THE ROLE OF ENOXIMONE IN CARDIAC SURGERY

British Journal of Anaesthesia 1992; 69: 45-50

THE ROLE OF ENOXIMONE IN CARDIAC SURGERY J. BOLDT, C. KNOTHE, B. ZICKMANN, M. BALLESTEROS, W. RUSS, F. DAPPER AND G. HEMPELMANN

SUMMARY

KEY WORDS Heart: enoximone. Surgery: cardiopulmonary bypass.

During and after weaning from cardiopulmonary bypass (CPB) pharmacological support is often required in patients with pre-existing myocardial dysfunction and, occasionally in those with normal preoperative ventricular function [1]. Abnormalities of both systolic and diastolic function occur in this situation. Some patients suffer from "stunned myocardium", a failure of ventricular function in an ischaemic region to return to normal after CPB [2]. Additionally, microcirculatory derangements with a limited organ perfusion are associated with myo-

PATIENTS AND METHODS

We studied 80 patients undergoing cardiac surgery after obtaining informed consent and approval from the Ethics Study Board of the hospital. Every day one patient was selected by chance to participate in the study, and allocated randomly to one of two groups: Group 1 (« = 40). Approximately 10 min before the patient was weaned from CPB, enoximone 1.0 mg kg"1 was given i.v. within 5 min (enoximone patients). Group 2 (« = 40). No PDE-inhibitor was given before weaning from bypass (control patients). Volume therapy was administered when necessary (5 % human albumin when pulmonary capillary wedge pressure (PCWP) was < 8 mm Hg). Additional pharmacological inotropic support (adrenaline when cardiac index was < 2.0 litre min"1 m~l; J. BOLDT, M.D., C. KNOTHE, M.D., B. ZlCKMANN, M.D., M . BAIXESTEROS, M.D., W. RUSS, M.D., G. HEMPELMANN, M.D.

(Department of Anaesthesiology and Intensive Care Medicine); F. DAPPER, M.D. (Clinic of Cardiovascular Surgery); JustusLiebig-University Giessen, D-6300 Giessen, Germany. Accepted for Publication: January 13, 1992.

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After cardiopulmonary bypass (CPB). some patients may require circulatory support. This study examined the role of the phosphodiesterase-lll inhibitor, enoximone, in cardiac surgery. Eighty patients selected by chance were allocated randomly to two groups: 40 patients received enoximone 1.0 mg kg~' approximately 10 min before weaning from CPB and 40 served as a control group. Additional pharmacological therapy (adrenaline, noradrena/ine, nitroglycerin) was given, when necessary, by anaesthetists who were not involved in the study. In addition to standard monitoring, skin capillary blood flow was assessed using a laser Dopp/er technique before, during and after CPB until 2 h after the end of the operation. In the period after bypass, cardiac index was always significantly greater in the enoximone than in the control group. Systemic and pulmonary vascular resistance were less in the enoximone-treated patients, indicating a reduction in right and left ventricular wall stress. Oxygen consumption in the enoximone patients was significantly greater after CPB, whereas intrapulmonary shunting was comparable in the two groups. In comparison with baseline values, skin capillary blood flow in the enoximone patients was always greater than that in the control group. In comparison with the control patients, significantly fewer enoximone patients needed adrenaline, and in a smaller dose, even 2 h after operation, whereas more enoximone patients required noradrenaline therapy for a short period. We conclude that the use of enoximone before weaning from CPB improved overall cardiac function, reduced the need of catecholaminergic inotropic support, and provided increased organ perfusion up to 2 h after operation.

cardial dysfunction [3]. Most drugs used in this situation act on alpha, beta or dopaminergic receptors. However, the observation of the phenomenon of beta! receptor down-regulation led to the development of drugs which act independently of the beta receptor [4-7]. Thus in recent years considerable interest has been focused on the phosphodiesterase (PDE) inhibitors, a new class of agent with positive inotropic activity based on inhibition of phosphodiesterase type III (new nomenclature type IV [8]), which result in increased concentrations of cAMP and myocardial performance [9]. Some PDEIII inhibitors appear to possess additional pharmacological properties: several of these substances induce alterations in the response of the myofilaments to calcium,—that is, they induce an increase in Ca2+ sensitivity [10]. The imidazolone derivative, enoximone, is a PDEIII inhibitor with positive inotropic and vasodilator properties [11, 12]. Although its beneficial effects have been demonstrated in low output failure in cardiac surgery [13, 14], the indications for its use are controversial [15]. The aim of this study was to examine further the role of PDE-III inhibitor enoximone in the management of cardiac surgery patients.

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46 TABLE I. Patient data (mean (SD) [range]). LVEF = Left ventricular ejection fraction; LVEDP = left ventricular end-diastolic pressure; CPB = cardiopulmonary bypass; A VR = aortic valve replacement; MVR = mitral valve replacement; CABG = coronary artery bypass grafting

Enoximone

60.8 [43-77] 76.2 (11.5) [46-98] 62.2 (9.0) [43-74] 13.5 (5.5) [14-^0] 33 3 3 2

88.8 (33.5) [34-233] 51.5 (21.9) [19-133] + 500(300) [-1350 to+ 2200]

340 (100) [100-500]

day

1st day after op.

600 (150)[230-880]

550 (190) [200-760]

noradrenaline when systemic vascular resistance was less than 500 dyn s cm"6; nitroglycerin when PCWP was > 20 mm Hg) during and after weaning from bypass was administered when indicated by the attending anaesthetists, who were not involved in the study. Anaesthesia was similar in all patients and consisted of i.v. administration of fentanyl (total dose 0.035 mg kg"1), midazolam (total dose 0.7 mg kg"1) and pancuronium (0.25 mg kg"1). During CPB, midazolam 5 mg and fentanyl 0.1 mg were given every 30 min. No volatile anaesthetics were used. During the study, controlled ventilation was performed to achieve normocapnia in all patients. CPB was carried out using a membrane oxygenator (Sorin 41, Sorin, Torino, Italy). A flow of 2.4

Statistics Results are expressed as mean (SD). Data were analysed using one-way analysis (biometric data,

TABLE II. Changes in haemodynamic variables {mean (SD)). MAP = Mean arterial pressure; HR = heart ratt; CVP = central venous pressure ; PAP -• pulmonary artery pressure ; PCWP = pulmonary capillary wedge pressure. No significant differences between groups

After CPB 2 h after

Before Baseline

CPB

5 min

45 min

op.

76.2 (8.8) 78.9(12.1)

74.3(11.6) 75.8(11.1)

71.9(9.1) 77.2(12.1)

82.3 (10.7) 89.6(10.1)

92.6(14.3) 93.3 (12.2)

73 (13) 72(12)

81 (14) 83(13)

101(13) 94(11)

100(13) 98(11)

99.4 (14.6) 92.1 (16.1)

7.4 (2.3) 7.2 (2.3)

6.9 (2.8) 6.9 (4.2)

7.9 (2.5) 8.7 (2.2)

9.2 (2.3) 9.6 (3.0)

9.0 (2.6) 8.3(3.1)

16.9 (2.9) 17.8 (3.3)

17.3 (4.3) 17.9 (6.0)

17.2 (3.2) 18.7 (4.1)

18.4 (2.8) 19.8 (5.4)

18.7 (3.2) 18.6 (3.4)

9.7 (2.9) 10.2 (3.7)

10.1 (2.2) 10.4 (4.0)

11.0(2.3) 11.0(2.2)

11.5(2.8) 12.3(4.1)

11.5(3.1) 11.0(2.9)

MAP (mm Hg) Enoximone

Control HR (beat min"1) Enoximone Control CVP (mm Hg) Enoximone Control PAP (mm Hg) Enoximone Control PCWP (mm Hg) Enoximone Control

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61.7 [41-83] Age (yr) Weight (kg) 74.5 (11.6) [50-101] LVEF(%) 59.1 (10.1) [30-70] LVEDP 15.3 (6.4) [12-35] (mmHg) 31 CABG (No.) 3 AVR (No.) 4 MVR (No.) 2 AVR and MVR (No.) CPB (min) 93.2 (39.3) [39-300] Ischaemia 51.9 (19.2) [21-129] (min) Fluid + 690(450) balance [-800 to+ 2300] during CPB (ml) Blood loss (ml) Operation 330 (130) [110-550]

Control

litre min"1 m"2 was used during the entire bypass period and almost normothermia (lowest rectal temperature 34.0 + 0.5 °C) was maintained. The circuit was primed with Ringer's solution 1000 ml, 5 % glucose 1000 ml and 5 % human albumin 250 ml. Bretschneider's cardioplegic solution was used for myocardial protection. Venous blood was returned to the extracorporeal circuit via a two-stage cannula (mono-atrial cannulation technique). A haemofiltration device (HF-80, Fresenius, Bad Homburg, FRG) was used to salvage the blood remaining in the circuit after discontinuation of CPB and this was retransfused before until the end of surgery. During weaning from bypass, fluid from the CPB was infused to maintain PCWP between 8 and 12 mmHg. We measured heart rate (HR), mean arterial pressure (MAP), pulmonary arterial pressure (PAP), PCWP, right atrial pressure (RAP) and cardiac output (CO) (thermodilution technique). Derived haemodynamic parameters (cardiac index (CI), systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) and oxygen delivery (DOj), oxygen consumption (Fo ? ), and intrapulmonary right-to-left shunting (Qs/Qx.)) were calculated from standard formulae. Changes in capillary skin blood flow were measured using a two-channel laser Doppler skin blood flux monitor (MBF-3D, Moor Instruments, Devon, Great Britain). Measurements of laser Doppler flow (LDF) were performed simultaneously on the patient's forearm (probe 1) and at the forehead (probe 2) [16, 17]. Measurements were recorded at the following times: after induction of anaesthesia in stable haemodynamics (baseline values), before start of CPB (pericard open), 20 min after start of CPB, 5 min after weaning from CPB, at the end of the operation and 2 h after the operation (on intensive care unit).

ENOXIMONE IN CARDIAC SURGERY

47

TABLE III. Changes in haemodynamic variables (mean (SD)). CI = Cardiac index; SVI = stroke volume index; SVR •• systemic vascular resistance; PVR = pulmonary vascular resistance. *P < 0.05 compared with control group After CPB Before Baseline

CPB

2h after 5 min

45 min

op.

1

CI (litre min" m *) Enoximone Control SVI (ml min-1) Enoximone Control SVR (dyn s cm"') Enoximone Control PVR (dyn s cm"') Enoximone Control

3.52 (0.3) 3.54 (0.6)

3.35 (0.9) 3.11(0.7)

5.10(0.9)* 3.40 (0.8)

3.80 (0.8)* 3.01 (0.7)

3.65 (0.6)* 2.90 (0.7)

50.2(11.0) 49.2 (9.9)

44.9(11.1) 38.6(10.1)

50.1 (10.2)* 38.9(12.1)

43.3(10.1)* 34.7 (9.2)

37.2 (9.1)* 31.5(10.2)

912(208) 943 (192)

1096 (272) 1100(320)

612(147)* 1119(230)

956 (220)* 1198(202)

1040 (220)* 1399 (266)

86 (26) 88(24)

86(20) 99 (24)

61 (20)* 99(27)

69 (23)* 98 (23)

90 (24)* 119(33)

After CPB Before Baseline Pao./Flo, (mm Hg) Enoximone Control Do, (ml min"1) Enoximone Control Vot (ml min"1) Enoximone Control

&I& (%)

Enoximone Control

CPB

2 h after 5 min

45 min

op.

397 (61) 404(85)

399 (66) 405 (74)

393 (88) 354 (88)

404(81) 375(63)

430(72) 378 (66)

1226 (210) 1181(233)

1257 (233) 1107(301)

1407 (209)* 1059 (259)

1278(149)* 1020 (231)

1251 (207)* 999 (210)

221(49) 216(62)

208(44) 199 (43)

278 (44)* 229 (53)

249 (75) 230 (53)

321 (46)* 278 (54)

17.7(5.4) 15.6(5.5)

16.9 (3.3) 16.7 (4.4)

19.5 (5.7) 19.9 (6.6)

19.5 (6.2) 18.5 (7.0)

16.8 (4.6) 16.6(5.5)

as were MAP, HR, CVP, PAP and PCWP during the entire study (table II). CI in the enoximone group was significantly greater during the post-bypass period than in the control patients; this persisted for 2 h after the end of the operation (table III). SVI also was greater in the enoximone patients throughout the study (table III). SVR and PVR were significantly less after CPB in those patients who were treated with enoximone. Two hours after operation, both SVR and PVR were less than in the control patients (P < 0.05) (table II). RESULTS PaoJFiOi and Qs/Qx. were similar in both groups (table IV). After bypass, Do2 increased only in the Patient characteristics and data from heart catheterenoximone-treated patients (max. + 15 % from baseization did not differ significantly between the groups line value), whereas it decreased in the control (table I). Preoperative medication (particularly beta group (max.— 16%). In the post-bypass period, blockers and nitrates) was similar in the two groups, Vot was always greater in the enoximone group (table IV). Capillary skin blood flow (LDF) measTABLE V. Changes in laser Dopplerflotv (LDF) from baseline values ured both at the forearm and forehead increased (mean (SD)). *P <0.05 compared with control group more in the enoximone-treated patients and remained significantly greater during the post-bypass After CPB period in these patients than in the control group Before 2 h after (table V). 5 min CPB 45 min op. Urine output at the end of the operation and 2 h Forehead flow (%) after operation was greater in the enoximone-treated Enoximone -4(3) + 31 (10)* + 9(3)* -12(10)* patients than in controls. The volume of fluid Control + 2(2) +10 (6) -17(8) -39(9) required to maintain PCWP similar to baseline Forearm flow (%) Enoximone + 5(4) + 85(17)* + 51 (12)* - 2 1 (9)* measurements was significantly greater in enoximone Control + 4(2) +15 (8) -5(4) -46(12) than in control patients (table VI). data from perioperative period) and two-way analyses of variance (all haemodynamic variables) including multivariate analysis of variance, followed by Scheffe's tests. Changes in microcirculation from baseline values are presented as percentage changes because output of the LDF monitor is in arbitrary flow units. Percentage changes were tested by H test (Kruskal-Wallis). P < 0.05 was considered statistically significant.

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TABLE IV. Changes in blood-gas variables (mean (SD)). Do, = Oxygen delwery; Vo,= oxygen consumption; intrapulmonary right-to-left shunting. * P < 0.05 compared vrith control group

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48

TABLE VI. Fluid input and urine output (mean (SD) [range]). * P < 0.05 compared with control group

Volume input (ml) Enoximone Control Urine output (ml) Enoximone Control

At end of op.

2 h after

During CPB 350 (150)[0-1000] 490 (200)[0-1500]

1350 (400)[1000-2500]* 700 (150)[550-950]

850 (150) [200-1000]* 250 (100) [0-250]

550 (160)[95-900] 490 (160) [70-850]

690 (240) [90-1050]* 440 (130) [50-650]

690 (250) (150-1200)* 320 (250) [90-800]

op.

TABLE VII. Use of catecholamines (adrenaline and noradrenaline) (mean (SD) [range]). * P < 0.05 compared with control group

Until end of op.

During weaning from CPB

op.

0* —

2*

2*

4.0 (0.4) [4.0-5.0]

2.0 (0.7) [2.5-3.0]

15

13

7

5.5 (2.4) [2.2-20.1]

5.6 (2.5) [3.2-15.2]

3.9 (0.6) [2.2-5.4]*

11*

10*

2.0 (0.6) [0.6-5.5]

1.0 (0.2) [0.3-2.9]*

2

5

1.5 (0.3) [0.5-3.0]

0.5 (0.1) [0.4-1.2]

More patients in the control group received adrenaline during weaning from bypass (15 m 0) and thereafter (table VII). In contrast, noradrenaline was given more often during weaning from CPB and thereafter in the enoximone group than in the control patients. None of the patients needed noradrenaline 2 h after operation (table VII). There was no peri- or postoperative mortality in the groups within the first 24 h. DISCUSSION

Cardiovascular dysfunction occurs commonly in cardiac surgery [1]. Reduced pump function is a consequence of both preoperative loss of viable myocardium and diminished myocardial contractility secondary to ischaemia during cross-clamping of the aorta. While heart failure is caused by myocardial abnormalities, many of the manifestations result from peripheral circulatory derangements [4]. Treatment is designed to enhance cardiac contractility, improve tissue oxygen delivery by improving the microcirculation and, when necessary, correct right heart function. The effectiveness of sympathomimetic agents in this situation is either limited or hindered by side effects such as arrhythmias, increased myocardial oxygen consumption, development of tolerance or periphereal vasoconstriction, particularly with larger doses. Beta receptor desensitization (" down-regulation ") may also limit the usefulness of catecholamines [5]. PDE-III inhibitors may counteract this loss of beta receptor responsiveness, which may occur in severe heart disease, during ischaemia and during exposure of the heart to catecholamines.

— — — —

Attention should be paid to the effect of inotropic therapy on myocardial oxygen demand. Adrenaline may be associated with myocardial ischaemia and an increase in diastolic filling pressures [18]. By producing vasodilatdon (significantly smaller SVR than in the control group), enoximone may induce decreased end-diastolic wall stress and systolic wall stress. Thus enoximone was reported to improve myocardial performance without requiring an increase in myocardial oxygen demand [19, 20]. An additional property of the PDE-III inhibitors is a beneficial effect on diastolic function, including relaxation, compliance and filling [21,22]. Kereiakas, Viquerat and Lanzer [23] reported' an improvement in overall left ventricular distensibility after enoximone. When patients undergoing cardiac surgery are treated, alterations in the microcirculation should also be taken into account. A consequence of artificial perfusion during CPB is development of systemic vasoconstriction. The perfusion deficit which may occur during CPB is associated with a risk of local hypoxaemia, reperfusion injury by oxygen radical formation and endothelial wall damage. Catecholamines may induce a further reduction in capillary flow and inadequacy of tissue perfusion [3]. Skin capillary blood flow measured by a laser Doppler technique (LDF) in the present study revealed improved microperfusion in the enoximone patients in the entire post-bypass period (even 2 h after operation). Thus the concept of optimizing flow rather than pressure [24] was fulfilled better in these patients than in the control group. Laser Doppler flowmeters measure only capillary skin blood flow; it is known that the microcirculation differs greatly in

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Adrenaline (ng min ') Enoximone group No. receiving Amount given Control group No. receiving Amount given Noradrenaline (ng kg"1) Enoximone group No. receiving Amount given Control group No. receiving Amount given

Until 2 h after

ENOXIMONE IN CARDIAC SURGERY

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different organs, and changes in capillary skin blood flow may not be representative of the microcirculation in other tissues. However, there are reports that laser Doppler flowmeters are of value in intensive care patients who are often at risk of an impaired microcirculation [25]. As enoximone is an effective vasodilator, it may be beneficial when spasm in internal mammary artery grafts occurs. This has been reported in the immediate postoperative period [26]. Enoximone is reported to possess potent vasodilator properties and it seems to be devoid of the risk of inducing vasospasm. Right ventricular performance may be affected also during cardiac surgery, sometimes limiting the overall success of surgery [27]. PDE-III inhibitors are reported to cause pulmonary vasodilatation [28]. PVR in the enoximone-treated patients was always less than in the control group and this was most pronounced 2 h after operation. It is difficult to identify patients who are at risk of cardiovascular dysfunction secondary to CPB. Thus we decided to give enoximone before weaning from bypass commenced, although we do not have haemodynamic data for this period. We compared the effects of pretreatment with enoximone with our standard management of cardiac surgery patients, which consisted of administration of adrenaline, as used by other investigators [29]. In a study in which enoximone was given after skin incision, Knape [15] demonstrated overall beneficial haemodynamic effects during and after weaning from bypass. Also, Moore and colleagues [30] advocated enoximone in preference to conventional catecholamines. Although we observed that more enoximone patients required noradrenaline (significant only at the end of the operation), this may reflect the rather high loading dose of enoximone used in this study (1.0 mg kg"1). A dose of 0.5 mg kg"1 was associated with less risk of decreasing SVR (and arterial pressure) excessively and administration of alpha! vasocontrictors was not necessary in order to maintain adequate myocardial perfusion pressure [31].

49

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256-258. 30. Moore NA, Tarr TJ. PDE-inhibitors in heart failure: periand postoperative treatment. In: van Zwieten PA, ed. The

31. Boldt J, Kling D, Dieterich HA, Marck P, Hempelmann G. The new phosphodiesterase inhibitor enoximone in patients following cardiac surgery—pharmacokinetics and influence on parameters of coagulation. Intensive Care Medicine 1990; 16: 54-59.

Role of Phosphodiesterase-Inhibitors in Heart Failure. Inter-

national Congress and Symposium Series, Vol. 178. London: Royal Society of Medicine Services, 1991; 51-58.

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