Ischemic heart disease often leads to mitral insufficiency because of dilation of the left ventricle and mitral annulus in association with myocardial infarction and chronic myocardial ischemia. More severe coronary disease can lead to papillary muscle ischemia and dysfunction and, in many cases, papillary muscle rupture after myocardial infarction can cause severe acute mitral insufficiency and left ventricular failure. In these patients, mitral valvuloplasty or mitral valve replacement can be performed at the same time as coronary artery bypass graft (CABG) surgery (1–3). However, in patients with only mild mitral regurgitation (MR) and no clinical symptoms, coronary revascularization alone is often performed. Many patients who do not need mitral valve surgery currently undergo off-pump CAB (OPCAB). This procedure avoids the need for cardiopulmonary bypass and aortic clamping, but ischemia associated with blockage of coronary vessels or manipulation and compression of the still-beating heart can result in decreased cardiac index (CI) and increased mean pulmonary artery pressure (MPAP), complicating circulatory management. Couture et al. (4) and Al-Ruzzeh et al. (5) reported hemodynamic instability and exacerbated MR during OPCAB anastomosis in patients with coexisting mild MR. Increases to 3+ or 4+ MR during anastomosis could lead to increased MPAP and decreased CI, requiring conversion from OPCAB to on-pump CABG. However, no prospective, double-blind studies have investigated treatments to increase MPAP and decrease CI during OPCAB.
We hypothesized that during OPCAB anastomosis, MR would be exacerbated, CI would decrease, and MPAP would increase in patients with preexisting MR. Milrinone exerts positive inotropic and vasodilatory effects (6) and is effective in treating severe MR (7). We therefore also hypothesized that milrinone could improve hemodynamic function and MR. The present study evaluated hemodynamic function during OPCAB in patients with 1+ or 2+ MR. Patients with 1+ or 2+ MR were randomly assigned in a double-blind manner to receive milrinone and undergo evaluation of effects on hemodynamic variables.
Subjects comprised 140 elective-surgery patients undergoing OPCAB at Kagoshima University Hospital between August 2002 and March 2004. Milrinone is excreted through the kidneys, so patients with decreased renal function (preoperative creatinine level ≥2 mg/dL) were excluded from the present study. Patients with acute myocardial infarction, who were pregnant or who may have been pregnant at the time of the study, with preoperative uncontrolled cardiac failure, with diabetic ketoacidosis, or with active infection were likewise excluded from the present study. Patients were evaluated before anesthesia in the Department of Cardiovascular Medicine for presence of MR using transthoracic echocardiography. Severity of MR was determined by the ratio of color Doppler jet area to left atrial area in midsystole. MR was graded in semiquantitative fashion (0+ = none; 1+ = trace; 2+ = mild; 3+ = moderate; and 4+ = severe) on the basis of ratios of >0%–10%, >10%–20%, >20%–40%, and >40%, respectively (8,9). Subjects were divided into three groups: those without MR (MR(-) group; n = 57), those with 1+ or 2+ MR (MR(+) group; n = 41), and those with 1+ or 2+ MR who also received milrinone (M+MR(+) group; n = 42). Patients with grade 3+ or 4+ MR underwent valve repair/replacement using on-pump CABG and were thus excluded from the present study. Of the 140 patients, 1 patient in the MR(+) group developed ventricular fibrillation and was converted from OPCAB to on-pump CABG. This patient was excluded from analysis. Study protocols were approved by the Ethics Committee at Kagoshima University, Japan, and written informed consent was obtained from all patients.
Hemodynamic variables were compared between MR(-) and MR(+) groups and between MR(+) and M+MR(+) groups. Comparisons between MR(+) and M+MR(+) groups were conducted in a prospective, randomized, double-blind, placebo-controlled manner. Patients with MR were randomly allocated to the MR(+) or M+MR(+) groups using a sealed envelope technique to receive either milrinone or saline. Syringes containing milrinone or saline were prepared, in double-blind fashion, by a collaborator not involved in data recording. Study medication was randomized and prepared in the intensive care unit. The surgeon, anesthesiologist, and echocardiographer were all blinded to the treatment group assignment of patients.
In the MR(+) group, physiological saline was administered from immediately after the induction of anesthesia until completion of surgery. Surgical compression (e.g., constriction of the right ventricular outflow tract) was confirmed by transesophageal echocardiography (TEE), and anastomosis was initiated after stabilizing the other areas. After eliminating decreases in CI and increases in PAP caused by surgical factors, catecholamine administration was initiated if hemodynamics did not improve. If hemodynamic instability (mean arterial blood pressure [MAP] <60 mm Hg and CI <2.0 L · min−1 · m2) developed during anastomosis, pacing was used first (heart rate [HR] = 70 bpm). Dopamine was then infused at a rate of 3–10 μg · kg−1 · min−1 and norepinephrine (0.03–0.2 μg · kg−1 · min−1) was infused. If MAP decreased to less than 60 mm Hg, with CI >2.0 L · min−1 · m2, norepinephrine was infused. If CI decreased to less than 2.0 L · min−1 · m2 with MAP >60 mm Hg, pacing was used first (HR = 70 bpm). Dopamine was then infused at a rate of 3–10 μg · kg−1 · min−1. Dopamine was titrated for increasing CI >2 L · min−1 · m2, and norepinephrine was titrated for increasing MAP >60 mm Hg. In the M+MR(+) group, milrinone was administered after the induction of anesthesia at an infusion rate of 0.5 μg · kg−1 · min−1 without use of an initial loading dose. Pacing and catecholamine administration were then performed according to the protocol.
Severity of MR was determined by the ratio of color Doppler jet area to left atrial area in midsystole. MR was graded in semiquantitative fashion according to the protocol. MR was graded after the induction of anesthesia and 3 min after the start of each grafting procedure. Echocardiography and measurement of hemodynamic variables were performed at the same time. Continuous intraoperative TEE was performed using a multiplane transducer and ProSound SSD-5500SV (Aloka CO, Mitaka, Tokyo). MR was monitored during grafting in multiple midesophageal views. Videotape of TEE was later reviewed by an echocardiographer.
Hemodynamic variables, including MAP, MPAP, CI, pulmonary capillary wedge pressure, and mixed venous O2 saturation (Svo2) were measured. MAP was measured after inserting a catheter into the radial artery. An Opti Q Svo2/CCO catheter (Abbott Laboratories, North Chicago, IL) was inserted in all patients to measure PAP, pulmonary capillary wedge pressure, central venous pressure, Svo2, and CI. A Q2 Continuous Cardiac Output/So2 computer (Abbott Laboratories) was used to measure Svo2.
Baseline hemodynamic data were obtained after the induction of anesthesia and before sternotomy. The target area was fixed using a stabilizer before anastomosis, and hemodynamic variables were measured at this time. Pacing and catecholamine administration were then performed according to the protocol. Anastomosis was initiated after hemodynamics were stabilized using catecholamines. Hemodynamic variables were again assessed 3 min after the start of anastomosis. Values at each time point were averaged after 3 measurements.
Anesthesia was managed according to the study protocol. As preanesthetic medication, morphine hydrochloride 0.2 mg/kg was administered IM 30 min before the induction of anesthesia. Anesthesia was induced by the administration of midazolam 0.08 mg/kg and fentanyl 5 μg/kg and maintained with 40% O2 and propofol 5 mg · kg−1 · h−1; the total intraoperative dose of fentanyl was 20 μg/kg. In all patients, a vasodilator (nicorandil 1.5 μg · kg−1 · min−1) was administered by IV infusion after the induction of anesthesia. IV crystalloid 1000–1500 mL was provided to maintain preload during sternotomy and harvesting of graft vessels. Total volume of fluid infusion was 2500–3500 mL.
Heparin 2.0 mg/kg was administered after dissection of the internal mammary artery, and activated clotting time was maintained at >250 s during anastomosis. Protamine sulfate 1 mg/kg was used to reverse the heparin effect at the completion of surgical procedures.
The same surgeon performed all operations. Surgery was performed in all patients using a midline sternal incision. An Octopus 3 suction stabilizer (Medtronic Inc, Minneapolis, MN) was used to immobilize the heart.
A traction suture was placed in the oblique pericardial sinus to better visualize sites of left circumflex artery (LCX) and right coronary artery (RCA) anastomosis before the procedure. During anastomosis in LCX and RCA regions, patients were placed in the Trendelenburg position, and the bed was rotated 20 degrees to the right. The heart was displaced using the Spooner tape method (10). For anastomosis of the left anterior descending artery (LAD) and diagonal artery (Dx), the patient was placed in the Trendelenburg position if required. Anastomosis was started in the LAD and Dx, followed by the LCX and RCA. These manipulations were performed similarly in all groups before treatment and measurements.
To calculate sample size, the trial was designed to have 80% statistical power in detecting a 50% reduction in frequency of MR exacerbation (grade 3+ or 4+) in the M+MR(+) group, assuming that MR exacerbation occurred in 70% of patients without milrinone during anastomosis, with a two-sided significance level of 0.05. Hemodynamic data were analyzed to compare intergroup differences. Repeated-measures analysis of variance was performed for intra- and intergroup comparisons. Mean values are presented with sd and were compared using two-sample t-tests. Non-normally distributed continuous variables are presented as medians and were compared using the Mann-Whitney test. Dichotomous data were compared using Fisher’s exact test.
No significant differences in patient clinical characteristics were observed among groups (Table 1). In addition, no significant differences in operation time or number of anastomoses were identified (Table 2).
Table 3 shows rates of catecholamine and pacemaker use. Comparison among groups showed no significant difference in use of norepinephrine or pacemakers. However, the percentage of patients requiring dopamine during LAD, Dx, and LCX anastomosis was significantly larger in the MR(+) group than in the MR(-) group. Furthermore, the percentage of patients requiring dopamine was significantly larger in the MR(+) group than in the M+MR(+) group during anastomosis at all sites.
No significant differences in baseline values were seen among groups. Table 4 shows hemodynamic variables in the MR(-) and MR(+) groups. Comparison between MR(-) and MR(+) groups showed no significant differences in MAP during anastomosis at any site. CI was significantly lower in the MR(+) group than in the MR(-) group during LAD, Dx, and LCX anastomosis. In addition, MPAP was significantly higher in the MR(+) group than in the MR(-) group during LAD, Dx, and LCX anastomosis. HR in the MR(+) group was significantly higher during LCX anastomosis. Frequency of grade 3+ or 4+ MR in the MR(+) group was significantly increased during LAD, Dx, and LCX anastomoses compared with the MR(-) group. Grade 3+ or 4+ MR occurred in 28% of MR(+) patients during LAD anastomoses and 39% of MR(+) patients during Dx anastomoses. Grade 3+ or 4+ MR occurred in 78% of MR(+) patients during LCX anastomoses (Fig. 1).
Table 5 shows hemodynamic variables in MR(+) and M+MR(+) groups. Comparison between MR(+) and M+MR(+) groups showed no significant differences in MAP during anastomosis at any site. CI was significantly higher in the M+MR(+) group than in the MR(+) group during LAD, Dx, and LCX anastomosis. In the M+MR(+) group, MPAP was significantly lower during LAD, Dx, and LCX anastomosis than in the MR(+) group. HR was significantly more rapid in the MR(+) group than in the M+MR(+) group during LCX anastomosis. Frequency of grade 3+ or 4+ MR was reduced from 28% to 7% during LAD anastomosis and from 39% to 4% during Dx anastomosis in the M+MR(+) group, whereas the frequency of grade 3+ or 4+ MR was reduced from 78% to 20% during LCX anastomosis (Fig. 1).
The main findings of the present study are that 3+ and 4+ MR could lead to decreased CI and increased MPAP during anastomosis of the left coronary arteries in patients with 1+ or 2+ MR, and milrinone improves hemodynamic function and 1+ and 2+ MR during OPCAB.
OPCAB is now widely used as a less invasive approach to cardiac surgery. The development of devices such as suction stabilizers has enabled the use of OPCAB for complete revascularization (11). In our institution, the mean number of vessels grafted was more than 4. However, patients with angina pectoris often display coexisting ischemic MR. This may have little effect on hemodynamic function before surgery, but MR can worsen during OPCAB surgery and thus complicate circulatory management (4,5). However, no prospective, double-blind studies have investigated the treatment of hemodynamic change during OPCAB. We evaluated the impact of preoperative 1+ or 2+ MR on hemodynamic function during OPCAB anastomosis.
George et al. (12) used intraoperative three-dimensional echocardiography in patients with OPCAB. They reported distortion of the mitral annulus caused by vertical heart displacement during LCX and RCA anastomosis, which could result in either functional mitral stenosis or increased MR. In the present study, however, presence or absence of preoperative MR exerted no significant influence on MR or hemodynamic variables. This was confirmed by the fact that regardless of the presence or absence of MR, anastomosis of the RCA was not associated with any significant differences in hemodynamic variables or frequency of grade 3+ or 4+ MR during anastomosis. Direct compression of the left ventricle and displacement of the heart by the Octopus device during anastomosis of the LAD, Dx, and LCX might thus cause distortion of both the left ventricle and mitral annulus, increasing 3+ and 4+ MR.
In patients with MR during LAD, Dx, and LCX anastomosis, MPAP also differed significantly. In particular, MPAP was markedly higher during LCX anastomosis. In addition, increasing 3+ and 4+ MR led to further increases in MPAP and decreases in CI.
CI is typically maintained at ≥2.0 L · min−1 · m2 during OPCAB (13,14). O2 delivery at <7.3 mL · kg−1 · min−1 has been reported with a shift from aerobic to anaerobic metabolism (15). Based on these data, and given a mean minimum hemoglobin level of 10 g/dL, a CI of ≥2.0 L · min−1 · m2 is required. In patients with MR during LCX anastomosis, even with the administration of catecholamines, CI is 1.8 ± 0.3 L · min−1 · m2. To increase CI, afterload must be decreased and forward cardiac output increased. Drugs that reduce afterload include prostaglandin E1, nitroglycerin, β-adrenergic drugs (e.g., dobutamine), and phosphodiesterase (PDE) inhibitors. Vasodilators such as prostaglandin and nitroglycerin reduce afterload but lack cardiotonic effects, so β-adrenergic drugs are also required to maintain arterial blood pressure. However, β-adrenergic drugs can increase HR. In OPCAB during coronary artery anastomosis, blood flow at the site of anastomosis is diminished. Although strict control of HR is no longer required with the advent of suction stabilizers (16,17), tachycardia in coronary artery disease does increase myocardial O2 demand and the risk of myocardial ischemia. Increases in HR and myocardial oxygen consumption must therefore be minimized. In our study, a significantly higher percentage of patients with MR during LCX anastomosis required dopamine and experienced increased HR compared with patients without MR. In contrast, milrinone does not increase HR or myocardial oxygen consumption (18–21). In our study, comparison of patients with and without milrinone indicated that pharmacotherapy increased cardiac output without any increase in HR.
Milrinone competitively inhibits PDEIII and exerts positive inotropic and vasodilatory effects (6). PDEIII inhibitors are used for circulatory management in OPCAB and can improve hemodynamic function (22). However, a CI of ≥2.0 L · min−1 · m2 can often be maintained using catecholamines alone, and milrinone is not required in all cases. In addition, catecholamines alone helped to maintain CI ≥2.0 L · min−1 · m2 in patients without MR in our study. However, in patients with MR undergoing OPCAB, we recommend treatment to prevent increases in regurgitation and deterioration of hemodynamic function. Milrinone is also reportedly effective in severe MR (7). We therefore evaluated whether milrinone would be effective in increasing CI and decreasing MPAP during anastomosis in patients with MR undergoing OPCAB. In treated patients, milrinone also prevented decreases in CI and increases in MPAP compared with untreated patients. In addition to decreasing frequency of 3+ and 4+ MR, milrinone prevents an increase in MPAP by virtue of its pulmonary vasodilatory effects (6).
Milrinone is generally administered as a bolus dose followed by IV infusion, but a recent study (23) has suggested that similar hemodynamic effects can be achieved within 30 min after starting IV infusion alone. To harvest grafts, 155 ± 42 min are required from anesthesia induction to vessel anastomosis. This allows sufficient time to achieve the desired hemodynamic effects of milrinone infusion alone. After the induction of anesthesia, milrinone infusion at a rate of 0.5 μg · kg−1 · min−1 was started without use of an initial loading dose.
In conclusion, we evaluated the influence of MR on hemodynamic function during OPCAB. Even in patients with only 1+ or 2+ MR before surgery, CI was decreased and MPAP was increased during left coronary anastomosis in OPCAB, presumably because of increased regurgitation. In patients with 1+ or 2+ MR undergoing OPCAB, treatment with milrinone helps to prevent decreases in CI and increases in MPAP during anastomosis.
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