Eur J Cardiothorac Surg 2005;27:289-295
© 2005 Elsevier Science NL
Dobutamine improves thoracic aortic blood flow during off-pump coronary artery bypass surgery: results of a prospective randomised controlled trial
Thomas Modinea,
Christophe Decoenea,
Sharif Al-Ruzzehb,
Thanos Athanasioub,
Pierre Poivrea,
Annie Pola,
Georges Fayada,*
a Service de Chirurgie Cardiovasculaire, Pr. H. Warembourg, Hopital Cardiologique, CHRU de Lille, France
b The National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK
Received 12 July 2004;
received in revised form 16 October 2004;
accepted 31 October 2004.
* Corresponding author. Tel.: +33 3 2044 5028; fax: +33 3 2044 6992. (E-mail: g-fayad{at}chru-lille.fr).
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Abstract
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Objective: Dobutamine is commonly used to improve ventricular performance in cardiac surgery. The aim of this prospective randomised controlled study was to assess the effectiveness of using low doses of dobutamine during off-pump coronary artery bypass (OPCAB) surgery in order to reduce haemodynamic compromise due to heart displacement. Methods: Thirty-two patients undergoing elective coronary artery bypass grafting (CABG) surgery using OPCAB technique for more than two vessels were approached and recruited. We analysed the changes in the thoracic aortic blood flow (TABF) during OPCAB using transoesophageal Doppler and by other conventional monitoring methods as cardiac output, invasive pulmonary and radial pressures and mixed venous oxygen saturation. Results: The two groups were similar in preoperative characteristics. No postoperative complications were observed in the study patients. The heart rate, right atrial pressure, cardiac output measured by thermodilution and TABF changed significantly during the procedure. Also significant changes in descending thoracic aortic diameter were observed. The postoperative creatinine was significantly lower in the dobutamine group (P=0.04). Dobutamine was found responsible for the improvement in the descending TABF (P=0.006). Conclusions: This study showed that intra-operative intravenous infusion of dobutamine at 5µg/kg per min in routine OPCAB patients safely increased cardiac output even without such changes been detected by conventional monitoring methods.
Key Words: Off-pump surgery • Transoesophageal Doppler • Thoracic aortic blood flow
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1. Introduction
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Dobutamine, a ß-receptor agonist, is frequently used in the peri-operative management of patients undergoing coronary artery bypass grafting (CABG) surgery mainly as an inotrope for temporary support of myocardium. Several clinical studies evaluated the use of dobutamine in different dose ranges postoperatively in CABG patients [1]. Inotropes are used to improve systemic, as well as, regional perfusion and hence tissue oxygen delivery following CABG surgery [2].
Dobutamine is a synthetic sympathomimetic amine with predominant ß1-adrenergic activity. It is rapid acting and easy to manipulate with short elimination half life, however, it is believed to increase myocardial consumption and thus could be hazardous in the setting of potential myocardial ischaemia [3]. Dobutamine increases cardiac output (CO) by improving coronary blood flow, decreasing left ventricular end diastolic pressure and thus enhancing cardiac contractility [4].
Little is known about the effect of using inotropes on the outcome of patients undergoing OPCAB surgery. This type of surgery is associated with acute and rapid changes in CO. Therefore, the presence of a fast and adequate response system to counteract those changes would be extremely beneficial for the intra-operative anaesthetic management.
The aim of this prospective randomised study was to assess the benefit and effectiveness of the intra-operative use of intravenous dobutamine on haemodynamic parameters measured by conventional methods and by transesophageal Doppler in patients undergoing elective OPCAB surgery.
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2. Patients and methods
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Thirty-two patients undergoing elective OPCAB surgery for more than two vessels were recruited following an informed consent. Sixteen patients received dobutamine infusion intra-operatively and the other 16 patients did not. An institutional approval was obtained for the study. Patients were excluded if they had gastric or oesophageal disease due to the fact that this will be a contraindication for the use of the trans-oesophageal echocardiography (TOE). The preoperative characteristics of the study patients are presented in Table 1.
2.1. Anaesthetic and surgical techniques
Following induction, a pulmonary catheter (CCOmbo®, Edwards Life Science LLc, Irvine, CA) and a central venous catheter (in the right jugular vein), a urinary catheter and a rectal temperature probe were inserted. Normothermia was maintained by warm fluid infusion and warm air blankets on the head and the non-harvested radial artery arm.
A nasal transoesophageal Doppler probe was inserted preoperatively and was connected to a specific monitor allowing an instantaneous M-mode echographic measurement of the aortic diameter (Hemosonic® Arrow Int. Inc., Reading, PA). Doppler measurements were only performed when the best aortic diameter and Doppler signal were obtained. The operation was performed through median sternotomy using Octopus III® (Medtronic Inc., Minneapolis, MN).
Haemodynamic management aimed to maintain mean arterial pressure (MAP) above 70mmHg first by intravenous fluids only in the non-Dobutamine group or by both intravenous fluids and continuous infusion of dobutamine 5µg/kg per min commencing 10min before the first coronary anastomosis in the dobutamine group. The recorded parameters included: MAP, right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP), cardiac output by the continuous thermodilution method (COTD), mixed venous oxygen saturation (SVO2). The Hemosonic® Doppler probe recorded the thoracic aortic blood flow (TABF) and, based on this, the cardiac output (COABF) was calculated. Thoracic aortic diameter (TAD) was measured by the M-mode echographic method.
The haemodynamic measurements were performed at six time points: baseline preoperative measurement just before the chest skin incision (T1), prior to the first coronary anastomosis and before any heart manipulations (T2), during the first coronary anastomosis (T3), during the second coronary anastomosis (T4), during the third coronary anastomosis (T5) and at chest closure (T6). Measurements were performed exactly after finishing half the coronary anastomoses at T3, T4 and T5.
2.2. Statistical analysis
The difference analysed between groups was based on clinical and haemodynamic data collected prospectively until discharge. The correlation between continuous variables was tested with Pearson's correlation test. Categorical variables were compared using the Fisher exact test or the 
2 test as appropriate. Continuous variables were analysed by one way analysis of variance (ANOVA) for normally distributed data in order to identify significant haemodynamic changes between different time points (T1–T6). Before performing the analysis, we evaluated normality and homogeneity between groups by using Kolmogorov–Smirnov test and Levene test, respectively. Bonferroni test was used for post-hoc comparisons. The behaviour over time of variables was measured at multiple time points in each subject of each of the treatment groups (with or without Dobutamine) was analysed by repeated-measures ANOVA.
A P-value less than 0.05 was considered statistically significant and all tests were two-sided. Statistical analysis was performed using the SPSS 11.0 for Windows software package and for power analysis the Sample Power 2.0 for Windows (SPSS Inc., Chicago, IL, USA).
Power analysis, in order to identify a difference in the mean value of CO of 1l/min for a one way fixed effects analysis of variance with six levels, showed that five cases per cell are required for a total of 30 cases. The criterion of significance (
was set at 0.05) with effect size for F=1 which yields a power of 1.0.
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3. Results
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Preoperative characteristics of the patients included in the study are presented in Table 1. The two groups were similar in all preoperative characteristics except the mean weight, which was significantly lower (P=0.04) in the dobutamine group (73.7±11.7) in comparison to the non-dodutamine group (83.3±13.3). No postoperative complications were observed in the study patients and the mean postoperative serum troponin level was 1.48±1.5 versus 2.1±3.8ng/ml in the two groups, respectively (P=0.5). The postoperative time ventilation time was 6.4±2.1h and all patients were discharged from ITU within 36h postoperatively. The average time period of ‘myocardial mobilisation and ischaemia’ from the LAD exposure to the completeness of the last coronary suture was 76±9min. The study patients were given an average amount of intravenous fluids of 1250±250ml intra-operatively.
Although the preoperative creatinine was not significantly different between the two groups 115±49.3 versus 100±17.5, respectively, the postoperative creatinine was significantly lower in the dobutamine group 89.11±44.9 versus 100±17.5 in the non-dobutamine group (P=0.04). Changes of the haemodynamics parameters over the six time points of the study are presented in Figs. 1–4 and the results of ANOVA and repeated measures analysis are presented in Tables 2 and 3, respectively.
The HR, RAP, COTD and TABF did change significantly during the procedure. Also significant changes in descending TAD were observed. A significant decrease in MAP was observed between groups (T2–T3), F=2.6 and P=0.02. This change (Fig. 1a) was related to a significant reduction of MAP during T2 compared to T3 (87.5±16.7 versus 74.8±16.9mmHg, with 95% CI of 1.11–24.29, P=0.02). Also the changes in MAP were associated with a significant increase in HR (Fig. 1b) between groups, F=5.73 and P<0.001 and especially at T6 in comparison to T1, T2 and T3.
RAP differed between groups (Fig. 2a), F=2.97 and P=0.01 especially at T4 in comparison to T3 (6.8±3.23 versus 10.5±5.41mmHg, with 95% CI of –7.05 to –0.16 and P=0.03). Also significant change of SVO2 between (T1–T6) was observed (Fig. 2b), F=6.45 and P<0.001 and especially at T4 in comparison to T1, T2, T3, T6. COTD differed significantly between groups (T1–T6), F=5.25 and P<0.001 especially a significant reduction was observed during T4 and continued to decrease during further heart manipulation during T5, respectively, from 3.71±0.95l/min at T4 (95% CI of –1.7 to –0.11 and P=0.01), to 3.3±1.01l/min at T5 (95% CI of –2.1 to –0.49 and P=0.000) in comparison to T6 (Fig. 3a).
TABF at (T4, T5) decreased significantly in comparison to (T1, T2), but returned to normal values at chest closure T6 (Fig. 3b). Regarding the changes in TAD (Fig. 4a), we found that although a marginally significant change was observed between groups (T1–T6), F=2.58 and P=0.02 in the post-hoc comparison none of the groups was found to be responsible for a statistically significant difference.
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Fig. 4. (a) Variation of TAD during T1–T6; (b) plot of marginal means demonstrating the interaction between TABF and use of dobutamine.
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Repeated measures analysis (Table 3) showed that dobutamine was not responsible for the variation in SVO2 (F=1.6, P=0.21) or COTD (F=1.17, P=0.28) between subjects. However, dobutamine was responsible for the variation of the improvement in the TABF (F=8.9, P=0.006). Fig. 4b represents a profile plot, which is a line plot in which each point indicates the estimated marginal mean of a dependent variable (TABF) at each time point (T1–T6), while the presence or absence of dobutamine was used to make separate lines.
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4. Conclusion
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This prospective randomised controlled study showed that intra-operative infusion of dobutamine at 5µg/kg per min during routine OPCAB surgery safely increased cardiac output without changes in SVO2 and heart rate. Interestingly, this increase was detected only by transoesophageal Doppler measuring COABF but not detected by COTD which is measured by thermodilution. In addition, dobutamine preserved the kidney function, as postoperative serum creatinine was significantly lower in the dobutamine group.
Dobutamine significantly reduced RAP and SVO2 while exposing coronary arteries. A significant reduction of COTD was also observed during the first coronary anastomosis and continued to decrease with further heart manipulation during the second coronary anastomosis. The TABF decreased significantly in comparison to the early time points before heart manipulation and returned to normal values at chest closure and dobutamine was responsible for the variation of the improvement in the descending TABF.
OPCAB has shown some improvement of the outcome in high-risk patients when compared with conventional CABG using cardio-pulmonary bypass (CPB), although, better postoperative cardiac function was rarely demonstrated [5]. Ascione and colleagues showed in a prospective randomised trial, excluding patients with ejection fraction of <30% and disease involving the distal circumflex, that heart-rate (HR) was higher in the CPB group, while the other haemodynamic variables studied, e.g. mean arterial pressure (MAP), central venous pressure (CVP) did not differ in spite of the fact that dopamine inotropic support was higher in the CPB group but did not reach statistical significance [6]. Furthermore, OPCAB was shown to be superior to conventional CABG using CPB in patients with renal disease or severe aortic atherosclerosis [7].
The two main challenges that face the operating team during OPCAB are first to detect and prevent any myocardial ischaemia and secondly ensure adequate blood delivery to the brain, kidney, liver and gut, and both challenges are closely related [8]. This underlines the need for reliable and sensitive monitoring tools [9]. Haemodynamic changes during heart displacement occur during OPCAB surgery. Small and rapid changes in ventricular filling and myocardial perfusion can markedly change global ventricular performance [10]. Methods aimed to improve haemodyamic parameters, e.g. fluid loading, blood redistribution and inotropic agents, were used with no evidence of efficacy as assessed by conventional monitoring.
During OPCAB, preventing deterioration in cardiac function due to heart manipulation is a challenge to avoid multi-organ dysfunction. Recently, Ensingher and associates reported an increase in cardiac index, splanchnic blood flow, femoral blood flow and arterial-gastric mucosal PCO2 gap, by using dobutamine, without increasing metabolic demands [11].
Little is known about aortic blood flow distribution during OPCAB, although the period of haemodynamic instability could last for a relatively long time, particularly in cases requiring three or four coronary anastomoses. Global haemodynamic disturbance during OPCAB has been previously studied by the use of the pulmonary artery catheter and the radial arterial line [12], although the accuracy of the pulmonary artery catheter measurements in such cases, where the heart is twisted, may not be reliable.
Aortic blood flow measurement by an oesophageal pulse Doppler velocimeter is often used as a non-invasive method for cardiac output monitoring [13] and successfully used in measuring descending TABF [14]. We have recently shown that low TABF occurred without concomitant significant changes in the measurements obtained by conventional haemodynamic monitoring methods during OPCAB surgery [15]. The observed discrepancy between the two methods was partially related to blood distribution during OPCAB. Extrapolation of descending aortic blood velocities for cardiac output estimation needs the knowledge of the ascending/descending aortic blood flow ratio [16]. Recently, Leather and Wouters have found that lumbar epidural anaesthesia increases TABF by inducing a lower body vasodilatation and thus consequently changing the ascending/descending aortic blood flow ratio [17]. Moreover little is known about the accuracy of the COTD method in OPCAB procedures where the heart gets twisted and rotated in un-physiologic positions. With anterior heart displacement, Mathison and colleagues found that the right heart cavities were compressed and lost their shape, although this was not associated with any right outflow obstruction or significant regurgitation [18].
The manoeuvres used to expose coronary arteries during OPCAB result in hemodynamic impairment [19]. This decrease can be deleterious in patients with previous critical low blood flow delivery to the kidneys or the gut before surgery. Ascione and associates have found that OPCAB decreases the incidence of further renal deterioration in patients with preoperative renal insufficiency [20]. However, the benefits of avoiding CPB, aortic cannulation, systemic inflammatory reaction and cerebral emboli may be outweighed by the risk of renal and gut hypoperfusion especially in patients with renal insufficiency [21].
Continuous monitoring of SVO2 is closely related to oxygen delivery by cardiac output to the tissues while haemoglobin level and oxygen consumption remain unchanged. We observed in this study that SVO2 changes were more related to a TABF decrease rather than other haemodynamic parameters especially during the short periods of heart manipulation. In order to maintain SVO2 around 75–80%, we planed to use low doses of dobutamine (<5µg/kg per min). This dose allows increase cardiac output and consequently improves mesenteric perfusion without increasing myocardial oxygen consumption.
To correct haemodynamic disturbances during OPCAB, -agonist vasoconstrictors are currently recommended to increase the coronary perfusion pressure and ß-agonists are usually avoided in order to limit myocardial oxygen consumption. The vasoconstrictors increase MAP but can induce redistribution of the aortic blood flow decreasing the blood delivery to the kidneys and the gut [8,9]. Low doses of dobutamine (<5g/kg per min) would not have much effect on myocardial oxygen consumption, but increase cardiac output and probably improve both mesenteric and kidney blood delivery. This drug should be preferred especially in patients with renal insufficiency or those who are at risk of mesenteric ischaemia. It has been recently shown that dobutamine could improve splanchnic perfusion and therefore prevent compromise the gut barrier leading to bacterial translocation, which is postulated to cause multi-organ dysfunction and failure [2]. In addition, we do not believe that the unavoidable significant difference in weight between the two groups, due to the randomised nature of the study, had any effect on the responsive of adreonoceptors and consequently distribution of blood and flow dynamics. This has been indirectly shown recently by the lack of association between adrenoceptors and obesity [22].
Haemodynamic changes during heart displacement have been studied in both animals and humans [8–10,23], and were found to be significant during the marginal and right coronary artery anastomoses rather than during the LAD anastomosis; however, they were thought always to be within the physiologic limits. Our study confirms the findings of those previous studies in that respect. Several investigators studied the haemodynamic tolerance during multi-vessel grafting, particularly in the circumflex territory [20,21]. The resultant impairment of cardiac output during OPCAB could be generally corrected with fluid redistribution.
Up to our knowledge this is the first randomised trial to study the effectiveness of the intra-operative use of dobutamine infusion in patients undergoing OPCAB surgery on haemodynamic, clinical and echographic outcomes. Furthermore, we believe that dobutamine exerted some degree of renal protection as reflected at a biochemical level by the significant difference in creatinine postoperatively between the two groups, although, those favourable results were not translated into clinical benefits for the patients. Indeed, the small number of patients precludes from demonstrating such a difference in clinical outcome. However, these results suggest that empirical intra-operative use of dobutamine in patients borderline renal function undergoing OPCAB may be of some value.
The study is limited by the lack of objective evaluation of the perfusion of the peripheral organs like the kidney, gut and brain by means of saturation measurements or transcranial Doppler which would have added some confirmation of the study findings.
In conclusion, this study has shown that intra-operative intravenous infusion of dobutamine at 5µg/kg per min in routine OPCAB patients safely increased cardiac output even without such changes been detected by conventional monitoring methods.
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Acknowledgments
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The authors would like to thank Mrs Laurence Ledar, who has died recently, for the invaluable assistance in the planning and conduction of this randomised clinical trial.
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Abstract
1. Introduction
