Eur J Cardiothorac Surg 2004;26:687-693
© 2004 Elsevier Science NL
Efficacy of pre-emptive milrinone in off-pump coronary artery bypass surgery: comparison between patients with a low and normal pre-graft cardiac index
Y.L. Kwaka,
Y.J. Oha,
S.H. Kima,
H.K. Shinb,
J.Y. Kima,
Y.W. Honga,*
a Department of Anesthesiology and Pain Medicine and Anesthesia and Pain Research Institute, Yonsei Cardiovascular Research Institute, Yonsei University School of Medicine, 134 Shinchon-Dong, Seodaemun-Gu, Seoul 120-752, South Korea
b Department of Anesthesiology and Pain Medicine, Inha University School of Medicine, 7-206, 3rd St. Shinheung-Dong, Chung-Gu, Inchon 402-751, South Korea
Received 18 March 2004;
received in revised form 22 June 2004;
accepted 1 July 2004.
* Corresponding author. Tel.: +82-02-361-7200; fax: +82-02-361-2951. (E-mail: ywhong{at}yumc.yonsei.ac.kr).
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Abstract
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Objective: The effect of pre-emptive milrinone without bolus during off-pump coronary artery bypass surgery (OPCAB) was evaluated in two groups of patients with low and normal pre-graft cardiac index. Methods: Eighty-two patients were divided into two groups based on their pre-graft cardiac index. Each group was randomly subdivided into two groups to receive either milrinone or normal saline. After the internal mammary artery was harvested, the infusion of milrinone, or normal saline was started and maintained until the end of the anastomosis. The haemodynamic variables were measured: just before the start of milrinone or normal saline after pericardiotomy (baseline value); 10min after the tissue stabilizer had been applied for the anastomosis of left anterior descending artery, left circumflex artery and right coronary artery; and after the sternal closure. Results: Milrinone reduced the extent of the decrease in cardiac index and stroke volume as well as the extent of the increase in systemic and pulmonary vascular resistance. The extent of the decrease in cardiac index and mixed venous oxygen saturation were greater in normal pre-graft cardiac index group than in low pre-graft cardiac index group regardless of milrinone infusion during anastomoses. The effect of milrinone on haemodynamics showed no significant difference between low and normal pre-graft cardiac index groups. Conclusions: Pre-emptive milrinone infusion without bolus effectively improved cardiac performance during OPCAB and was especially useful for patients with low pre-graft cardiac index to prevent the decrease in cardiac index and stroke volume index below the critical level.
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1. Introduction
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Recently, a rapid expansion of off-pump coronary artery bypass surgery (OPCAB) has occurred in the field of cardiac surgery [1–3]. However, the haemodynamic instability associated with positioning and stabilizing the heart as well as the interruption of the coronary artery flow is an important factor limiting the performance of OPCAB. Numerous studies regarding the changes in haemodynamics and its management have been performed [4–6].
Milrinone, a phosphodiesterase III inhibitor, is a non-catecholamine, non-glycoside drug that is not associated with ß-adrenergic receptors or plasma catecholamine concentrations [7]. Milrinone improves cardiac function and facilitates weaning from cardiopulmonary bypass (CPB) in cardiac surgical patients [8,9]. There is no significant increase in myocardial oxygen consumption [10] and its myocardial oxygen consumption is lower compared to that of dobutamine [11]. Milrinone has a direct vasodilating effect on arterial grafts [12] and also increases the blood flow in grafted internal mammary artery after cardiopulmonary bypass [13]. It's positive effect on myocardial contractility and coronary blood flow with minimal increase in heart rate and myocardial oxygen consumption make milrinone an inotropic agent of choice for patients undergoing OPCAB.
In previous study, we observed that pre-emptive milrinone without loading dose decreased the extent of the decrease in cardiac index (CI) and mixed venous oxygen saturation (SvO2) during coronary artery anastomosis with no severe complications [14]. Feneck et al. [15] reported that the response to intravenous milrinone was partially determined by the haemodynamics before the treatment in cardiac surgical patients. In the present study, we evaluated the effect of milrinone on haemodynamics during OPCAB in two groups of patients with low and normal pre-graft CI.
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2. Methods
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With institutional review board approval, 33 patients undergoing OPCAB surgery were studied after having obtained written informed consent. The data used in this study included the data from previous study [14] conducted with 49 patients with triple vessel disease or left main coronary artery disease. The patients were informed about the repeated use of their data in this study and for those 49 patients, written consents were obtained retrospectively. The study protocol had no difference between previous and this study.
Haemodynamic data of 25 patients with normal pre-graft-CI and 24 patients with low pre-graft CI from the previous study were used in this study. Seventeen patients with normal pre-graft-CI and 16 patients with low pre-graft CI were added. Each group was randomly subdivided into two groups to receive either milrinone or normal saline: patients with low pre-graft CI (<2.5l/min/m2) receiving milrinone (LCI-M); patients with low pre-graft CI receiving normal saline (LCI-S); patients with normal pre-graft CI (
2.5l/min/m2) receiving milrinone (NCI-M); and patients with normal pre-graft CI receiving normal saline (NCI-S). All patients had triple vessel disease or left main coronary artery disease that needed more than 3 grafts. Patients known to have clinically significant pre-operative renal or hepatic dysfunction, thrombocytopenia, or coagulopathy were excluded from the study. Patients with supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, clinically significant ventricular ectopic activity, those receiving inotropic agents, or having a single coronary artery disease were also excluded from the study.
2.1. Anaesthetic management
All recent cardiac medications except digoxin and diuretics were given until the morning of the surgery. As pre-medication, morphine 0.05mg/kg IM was injected an hour before the surgery. On arrival in the operating room, ECG leads II and V5 were monitored and the radial artery was cannulated for continuous monitoring of systemic arterial pressure (SAP) and blood gas analysis. For continuous cardiac output and SvO2 monitoring, pulmonary artery catheter (Swan-Ganz CCOmbo/SvO2 Model 744HF75®, Baxterhealthcare Corp., CA, USA) was inserted through the right internal jugular vein before the anaesthesia. Anaesthetic technique was standardized for all patients. Anaesthesia was induced with 2.0–3.0mg of midazolam, 1.5–3.0µg/kg of sufentanil, and 50mg of rocuronium and maintained with 0.2–0.5vol% of isoflurane and continuous intravenous infusion of 0.3–0.5µg/kg/h of sufentanil. Ventilation was controlled with oxygen–air mixture (FIO2 0.6) to maintain end-tidal CO2 in 4.0–4.7kPa. Isosorbide dinitrate 0.5µg/kg/min was started after the induction of the anaesthesia. Transoesophageal echocardiography (TOE) was monitored at short-axis midpapillary muscle view. To avoid hypothermia, the temperature of the operating room was kept above 21°C and the fluid was warmed. Warm humidifier was connected to the breathing circuit. Patients were also warmed with warm mattress and lower limbs were wrapped with aseptic forced air blanket after the vein harvest.
2.2. Surgical and monitoring techniques
After median sternotomy, fluid was given to maintain the pre-load during the dissection of the graft vessels. In case of hypotension, norepinephrine was given to maintain mean SAP above 60mmHg. After the dissection of the internal mammary artery (IMA), 1mg/kg of intravenous heparin was injected and activated clotting time was maintained over 250s during the anastomoses. After pericardial suture was placed between the left and right pulmonary veins in the posterior aspect of the pericardial reflection, a 2cm width tape was connected for the effective lifting of the cardiac apex to expose the lateral wall. To expose the coronary artery, the heart was displaced in various directions and angles along the vessel to be anastomosed and tissue stabilizer (Octopus Tissue Stabilization System®, Medtronic, USA) was attached. Same surgeon, using the same technique, performed all cases and Y-graft between the IMA and the radial arterial graft was created in all patients, except two patients in whom harvested vein was used to create Y-graft.
2.3. Measurement and data collection
After IMA harvesting, milrinone or normal saline was infused in 0.5µg/kg/min until the end of the anastomosis. The haemodynamic variables were measured: just before the start of milrinone or normal saline after pericardiotomy (baseline value, T1); 10min after the tissue stabilizer had been applied for the anastomosis of left anterior descending artery (LAD, T2), left circumflex artery (LCX, T3) and right coronary artery (RCA, T4); and after the sternal closure (T5). There is 3–6min of time delay in the measurement of cardiac output (CO) using the Vigilance monitor®. Therefore it does not provide the real-time information regarding the changes in CO. The coronary anastomosis time varied between 10–15min. After application of the tissue stabilizer, it took several minutes to prepare the vessel and to insert a shunt or to apply an occlusive tape. Considering this time interval, it is pertinent to record hemodynamics at 10min with the Vigilance monitor®. The following variables were measured; CO, heart rates (HR), SAP, pulmonary artery pressure (PAP), central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), and SvO2. Using these variables, CI, systemic and pulmonary vascular resistance indices (SVRI and PVRI, respectively) and stroke volume index (SVI) were calculated according to standard formulae. The percent changes of haemodynamic variables at each time point for the values at baseline (%variable) were also calculated. The ST segment change and the amount of norepinephrine infused during the anastomosis of each coronary artery were recorded.
During displacement of the heart, the operating table was tilted to head-down position, and 0.03–0.05µg/kg/min norepinephrine was intermittently infused if the mean SAP decreased below 60–65mmHg. A shunt Florester® (Bio-Vascular, USA) was inserted during LAD and proximal portion of RCA anastomosis. Emergency CPB was performed when mean SAP fell below 50mmHg despite volume loading and drug treatment, change in the ST segment was more than 4mm during the coronary artery anastomosis, or when ventricular fibrillation did not respond to cardioversion.
2.4. Statistical analysis
All measurements were expressed as the mean (SD) or number (proportion) of patients. The number of patients with pre-operative medical history and cardiovascular medication were analyzed by the 
2-test, supplemented by Fisher's exact test for pair-wise comparisons. Comparisons of demographic data, haemodynamic variables, and percent change of haemodynamic variables for baseline values between the groups were performed with one-way analysis of variance followed by the Tukey's multiple comparison test. Mixed model analysis was used for the analysis of interactive effect between CI and milrinone on haemodynamic variables and baseline measurements were used as a covariate at that time. A P-value less than 0.05 was considered statistically significant. Statistical analyses were performed with statistical software (SAS 8.01; SAS Institute, Cary, NC) for windows on a personal computer.
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3. Results
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The data from 82 patients are included in statistical analysis. Among them, data from 49 patients (12 patients in LCI-M group, 12 patients in LCI-S group, 13 patients in NCI-M group, 12 patients in NCI-S group) are from the previous study [14]. The numbers of patients are 20, 20, 21, and 21 in LCI-M, LCI-S, NCI-M, and NCI-S group, respectively.
All patients had successful operation without converting to emergency CPB. There was no significant difference in age, sex, and body surface area among four groups. The incidence of the history of hypertension, diabetes mellitus, previous myocardial infarction or cerebrovascular disease, and the pre-operative use of calcium channel blocker or beta-receptor blockers were not different among four groups. There was also no difference in number of grafts among four groups (Table 1).
After pericardiotomy, there was significant difference in CI (P<0.001), SVI (P<0.001), SVRI (P<0.001) and PVRI (P=0.005) between the groups. CI, and SVI at T1 were greater in normal pre-graft CI groups than in low pre-graft CI groups. SVRI at T1 were lower in normal pre-graft CI groups than in low pre-graft CI groups and PVRI at T1 was lower in NCI-S group than in LCI-M group. During LAD anastomosis, CI (P=0.035), SVI (P=0.015) and SVRI (P=0.012) were significantly different between groups. CI at T2 was greater in NCI-M group than in LCI-S group and SVI at T2 was greater in NCI-S group than in LCI-S group. SVRI at T2 was greater in LCI-S group than in NCI-M group. During LCX anastomosis, CI (P=0.001), SVI (P=0.018), and SVRI (P=0.003) were significantly different between groups. CI and SVI at T3 were less in LCI-S group than in NCI-S group and SVRI at T3 was greater in LCI-S group than in NCI-M and NCI-S groups. During RCA anastomosis and after sternal closure, there was no significant difference in haemodynamic variables between groups (Table 2).
There was no difference in HR, mean SAP, mean PAP, PCWP and CVP at T1–T5 between groups (Table 3). Percent CI, %SVI, and %SVRI were significantly different between groups at T2–T5. Percent CI and %SVI at T2–T5 was greater in LCI-M group than in NCI-M and NCI-S groups. Percent CI was greater in LCI-S group than in NCI-M group at T4 and T5 and than in NCI-S group at T2, T4, and T5. Percent SVI was greater in LCI-S group than in NCI-M at T5 and than in NCI-S group at T2, T4, and T5. Percent SvO2 at T5 was greater in LCI-M group than in NCI-S group. Percent SVRI in NCI-S group was greater than that in LCI-M, LCI-S and NCI-M group at T2–T5, T2 and T4, and at T4, respectively. Percent SVRI was also greater in NCI-M than in LCI-M and LCI-S group at T5. (Table 4).
In the mixed model analysis, there were significant differences in change in the CI (P=0.0038), SvO2 (P=0.0003), HR (P=0.0154) and SVRI (P=0.0084) according to pre-graft CI and treatment with milrinone made differences in change in the CI (P=0.0008), SVI (P=0.0347), and HR (P=0.0072). There was no significant difference in effect of milrinone on haemodynamics between low and normal pre-graft CI groups (Table 5).
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4. Discussion
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The haemodynamic derangement during coronary anastomosis is an important issue in managing patients undergoing OPCAB [16] and this is the first study to report that the pre-graft CI is associated with the extent of haemodynamic change during OPCAB. Pre-emptive milrinone increased the CI and SVI, but the effect of milrinone on the extent of change in CI and SVI seemed to be less than the effect of pre-graft CI. Pre-graft CI affected significantly on the changes in CI, SvO2, HR and SVRI in mixed model analysis.
Although there was no difference in effect of milrinone between low and normal pre-graft CI in mixed model analysis, milrinone effectively maintained or increased CI and SVI above critical level in patients with low pre-graft CI, especially during distal anastomosis for LCX, which is known as the most troublesome period during OPCAB [3,5,6]. As a result, the difference in CI and SVI existed before the anastomoses between LCI-M group and normal pre-graft CI groups disappeared during distal anastomoses. It has been reported that multi-vessel OPCAB can be performed safely in patients with severe LV dysfunction [17]. Less haemodynamic change during anastomosis in patients with low pre-graft CI in this study accentuates the safety of OPCAB in theses patients. However, significant decrease in CO may occur despite relatively well-preserved mean SAP and it is conceivable that the cumulative effect of these transient episodes of reduced CO and reduced perfusion pressure due to elevated RAP in the course of distal anastomoses during OPCAB resulted in a degree of ischemic organ injury at least comparable to CPB [18]. Since milrinone has been reported to have little effect on myocardial oxygen consumption [10] unlike other inotropic agents [11] and to dilate arterial bypass graft [12,13], maintaining or increasing CI and SVI within acceptable range with milrinone in patients with low pre-graft CI was considered to be useful. However, the effect of milrinone on post-operative course seemed to be subclinical. Although milrinone effectively improved CI and SVI in patients with low pre-graft CI, there was no remarkable difference in clinical outcome evaluated by routine clinical examination between groups in this study. There was no significant difference in hemodynamics, major post-operative complications, inotropic use at ICU and the duration of intensive care unit (ICU) and hospital stay between groups. CK-MB increased in 5 patients in NCI-S group and 1 patient in LCI-M group without definite Q wave on ECG at 24h after arrival in the ICU and the difference in the incidence between groups was not statistically significantly. Further detailed examination is needed to clarify the effect of hemodynamic change during distal anastomosis on clinical outcome.
Feneck et al. reported that therapeutic response to intravenous milrinone following cardiac surgery is partially determined by pre-treatment haemodynamic [15]. They just compared percent change in CI induced by milrinone between patients with normal and low pre-treatment CI and observed greater increase in CI in low pre-treatment CI group compared to that in normal pre-treatment CI group. On the other hand, Yamada et al reported no interaction between pre-treatment CI and milrinone on CI [19]. In this study, there was no significant difference in the effect of milrinone on the CI, SVI and SvO2 between normal and low pre-graft CI groups in mixed model analysis. Although differences in statistical analysis and type of operation were likely to affect the result, reason for this discrepancy is not clear.
The major problem associated with the use of milrinone is that an initial bolus is required for an effective plasma concentration to be reached, and this initial bolus frequently causes significant hypotension [20,21]. Baruch et al. [22] reported that significant haemodynamic effect appeared 30min after the start of milrinone infusion without bolus, and Shibata et al. [23] reported that a continuous infusion without an initial loading dose significantly increased the CI without significant hypotension and arrhythmia, in patients undergoing coronary artery bypass graft surgery. No patient needed norepinephrine before the anastomosis in both LCI-M and NCI-M groups in this study and there was no significant difference in the amount of norepinephrine infused to maintain mean SAP during anastomoses between the groups. Feneck et al. [15] reported that the hypotensive effect of milrinone was increasingly obtunded in patients with lower pre-treatment mean SAP. Relatively preserved CI and SVI in milrinone group during anastomoses might have contributed the result. In low pre-graft CI groups at pericardiostomy, the infusion of milrinone reduced SVRI around the normal value.
The limitations of this study are: first, it was not a blinded study. At first, it was designed as a blinded study but the CI increased in LCI-M and NCI-M groups during pre-emptive infusion of milrinone and patient's group was known. Second, Plasma concentrations of milrinone were not measured in the study. It is possible that plasma concentration of milrinone was not enough to exert maximal effect on CI in the study. Baruch et al. [22] reported that significant haemodynamic effects appeared 30min after the start of infusion of milrinone without bolus and the plasma concentration reached the same level as when the continuous infusion was initiated with a bolus in patients undergoing cardiac catheterization after 1h. An average of 35–40min were required to create the Y-graft between the harvested IMA and the radial artery in this study. Because duration for harvesting IMA was variable, we started milrinone after harvesting of IMA to reduce the difference in duration of pre-emptive infusion of milrinone and the risk of hypotension which occurred gradually during milrinone infusion [22]. However, earlier infusion can raise the plasma concentration of milrinone more definitely. Third, the reason for less extent of decrease in the CI and SVI in low pre-graft CI groups than that in normal pre-graft CI groups is not clear. There was no difference in the amount of fluid loaded before and during the anastomosis and the number of grafts. It is not likely that there was a difference in the degree of rotation and mechanical compression of the heart between groups because the same surgeon performed all operations using the same surgical technique. Possible mechanism such as, activation of cardiovascular reflex mechanism to maintain blood flow, should be further evaluated. Forth, although patients were randomly divided into milrinone and normal saline group, this study is not a prospective and randomized study since part of the data used in this study was derived from the previous study.
In conclusion, pre-emptive infusion of milrinone increased the CI and SVI in both low and normal pre-graft CI groups without significant systemic hypotension. There was no difference in the effect of milrinone on hemodynamics between low and normal pre-graft CI groups. Although haemodynamic derangement during distal anastomoses was less significant in low pre-graft CI groups than in normal pre-graft CI groups, pre-emptive infusion of milrinone without an initial bolus can safely be used in patients with low pre-graft CI to prevent decrease in the CI and SvO2 below critical level during distal anastomoses in OPCAB.
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Abstract
1. Introduction
