giessen, D-6300 Giessen, F.R.G. Accepted for Publication: September 29, 1989. Correspondence to J. B.
Downloaded from http://bja.oxfordjournals.org/ at University of Auckland on March 26, 2015
J. BOLDT, D. KLING, B. ZICKMANN, F. DAPPER AND G. HEMPELMANN
612
15 and 20 min after enoximone or start of dobutamine administration. After these measurements, arterial and venous cannulae were inserted and cardiopulmonary bypass was started. One- and two-factorial analyses of variance followed by the Scheffe test were used for statistical analysis. P < 0.05 was considered significant. RESULTS
There was no difference in demographic data between groups. All patients were NYHA functional class II without severe impairment of myocardial function (LVEF > 50%; LVEDP < 15 mm Hg) (table I).
100 n
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I
80 70
120 ^
110
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- 100
i
90 80 7
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100 beat min"1) in the presence of an adequate mean arterial pressure (MAP) (> 70 mm Hg) and precapillary wedge pressure (PCWP) ( > 8 m m H g ) before cannulation for bypass. In this situation, 10 min before administration of the P-blocker esmolol, fentanyl 5 ug kg"1 and midazolam O.lmgkg" 1 were given to exclude light anaesthesia. Patients with persistent tachycardia (HR > 100 beat min"1) were given esmolol 500 ug kg"1 for 1 min, followed by a continuous infusion of 100 ug kg"1 min"1 until the end of the period of investigation. Twenty minutes after the start of administration of esmolol (when dP/dt max was decreased by more than 20%), patients were allocated randomly to two groups: group 1 (n = 10) received enoximone 0.5 mg kg"1 as a bolus, and group 2 (n = 10) received dobutamine 5 ug kg"1 min"1 as an infusion. Haemodynamic monitoring consisted of MAP (by radial artery cannulation), HR, pulmonary artery pressure (PAP), PCWP, right atrial pressure (RAP) and cardiac output (CO) using thermodilution technique. Derived haemodynamic variables (systemic vascular resistance (SVR), pulmonary vascular resistance (PVR) and cardiac index (CI)) were calculated from standard formulae. Left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP) and left ventricular contractility index (LVdP/drmax) (electronic differentiation, Hellige, Freiburg, West Germany) were obtained by direct cannulation of the left ventricle. All measurements were performed under steady-state haemodynamic and anaesthetic conditions before administration of esmolol (baseline values), 20 min after the start of esmolol and 5,10,
BRITISH JOURNAL OF ANAESTHESIA
ENOXIMONE AND DOBUTAMINE IN p-BLOCKED PATIENTS TABLB I. Mean (SD) demographic data and preoperative heart function in the two groups. L VEF = Left ventricular ejection fraction; L VEDP = left ventricular end-diastolic pressure Esmolol + dobutamine
56.8 (6.7) 80.1 (8.2) 175.0(7.8) 69.9 (4.6) 12.5 (3.3)
57.0 (8.2) 77.0 (3.5) 173.3(7.0) 71.1(3.8) 13.0(2.0)
9 1
8 2
Esmolol decreased HR significantly in both groups (-27%), whereas MAP and RAP were
unchanged (fig. 1). Enoximone and dobutamine did not change MAP and RAP significantly; enoximone increased HR slightly (+10%) for lOmin. None of the patients suffered from arrhythmia during the study. Mean CI was decreased by esmolol in both groups (—18.5 %) (fig. 2). Injection of enoximone 20 min after the start of infusion of esmolol was followed by a significant increase in CI ( + 35 %), whereas dobutamine produced no change in output. In comparison with baseline values, SVR increased significantly in the dobutamine-treated patients (+ 44 %). There was no change in SVR in the enoximone group. PVR increased only in patients who received dobutamine ( + 52%) (fig. 3).
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FIG. 2. Mean (SD) changes in cardiac index (CI), pulmonary artery pressure (PAP), and pulmonary capillary wedge pressure (PCWP) in the two groups ( • = enoximone 0.5 mg kg"1; O = dobutamine 5 ug kg"1 min"1). Significant differences (P < 0.05): *from baseline values; tbetween groups.
20
5 10 Time (min)
15
20
FIG. 3. Mean (SD) changes in systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) in the two groups ( • = enoximone 0.5 mg kg"1; O = dobutamine 5 ug kg"1 min"1). Significant differences (P < 0.05): * from baseline values; tbetween groups.
Downloaded from http://bja.oxfordjournals.org/ at University of Auckland on March 26, 2015
Age (yr) Weight (kg) Height (an) LVEF (%) LVEDP (mm Hg) Previous myocardial infarctions One (No. patients) Two (No. patients)
Esmolol + enoximone
613
BRITISH JOURNAL OF ANAESTHESIA
614
Esmolol produced adequate reduction in HR in our study by achieving steady state plasma 'S 130 concentrations (loading dose followed by a conx tinuous infusion) [1, 16]. Linear dose-related E J 120 haemodynamic effects have been demonstrated in man [1]. Esmolol was effective in reducing HR 110 during the pre-bypass period in our study. Myocardial contractility, however, was reduced 100 markedly with the dose used. Although 15 LVdP/dfmax is known to be dependent on HR and preload, this variable is accepted generally as an E indication of ventricular contractility. 10 Sympathomimetic amines are used widely for inotropic support and dobutamine in particular is favoured during coronary artery surgery because 5 of its reduced effect on HR [5, 17, 18]. However, 2500 as a reduced responsiveness to P-receptor agonists may be anticipated in these patients, it is reasonable to select new agents which do not affect 0receptors and act at a site distal to the receptor x5 E 2000 [19,20]. Inhibition of phosphodiesterase-III offers an alternative treatment of depressed myocardial function [21-23]. Enoximone produces inhibition of only the membrane-bound high 1500 affinity cyclic adenosine monophosphatephosphodiesterase (phosphodiesterase III, or type 1200 IV phosphodiesterase by revised nomenclature [24]) [25]. It has been proven to be of benefit in 5 10 patients suffering from severely impaired myoTime (min) cardial function by increasing myocardial conFIG. 4. Mean (SD) changes in left ventricular pressure (LVP), tractility and by decreasing afterload because of left ventricular end-diastolic pressure (LVEDP), and its vasodilating properties [19]. It has been used as dP/dtmM3[ in the two groups ( • = enozimone 0.5 mg kg"1; a single dose, as in our study, or by continuous O = dobutamine 5 ug kg"1 min"1). Significant differences infusion [19,22]. A bolus of 0.5mgkg~ l sig(P < 0.05): *from baseline values; 7between groups. nificantly increased contractility [26], with modDirectly measured left ventricular haemo- erate effects on HR. In this study, enoximone dynamic variables (fig. 4) revealed no significant increased HR only slightly (+10%) and for a change in LVP and LVEDP. However, dP/dr max short period (10 min). decreased significantly in response to esmolol in Aldiough the use of positive inotropes is both groups (approximately —38%). Enoximone associated with the risk of increased myocardial increased dP/dfmax significantly ( + 39%), where- oxygen consumption, with detrimental effects on as dobutamine had no effect. No patient required global myocardial function [27], enoximone seems pharmacological or mechanical support during not to affect myocardial oxygen consumption or weaning from cardiopulmonary bypass and all even decrease it because of a concomitant rehad an uneventful postoperative course. duction in systolic wall tension [28]. Moreover, an increased rate of ventricular relaxation occurs, attributable also to activation of the cAMP system DISCUSSION [29]. Direct coronary dilatator effects were reEsmolol is a cardioselective P,-blocker without ported after administration of enoximone [30] and sympathomimetic activity or membrane stabil- Mitrovic and colleagues [31] reported that enoxizing effects [1, 14]. Its distribution half-life is imone abolished stress-induced ischaemia in 2 min, and elimination half-life approximately patients with coronary artery disease. 9 min [15]. Our study confirms that enoximone increases 140
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ENOXIMONE AND DOBUTAMINE IN P-BLOCKED PATIENTS
REFERENCES 1. Kaplan JA. Dupont critical care lecture: role of ultrashortacting P-blockers in the perioperative period. Journal of Cardiothoracic Anesthesia 1988; 2: 683-691. 2. Gold MI, Sacks DJ, Grosnoff DB, Herrington C, Skillman CA. Use of esmolol during anesthesia to treat tachycardia and hypertension. Anesthesia and Analgesia 1989; 68: 101-104. 3. Anderson KE. Aspects of the pharmacology of Padrenoceptor agonists and antagonists. Acta Anaesthesiclogica Scandinavica 1982; 76: 12-19.
4. Foex, P, Francis CM, Cutfield GR. The interactions between p-blockers and anaesthetics. Acta Anaesthesiologica Scandinavica 1982; 76: 38-46. 5. Fowler MB, Timmis AD, Crick JP, Vincent R, Chamberlain AB. Comparison of haemodynamic responses to dobutamine and salbutamol in cardiogenic shock after acute myocardial infarction. British Medical Journal 1982; 284: 73-77. 6. Tarnow J, Komar K. Altered haemodynamic response to dobutamine in relation to the degree of preoperative Padrenoceptor blockade. Anesthesiology 1988; 68: 912-919. 7. Tinker JH, Tarhan J, White RD, Pluth RJ, Barnhorst DA. Dobutamine for inotropic support during emergence from cardiopulmonary bypass. Anesthesiology 1976; 44: 281-286. 8. Bristow MR, Ginsburg R, Minobe W, Cubiceiotti RS, Sageman WS. Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. New England Journal of Medicine 1978; 299: 1373-1377. 9. Colucci WS, Wright RF, Jaski BE, Fifcr MA, Braunwald E. Milrinone and dobutamine in severe heart failure: differing haemodynamic effects and individual patient responsiveness. Circulation 1986; 73 (Suppl. I l l ) : 175— 182. 10. Colucci WS, Wright RF, Braunwald E. New positive inotropic agents in the treatment of congestive heart failure. Second Part. New England Journal of Medicine 1986; 314: 349-358. 11. Rutman HI, Lejemtel TH, Sonnenblick EH. Newer cardiotonic agents: implications for patients with heart failure and ischemic heart disease. Journal of Cardiothoracic Anesthesia 1987; 1: 59-70. 12. Rettig GF, Bette L. Current therapy of acute heart failure. Cardiovascular Drugs and Therapy 1988; 2: 401-406. 13. Weber KT, Gill S, Janicki JS, Maskin CS, Jain MC. Newer positive inotropic agents in the treatment of chronic cardiac failure. Drugs 1987; 33: 503-519. 14. Kirshenbaum JA. Use of an ultrashort-acting beta-blocker in patients with acute myocardial ischemia. Circulation 1985; 72: 873-877. 15. Sum CY, Yacobi A, Kartzinek R, Stampfli H, Davis CS, Lai CM. Kinetics of esmolol, an ultra-short acting beta blocker, and of its major metabolite. Clinical Pharmacology Therapy 1983; 34: 427-434. 16. Girard D, Shulman BJ, Thys DM. The safety and efficacy of esmolol during myocardial revascularization. Anesthesiology 1986; 65: 157-164. 17. DiSesa VJ, Brolon E, Methge GH. Haemodynamic comparison of dopamine and dobutamine in the postoperative volume-loaded, pressure-loaded and normal ventricle. Journal of Thoracic and Cardiovascular Surgery 1982; 83: 256-260. 18. Gillespie TA, Ambos HD, Sobel B. Effects of dobutamine in patients with acute myocardial infarction. American Journal of Cardiology 1977; 39: 588-593. 19. Dage RC, Roebel LE, Hsieh CP, Weiner DL, Woodward JK. Cardiovascular properties of a new cardiotonic agent: MDL 17,043. Journal of Cardiovascular Pharmacology 1982;4: 500-508. 20. Evans DB. Overview of cardiovascular physiologic and pharmacologic aspects of selective phosphodiesterase peak III inhibitors. American Journal of Cardiology 1989; 63: A9. 21. Installe E, Gonzalez M, Jacquemart-Collard P, Roulette
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myocardial contractility in spite of an effective block of P-adrenoceptors by esmolol. In animals, in which sympathetic-mediated reflex-induced changes in HR were blocked by the fj-adrenoceptor antagonist nadolol, both improvement in ventricular contractility and ventricular relaxation were achieved by the phosphodiesterase-III inhibitor milrinone [20]. In contrast with this, acute pretreatment with esmolol blocked the P^adrenoceptor effects of dobutamine and led to a marked increase in peripheral resistance without accompanying cardiac stimulation. These results are in accordance with other investigations stressing that dobutamine might have detrimental haemodynamic effects in patients who have received long-term medication with P-blockers [6]. In experimental studies, propranolol was reported to abolish the positive inotropic effects of dobutamine, unmasking the a-adrenergic-receptor properties of dobutamine [32]. The dose of dobutamine in our study was small, but has been shown to be effective in patients with moderate myocardial dysfunction [7, 18]. Increasing doses (up to 40 ng kg"1 min"1), however, may cause a pronounced increase in HR with detrimental effects on myocardial oxygen consumption. Enoximone may be useful in treating patients with heart failure. These patients are often dependent on high sympathetic tone or rapid heart rate for an adequate cardiac output. However, tachycardia is a disadvantage with respect to myocardial oxygen consumption and, in this situation, p-blockers may precipitate heart failure. The use of an ultra-short acting P-blocker to reduce heart rate in combination with the inotropic effects of enoximone might be of value and this combination warrants further investigation. It is concluded that dobutamine is not the drug of choice for inotropic support in patients acutely pretreated with P-blockers, whereas enoximone may improve haemodynamic status even in patients who are P-blocked.
615
616
22.
23. 24.
26.
27.
F, Pourbaii S, Tremouroux J. Comparative effects on 28. Baim DS. Effects of phosphodiesterase inhibition on haemodynamics of enoximone (MDL 17,043), dobutmyocardial oxygen consumption and coronary blood flow. amine and nitroprusside in severe congestive heart failure. American Journal of Cardiology 1989; 63: A23. American Journal of Cardiology 1987; 60: 46C-52C. 29. Silver PJ. Biochemical aspects of inhibition of cardioWeber KT, Janicki JS, Jain MC. Enoximone (MDL vascular low cyclic adenosine-monophosphate-phospho17,043), a phosphodiesterase inhibitor, in the treatment of diestcrase. American Journal of Cardiology 1989; 63: 2A. advanced, unstable chronic heart failure. Journal of Heart 30. Viquerat CE, Kereiakes D, Morris DL, Daly PA, Transplantation 1976; 5: 105-112. Wexmann M, Frank P, Parmley WW, Chatterjee K. Scholz H. Inotropic drugs and their mechanism of action. Alterations in left ventricular function, coronary hemoJournal of American College of Cardiology 1984; 4: dynamics and myocardial catecholamine balance with 389-397. MDL 17,043, a new inotropic vasodilator agent, in patients with severe heart failure. Journal of American Appleman MM, Beavo JA jr, Hardman JG, Klee CB, College of Cardiology 1985; 5: 326-332. Thompson WJ. A subcommittee for nomenclature recommendations. Advances in Cyclic Nucleotide Protein Phos- 31. Mitrovic V, Thormann J, Neutzner J, Bahavar H, Volz phorylation Research 1984; 16: vi. M, Dieterich HA, Schleppcr M. Hemodynamic, antiDagc RC, Kariya T, Hsieh CP, Roebel LE, Cheng HC, ischemic, and neurohumeral effects of enoximone in Schnettler RA, Grisar JM. Pharmacology of enoximone. patients with coronary artery disease. American Heart American Journal of Cardiology 1987; 60: 10C-14C. Journal 1989; 7: 106-111. Boldt J, Kling D, Schuhman E, Dapper F, Hcmpelmann 32. Vatner SF, McRitchie RJ, Braunwald E. Effects of G. Hacmodynamic effects of the new phosphodiesterase dobutamine on left ventricular performance, coronary inhibitor enoximone in cardiac surgery patients. Anaesdynamics, and redistribution of cardiac output in conthesist 1989; 38: 238-244. scious dogs. Journal of Clinical Investigation 1974; S3: Katz AM. Potential deleterious effects of inotropic agents 1265-1273. in the therapy of chronic heart failure. Circulation 1986; 73 (Suppl. Ill): 184-187.
Downloaded from http://bja.oxfordjournals.org/ at University of Auckland on March 26, 2015
25.
BRITISH JOURNAL OF ANAESTHESIA
HAEMODYNAMIC EFFECTS OF THE PHOSPHODIESTERASE INHIBITOR ENOXIMONE IN COMPARISON WITH DOBUTAMINE IN ESMOLOL-TREATED CARDIAC SURGERY PATIENTS
SUMMARY In a randomized study, the haemodynamic effects of the new phosphodiesterase-lllinhibitor, enoximone, were compared with dobutamine in acutely (3-adrenoceptor blocked patients. Twenty patients scheduled for aortocoronary bypass grafting suffering from tachycardia (heart rate (HR) > 100 beat min-') were treated by infusion of esmolol, an ultra-short acting, selective fi,-b/ocker. Twenty minutes after the start of esmolol, either enoximone 0.5 mg kg-1 as a bolus (n = 10) or dobutamine 5 ng kg-1 min~1 was administered. Haemodynamic effects were monitored for 40 min, including measurement of left ventricular haemodynamics. Esmolol reduced HR (—27%) and d?ldxmtx (-38%) significantly in both groups. Cardiac index (Cl) was decreased also. Enoximone increased Cl (+35%) and dP/dx^ (+39%) significantly, while no change in dobutamine-treated patients was observed. Systemic vascular resistance increased only in the dobutamine group (+44%). KEY WORDS Heart: enoximone, dobutamine, esmolol. artery.
global cardiac performance [1,2]. However, block of adrenergic receptors may reduce myocardial contractility which is associated often with a decrease in cardiac output [3, 4]. Positive inotropes are sometimes necessary to reduce these cardiodepressant side effects of P-blockers. Traditionally, catecholamines such as dobutamine are used widely to increase myocardial performance and improve haemodynamic state [5—7]. Their action is based on (3-adrenoceptor stimulation, which may be associated with severe side-effects or be ineffective because of down-regulation in severe heart failure or iatrogenic pharmacological block [8,9]. Phosphodiesterase-III-inhibitors such as enoximone are a new class of drug with positive inotropic properties, offering an alternative for the treatment of depressed myocardial performance [10-13]. The aim of this study was to investigate how the haemodynamic profile of enoximone and dobutamine may be modified by P-adrenoceptor block during cardiac surgery.
PATIENTS AND METHODS
We studied 20 patients undergoing elective aortocoronary bypass surgery. Informed consent was obtained from each patient and the study was Surgery: coronary approved by the Institutional Human Ethics Committee of the hospital. All patients were premedicated with fluni-
The use of P-adrenergic blockers is established in the management of various cardiovascular disorders, such as angina pectoris, hypertension, tachycardia or arrhythmia [1]. Particularly in patients with coronary artery disease, tachycardiainduced ischaemia may compromise myocardial oxygen balance, followed by deterioration of
J. BOLDT, M.D., D . KLING, M.D.,
B. ZlCKMANN,
M.D.,
G.
HEMPELMANN, M.D. (Department of Anaesthesiology and Intensive Care Medicine); F. DAPPER, M.D. (Department of Cardiovascular Surgery); Klinikstr. 29, Justus-LiebigUniversity Giessen, D-6300 Giessen, F.R.G. Accepted for Publication: September 29, 1989. Correspondence to J. B.
Downloaded from http://bja.oxfordjournals.org/ at University of Auckland on March 26, 2015
J. BOLDT, D. KLING, B. ZICKMANN, F. DAPPER AND G. HEMPELMANN
612
15 and 20 min after enoximone or start of dobutamine administration. After these measurements, arterial and venous cannulae were inserted and cardiopulmonary bypass was started. One- and two-factorial analyses of variance followed by the Scheffe test were used for statistical analysis. P < 0.05 was considered significant. RESULTS
There was no difference in demographic data between groups. All patients were NYHA functional class II without severe impairment of myocardial function (LVEF > 50%; LVEDP < 15 mm Hg) (table I).
100 n
Is x 90 E
I
80 70
120 ^
110
E
- 100
i
90 80 7
Q.
100 beat min"1) in the presence of an adequate mean arterial pressure (MAP) (> 70 mm Hg) and precapillary wedge pressure (PCWP) ( > 8 m m H g ) before cannulation for bypass. In this situation, 10 min before administration of the P-blocker esmolol, fentanyl 5 ug kg"1 and midazolam O.lmgkg" 1 were given to exclude light anaesthesia. Patients with persistent tachycardia (HR > 100 beat min"1) were given esmolol 500 ug kg"1 for 1 min, followed by a continuous infusion of 100 ug kg"1 min"1 until the end of the period of investigation. Twenty minutes after the start of administration of esmolol (when dP/dt max was decreased by more than 20%), patients were allocated randomly to two groups: group 1 (n = 10) received enoximone 0.5 mg kg"1 as a bolus, and group 2 (n = 10) received dobutamine 5 ug kg"1 min"1 as an infusion. Haemodynamic monitoring consisted of MAP (by radial artery cannulation), HR, pulmonary artery pressure (PAP), PCWP, right atrial pressure (RAP) and cardiac output (CO) using thermodilution technique. Derived haemodynamic variables (systemic vascular resistance (SVR), pulmonary vascular resistance (PVR) and cardiac index (CI)) were calculated from standard formulae. Left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP) and left ventricular contractility index (LVdP/drmax) (electronic differentiation, Hellige, Freiburg, West Germany) were obtained by direct cannulation of the left ventricle. All measurements were performed under steady-state haemodynamic and anaesthetic conditions before administration of esmolol (baseline values), 20 min after the start of esmolol and 5,10,
BRITISH JOURNAL OF ANAESTHESIA
ENOXIMONE AND DOBUTAMINE IN p-BLOCKED PATIENTS TABLB I. Mean (SD) demographic data and preoperative heart function in the two groups. L VEF = Left ventricular ejection fraction; L VEDP = left ventricular end-diastolic pressure Esmolol + dobutamine
56.8 (6.7) 80.1 (8.2) 175.0(7.8) 69.9 (4.6) 12.5 (3.3)
57.0 (8.2) 77.0 (3.5) 173.3(7.0) 71.1(3.8) 13.0(2.0)
9 1
8 2
Esmolol decreased HR significantly in both groups (-27%), whereas MAP and RAP were
unchanged (fig. 1). Enoximone and dobutamine did not change MAP and RAP significantly; enoximone increased HR slightly (+10%) for lOmin. None of the patients suffered from arrhythmia during the study. Mean CI was decreased by esmolol in both groups (—18.5 %) (fig. 2). Injection of enoximone 20 min after the start of infusion of esmolol was followed by a significant increase in CI ( + 35 %), whereas dobutamine produced no change in output. In comparison with baseline values, SVR increased significantly in the dobutamine-treated patients (+ 44 %). There was no change in SVR in the enoximone group. PVR increased only in patients who received dobutamine ( + 52%) (fig. 3).
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20
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15
20
FIG. 3. Mean (SD) changes in systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) in the two groups ( • = enoximone 0.5 mg kg"1; O = dobutamine 5 ug kg"1 min"1). Significant differences (P < 0.05): * from baseline values; tbetween groups.
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Age (yr) Weight (kg) Height (an) LVEF (%) LVEDP (mm Hg) Previous myocardial infarctions One (No. patients) Two (No. patients)
Esmolol + enoximone
613
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Esmolol produced adequate reduction in HR in our study by achieving steady state plasma 'S 130 concentrations (loading dose followed by a conx tinuous infusion) [1, 16]. Linear dose-related E J 120 haemodynamic effects have been demonstrated in man [1]. Esmolol was effective in reducing HR 110 during the pre-bypass period in our study. Myocardial contractility, however, was reduced 100 markedly with the dose used. Although 15 LVdP/dfmax is known to be dependent on HR and preload, this variable is accepted generally as an E indication of ventricular contractility. 10 Sympathomimetic amines are used widely for inotropic support and dobutamine in particular is favoured during coronary artery surgery because 5 of its reduced effect on HR [5, 17, 18]. However, 2500 as a reduced responsiveness to P-receptor agonists may be anticipated in these patients, it is reasonable to select new agents which do not affect 0receptors and act at a site distal to the receptor x5 E 2000 [19,20]. Inhibition of phosphodiesterase-III offers an alternative treatment of depressed myocardial function [21-23]. Enoximone produces inhibition of only the membrane-bound high 1500 affinity cyclic adenosine monophosphatephosphodiesterase (phosphodiesterase III, or type 1200 IV phosphodiesterase by revised nomenclature [24]) [25]. It has been proven to be of benefit in 5 10 patients suffering from severely impaired myoTime (min) cardial function by increasing myocardial conFIG. 4. Mean (SD) changes in left ventricular pressure (LVP), tractility and by decreasing afterload because of left ventricular end-diastolic pressure (LVEDP), and its vasodilating properties [19]. It has been used as dP/dtmM3[ in the two groups ( • = enozimone 0.5 mg kg"1; a single dose, as in our study, or by continuous O = dobutamine 5 ug kg"1 min"1). Significant differences infusion [19,22]. A bolus of 0.5mgkg~ l sig(P < 0.05): *from baseline values; 7between groups. nificantly increased contractility [26], with modDirectly measured left ventricular haemo- erate effects on HR. In this study, enoximone dynamic variables (fig. 4) revealed no significant increased HR only slightly (+10%) and for a change in LVP and LVEDP. However, dP/dr max short period (10 min). decreased significantly in response to esmolol in Aldiough the use of positive inotropes is both groups (approximately —38%). Enoximone associated with the risk of increased myocardial increased dP/dfmax significantly ( + 39%), where- oxygen consumption, with detrimental effects on as dobutamine had no effect. No patient required global myocardial function [27], enoximone seems pharmacological or mechanical support during not to affect myocardial oxygen consumption or weaning from cardiopulmonary bypass and all even decrease it because of a concomitant rehad an uneventful postoperative course. duction in systolic wall tension [28]. Moreover, an increased rate of ventricular relaxation occurs, attributable also to activation of the cAMP system DISCUSSION [29]. Direct coronary dilatator effects were reEsmolol is a cardioselective P,-blocker without ported after administration of enoximone [30] and sympathomimetic activity or membrane stabil- Mitrovic and colleagues [31] reported that enoxizing effects [1, 14]. Its distribution half-life is imone abolished stress-induced ischaemia in 2 min, and elimination half-life approximately patients with coronary artery disease. 9 min [15]. Our study confirms that enoximone increases 140
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ENOXIMONE AND DOBUTAMINE IN P-BLOCKED PATIENTS
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myocardial contractility in spite of an effective block of P-adrenoceptors by esmolol. In animals, in which sympathetic-mediated reflex-induced changes in HR were blocked by the fj-adrenoceptor antagonist nadolol, both improvement in ventricular contractility and ventricular relaxation were achieved by the phosphodiesterase-III inhibitor milrinone [20]. In contrast with this, acute pretreatment with esmolol blocked the P^adrenoceptor effects of dobutamine and led to a marked increase in peripheral resistance without accompanying cardiac stimulation. These results are in accordance with other investigations stressing that dobutamine might have detrimental haemodynamic effects in patients who have received long-term medication with P-blockers [6]. In experimental studies, propranolol was reported to abolish the positive inotropic effects of dobutamine, unmasking the a-adrenergic-receptor properties of dobutamine [32]. The dose of dobutamine in our study was small, but has been shown to be effective in patients with moderate myocardial dysfunction [7, 18]. Increasing doses (up to 40 ng kg"1 min"1), however, may cause a pronounced increase in HR with detrimental effects on myocardial oxygen consumption. Enoximone may be useful in treating patients with heart failure. These patients are often dependent on high sympathetic tone or rapid heart rate for an adequate cardiac output. However, tachycardia is a disadvantage with respect to myocardial oxygen consumption and, in this situation, p-blockers may precipitate heart failure. The use of an ultra-short acting P-blocker to reduce heart rate in combination with the inotropic effects of enoximone might be of value and this combination warrants further investigation. It is concluded that dobutamine is not the drug of choice for inotropic support in patients acutely pretreated with P-blockers, whereas enoximone may improve haemodynamic status even in patients who are P-blocked.
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