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Eur J Cardiothorac Surg 2003;24:770-776
© 2003 Elsevier Science NL

Prophylactic milrinone during OPCAB of posterior vessels: implication in angina patients taking ß-blockers

^a Department of Anesthesiology, Seoul City Boramae Hospital, Shindaebang-Dong, Dongjak-gu, Seoul 156-707, South Korea
^b Department of Anesthesiology, Seoul National University Hospital, 28 Yongon-Dong, Chongno-gu, Seoul 110-744, South Korea
^c Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul, South Korea

Received 17 March 2003; received in revised form 9 June 2003; accepted 15 June 2003.

^* Corresponding author. Tel.: +82-2-760-2465; fax: +82-2-745-1525
e-mail: anesingle{at}yahoo.co.kr

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Objective: To determine whether a phosphodiesterase type 3 inhibitor can improve hemodynamics during off-pump coronary artery bypass grafting (OPCAB) of posterior vessels in patients on ß₁-adrenoreceptor blockers. Methods: Thirty patients scheduled for OPCAB of the obtuse marginal artery (OM), and taking atenolol 100 mg a day were randomized in a double-blind manner to receive either milrinone or placebo. Hemodynamic data were obtained after induction, before pericardial incision, during left anterior descending artery grafting, during OM grafting, and after removal of the stabilizer. During the OM grafting, dopamine was infused when the cardiac index (CI) decreased below 2.0 L/min/m², and phenylephrine was infused to maintain the arterial pressure with a CI above 2.0 L/min/m². Results: During OM anastomosis, there were significant differences in CI (milrinone [M] = +7.7%, control [C] = -13.7%, p=0.01), SVI (M=-21.5%, C=-35.8%, p=0.03), SvO₂ (M=-2.6%, C=-8.9%, p=0.02), and SVR (M=-28.1%, C=+1.1%, p=0.01) between the two groups, in terms of percentage change from baseline value. Dopamine was required more frequently and at a higher dose in the control group (M=13%, 5.0 µg/kg/min; C=67%, 10.1 µg/kg/min, p<0.05). Phenylephrine was infused in 33% of the patients in the milrinone group compared to 13% in the control group (p>0.05). Conclusions: Prophylactic milrinone improves CI, SVI and SvO₂ reducing the need for high doses of dopamine during OM anastomosis in patients taking atenolol. Therefore, it can be used as an alternative to dopamine improving hemodynamics and organ perfusion during OPCAB of posterior vessels in patients on ß₁-blockers.

Key Words: Atenolol • Cardiac index • Milrinone • Off-pump coronary artery bypass graft • Obtuse marginal artery

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Off-pump coronary artery bypass grafting (OPCAB) has demonstrated advantages of avoiding potentially detrimental effects associated with cardiopulmonary bypass and eliminating intraoperative global myocardial ischemia [1,2]. However, severe displacement of the heart during posterior vessel anastomosis may impair cardiac function by lowering systemic blood pressure, decreasing stroke volume and cardiac output, reducing coronary blood flow, and worsening regional myocardial ischemia [3]. Beta-adrenergic drugs such as dopamine, dobutamine or epinephrine are infused to restore cardiac output when the cardiac index (CI) decreases below 2.0 L/min/m² during OPCAB [4,5]. However, beta-adrenergic drugs may have adverse interactions with beta-blockers, which are usually taken by patients with chronic angina. In the presence of beta-blockers, the inotropic response to beta-adrenergics at usual doses is unpredictable, and higher doses of the beta-adrenergics are usually required [6].

Milrinone, a type III phosphodiesterase inhibitor, increases cardiac contractility and cardiac output by decreasing c-AMP breakdown [7]. Moreover, the inotropic effect of type III phosphodiesterase inhibitors is maintained in the presence of beta-blockade [8,9].

We hypothesized that prophylactic milrinone would improve hemodynamics and organ perfusion during OPCAB of posterior vessels in patients on ß₁-adrenoreceptor blockers; consequently, it would reduce the need for beta-adrenergic drugs. To our knowledge, there are no studies concerning the hemodynamic effects of milrinone during OPCAB, and it is yet to be determined whether milrinone is effective in improving hemodynamics during OPCAB of posterior vessels in patients on the ß₁-blocker.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Thirty patients who were scheduled for elective OPCAB of both obtuse marginal artery (OM) and left anterior descending artery (LAD) at Seoul National University Hospital from December 2001 to September 2002 were included in this study. All of them were taking atenolol 100 mg/day for at least 4 weeks. Patients who had clinically significant preoperative hepatic or renal dysfunction, thrombocytopenia, coagulopathy, or uncontrolled arrhythmia were excluded. Patients who were supported with intra-aortic balloon pump preoperatively or with cardiopulmonary bypass due to combined valvular heart disease, hemodynamic instability despite IABP support, severe intracoronary calcification, and intramyocardial coronary artery were also excluded. After Institutional Review Board approval, informed consent was obtained from all patients.

On the morning of the surgery, patients were given their usual cardiac medications. Nitroglycerin was infused at a dose rate of 0.5 µg/kg/min in all patients. In the operating room, patients were given intravenous midazolam (0.04 mg/kg) and received routine monitoring consisting of a five lead ECG with ST-segment analysis, pulse oximetry, capnography, nasopharyngeal temperature monitoring, and urine output measurements. A radial artery catheter was inserted under local anesthesia before induction of general anesthesia. Anesthesia was induced with midazolam (0.1 mg/kg), etomidate (0.2 mg/kg), vecuronium (0.15 mg/kg), and sufentanil (2 µg/kg); it was maintained with midazolam (0.05 mg/kg/h), vecuronium (0.1 mg/kg/h), and with sufentanil (2.5 µg/kg/h). A pulmonary artery catheter (Arrow International, Reading, USA), for measuring hemodynamic parameters and obtaining blood samples for mixed venous oxygen saturation measurements, was inserted after induction of anesthesia. Hemodynamic parameters measured included: heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), mean pulmonary arterial pressure (MPAP), cardiac output (CO), pulmonary capillary wedge pressure (PCWP), and mixed venous oxygen saturation (SvO2). The CO was derived from the mean of three thermodilution cardiac output measurements using 10 ml of cold saline. Reproducibility and stability were confirmed if the lowest measurement was within 20% of the highest. The cardiac index (CI) and the stroke volume index (SVI) were calculated according to the CO/body surface area and the CO/HR/body surface area, respectively. Systemic (SVR) and pulmonary vascular resistances (PVR) were calculated using standard formulae. Fluid intake was recorded at hourly intervals during the study.

Patients were assigned randomly in a double-blind manner to receive milrinone or placebo and received either a loading dose of 50 µg/kg of milrinone (continuous infusion at a rate of 0.83 µg/kg/min for 1 h) after the induction of anesthesia, followed by a continuous infusion of 0.40 µg/kg/min, or a matching volume of normal saline. Patients were transfused to maintain the preoperative Hct, and fluids were infused to increase right heart filling. The CVP and PCWP were elevated up to 10 and 15 mmHg, respectively, before pericardial incision. If hemodynamic instability (MAP<60 mmHg, CI<2.0 L/min/m²) developed during OM anastomosis, dopamine was infused at a rate of 5–15 µg/kg/min. When MAP dropped below 60 mmHg, with the CI above 2.0 L/min/m², phenylephrine (0.1–0.5 µg/kg/min) was infused. The arterial conduits, the two internal mammary arteries, were prepared through a median sternotomy. To maintain more than 300 s of an activated clotting time, 1.5 mg/kg of heparin was given. After opening the pericardium, deep pericardial sutures were placed to facilitate pericardial retraction for cardiac elevation and exposure. The operating table was tilted 10–20° to the patient's right side and the patients were placed in Tredelenburg position during OM anastotomosis. A compression-type mechanical stabilizer (CTS; Cardio-Thoracic System,Inc, Cupertino, USA) was used after coronary vessel exposure. OM anastomosis was performed after LAD anastomosis. Baseline hemodynamic data was obtained after induction of anesthesia (T1). Thereafter, milrinone or placebo was infused. Subsequent hemodynamic data were obtained 3 h after milrinone or placebo infusion but before pericardial incision (T2), 3 min after the beginning of LAD grafting (T3), 3 min after the beginning of OM grafting (T4), and 3 min after the removal of the stabilizer (T5).

To evaluate the incidence of perioperative myocardial infarction, serial determination of serum creatine kinase isoenzymes (CK-MB), electrocardiograms, and a postoperative transthoracic echocardiogram were performed. Perioperative myocardial infarction was defined as positive results of at least two of the three following tests: the peak serum CK-MB level (>200 IU/L), appearance of new Q waves on the electrocardiogram, or newly developed regional wall motion abnormalities on the postoperative echocardiogram.

All data was expressed as mean ± standard deviation. A repeated measure analysis of variance (ANOVA) was used to compare the percentage change from baseline within and between groups. Fisher's exact test was used for categorical data. Statistical calculations were made using SPSS 10.0 for Windows (SPSS, Chicago, USA), and p values less than 0.05 were regarded as statistically significant.

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Demographics of the patients show that the two groups were comparable for sex, age, height, weight, left ventricular ejection fraction, type of disease, and medication (Table 1). The two groups had comparable baseline hemodyanamic data including CI, SVI, HR, MAP, MPAP, CVP, PCWP, SVR, and SvO₂ (Table 2).

View larger version (12K): [in this window] [in a new window]   Fig. 1. Hemodynamic changes during obtuse marginal artery (OM) anastomosis in milrinone and control group. Hemodynamic parameters during OM anastomosis (mean±SD [baseline value]): M (n=15) – CI, 2.2±0.5 (2.0 ± 0.2) L/min/m2; SVI, 26 ± 4 (33±6) mL/m2; SVR, 1605 ± 734 (2205 ± 727) dyne s cm-5; HR, 84±14 (60±10) beat/min; MAP, 75±11 (82±10) mmHg; MPAP, 21±5 (14±4) mmHg; PCWP, 18±4 (11±2) mmHg; SvO2, 78±5 (79±5) %. C (n=15) – CI, 1.8±0.4 (2.1±0.3) L/min/m2; SVI, 23±6 (37±6) mL/m2; SVR, 2129±1052 (2094±624) dyne s cm-5; HR, 82±15 (60±9) beat/min; MAP, 76±11 (82±10) mmHg; MPAP, 23±3 (16±3) mmHg; PCWP, 19±3 (12±3) mmHg; SvO2, 73±4 (80±5) %. *Significant change within groups from baseline (p<0.05). Differences between groups at each time point are shown numerically. , milrinone; , control. (Abbreviations: CI, cardiac index; SVI, stroke volume index; SVR, systemic vascular resistance; HR, heart rate; MAP, mean arterial pressure; MPAP, mean pulmonary arterial pressure; PCWP, pulmonary capillary wedge pressure; SvO2, mixed venous oxygen saturation; NS, not significant.)

View larger version (8K): [in this window] [in a new window]   Fig. 2. The requirement of dopamine and phenylephrine during obtuse marginal artery anastomosis. Significant differences between groups (p<0.05) , milrinone; , control.

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
The main findings of the present study is that prophylactic milrinone improves hemodynamics and organ perfusion without the need for high doses of dopamine during OPCAB of posterior vessels in patients taking ß₁ blockers.

The use of atenolol, a selective ß₁-adrenoreceptor blocker, is well established in the management of angina pectoris. Beta-blockers are recommended as initial therapy in the absence of contraindication for patients with chronic stable angina [10]. However, beta-adrenergic blockade may reduce myocardial contractility which is often associated with a decrease in cardiac output [11,12].

During off-pump coronary artery bypass grafting (OPCAB), excessive heart displacements are required for access to posterior vessels such as the OM. In the pig model, severe anterior displacement of beating heart caused primarily right ventricular deformation and pump dysfunction, and often produced hemodynamic instabilities [3,13]. In selected patients, Trendelenburg maneuver effectively mitigates circulatory deterioration on exposure of the posterior wall. In two thirds of the cases, however, inotropic support remained necessary [14]. Although right heart bypass may normalize stroke volume and mean arterial pressure by increasing left ventricular preload [3], it is an impractical and time-consuming procedure. In the present study, despite preceding fluid loading and using Trendelenburg position, the CI and SvO₂ significantly decreased to 86.3% and 81.1%, respectively, of the baseline value during OM anastomosis in the control group (Table 3), and high doses of dopamine was required to maintain a stable hemodynamic status in 66.7% of the patients. These results suggest that increasing the preload alone cannot maintain an acceptable cardiac output during OM anastomosis in many patients on ß₁-blockers, and it should be combined with inotropics for stable hemodynamics. Moreover, the inotropic response to beta-adrenergics at usual doses may be unpredictable in the presence of beta-blockers, since they compete for the same receptor, and higher doses of adrenergic agonists are usually required [6]. On the other hand, the use of prophylactic milrinone significantly improved the CI and SVI during OM anastomosis in patients taking atenolol. Increased cardiac output would provide better organ perfusion during OM anastomosis, which was confirmed by improved SvO₂ (Table 4). In addition, milrinone reduced the incidence and the amount of dopamine requirement during OM anastomosis in these patients. These results are in accordance with previous studies showing that the inotropic effects of type III phosphodiesterase inhibitors is maintained in the presence of beta-blockade by esmolol, carvedilol, or metoprolol [8,9,15]. The maintenance of the effects of the type III phosphodiesterase inhibitors during beta-blocker therapy is consistent with their mechanism of action, which is distal to and independent of occupancy of the beta-adrenergic receptors [16].

During posterior vessel OPCAB, dopamine or dobutamine is not always necessary, and inotropics selectively infused when CI decreased below 2.0 L/min/m² could maintain stable hemodynamics [4,5]. These studies, however, were not designed for patients on beta-blockers. The present study revealed that selective infusion of dopamine is inefficient in restoring cardiac output and organ perfusion during OM anastomosis in the presence of ß₁-blockade, and suggested that prophylactic milrinone could be used as an alternative to dopamine, improving hemodynamics during OPCAB of posterior vessels in patients on beta-blockers. Milrinone improves ventricular relaxation and contractility by way of a c-AMP-mediated lusitropic and inotropic effect, increasing cardiac output [7]. Severe anterior displacement of heart during OPCAB predominantly affects right ventricular function [3]. Therefore, it can be inferred that the improved SVI are attributed to the milrinone's effect on right ventricular relaxation and compliance as well as left ventricular function.

During OPCAB, the act of displacing the heart, more than displacement itself, causes hemodynamic alterations. In many cases, unstable hemodynamics are normalized after a short adaptation period. However, sustained decrease of CO and blood pressure during anastomosis, especially of posterior vessels, may be targets for inotropics. According to a previous study by Grundeman et al. [17] anterior displacement of the beating heart decreased CO and coronary blood flow by 42 and 50%, respectively, and they suggested that the coronary blood flow was not mechanically obstructed, because augmentation of preloads restored coronary flow parallel to the recovery of CO and mean arterial pressure while the heart remained retracted by 90°. Therefore, we believe that, when hemodynamic alterations are unresponsive to augmentation of preloads, inotropic support may increase CO and eventually improve coronary flow during posterior anastomosis whilst inotropics may also increase myocardial oxygen consumption. However, whether inotropic support is beneficial or deleterious on the myocardial oxygen supply–consumption balance during OPCAB of posterior vessels remains to be determined. Monitoring of ST-segment values in the dislocated heart is not effective due to the loss of contact between the heart and the pericardium. Although measurement of coronary sinus lactate may be helpful, it is complex and impractical. Therefore, more effective methods to determine myocardial oxygen consumption or to detect intraoperative myocardial ischemia are required to guide the use of inotropics during OPCAB of posterior vessels. Of the available inotropics, milrinone appears to have some benefits on myocardial oxygen supply–consumption balance. Milrinone improves hemodynamics without increasing overall myocardial oxygen consumption [18]. Furthermore, milrinone may improve coronary flow reserve by direct coronary vasodilation and/or reduction in left ventricular diastolic pressure [19].

In the milrinone group, phenylephrine was required to maintain the MAP during OM anastomosis in 33.3% of the patients. We believe that this result is due to decreased SVR by milrinone [7,19,20]. The MAP, however, could be maintained by low doses of phenylephrine. In the presence of beta-blockers, catecholamine such as dobutamine and epinephrine increases peripheral vascular resistance, unmasking -adrenergic receptor property. However, despite the infusion of dopamine, there was no significant increase in SVR during OM anastomosis in the control group, which was accounted for by the fact that the patients had a high baseline SVR and that dopamine was not infused in 32.3% of the patients.

In the present study, a milrinone infusion was initiated at a rate of 0.83 µg/kg/min for 1 h and then decreased to a rate of 0.40 µg/kg/min. All of the coronary vessels anastomoses were performed at least 3 h after the milrinone infusion. A sudden decrease in blood pressure or reflex tachycardia did not develop in any patients; this can occur when milrinone is loaded by a bolus administration. According to a previous study [21], a continuous infusion of milrinone at a rate of 0.5 µg/kg/min, without a preceding 50 µg/kg bolus administration, has a similar CI change and milrinone level as that with the preceding bolus administration at 3 h after the start of the infusion.

A limitation is that measuring plasma atenolol levels or isoproterenol sensitivity test was not performed in the present study. Therefore, the extent of beta-adrenergic blockade could not be quantified. However, considering the dose of atenolol, mean body weight, and the baseline hemodynamic data, we did not think that there would be a significant difference in the degree of beta-adrenergic blockade between the two groups. Another limitation is that only patients taking atenolol, a selective ß₁-adrenoreceptor blocker were included in the present study, therefore, the results may not be directly applied to patients taking other beta-blockers. However, we believe that milrinone would also have benefit for patients taking some non-selective beta-blockers, since type III phosphodiesterase inhibitors maintain favorable hemodynamic responses in the presence of carvedilol [9,15].

In conclusion, prophylactic milrinone improves CI, SVI and SvO₂ without the need for high doses of dopamine during OM anastomosis in patients taking atenolol, therefore, it can be used as an alternative method to selective infusion of dopamine, maintaining hemodynamics and improving organ perfusion during OPCAB of posterior vessels in patients on ß₁-blockers.

	References

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Yong Lak Kim Ki-Bong Kim Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, J.-H. Articles by Kim, K.-B. Search for Related Content PubMed PubMed Citation Articles by Kim, J.-H. Articles by Kim, K.-B. Related Collections Anesthesia Cardiac - pharmacology Coronary disease