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Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, Hamamatsu, Japan
Address correspondence and reprint requests to Mutsuhito Kikura, MD, Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu 431-3192, Japan. Address e-mail to mkikura{at}hotmail.com
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Abstract |
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IMPLICATIONS: Preemptive milrinone or amrinone administration before separation from cardiopulmonary bypass in cardiac surgical patients not only ameliorates postoperative deterioration in cardiac function and oxygen transport, but also reduces dopamine requirement and increases serum lactate, glucose, and cellular enzyme levels, although milrinone may increase heart rate.
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Introduction |
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Phosphodiesterase III inhibitors provide an alternative means of inotropic support via non-ß1-adrenergic pathways and induce vasodilation (10,11). Several studies have shown that milrinone and amrinone improve ventricular function and hemodynamic status after CPB in patients already being treated with catecholamines and nitroglycerin (12–15). Early pharmacological intervention with amrinone or milrinone may not only prevent postoperative ventricular dysfunction and deterioration of oxygen transport, but also may reduce catecholamine or vasodilator requirements and increases in lactate and cellular enzymes through subsequent reduction of tissue hypoxia. Reduction of catecholamine dose might attenuate postoperative hyperglycemic responses related to stimulation of glycogenolysis and gluconeogenesis. However, no study has explored this hypothesis or clarified the different characteristics of preemptive use of milrinone and amrinone. We examined inpatients undergoing coronary artery bypass grafting (CABG) and whether milrinone or amrinone reduces deterioration in ventricular function and oxygen transport and reduces dopamine and nitroglycerine requirements, as well as increases lactate, glucose, and cellular enzymes.
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Methods |
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All patients were maintained under standardized large-dose fentanyl anesthesia (total dose, 36–110 µg/kg) supplemented with propofol by infusion (total dose, 30–35 mg/kg) and vecuronium bromide and were ventilated with inspired 100% oxygen and sevoflurane (0.5%–1.5%). All patients were monitored via radial and pulmonary arterial catheters and were monitored continuously with electrocardiograph leads II and V5 and with a 5-MHz multiplane transesophageal ultrasonic transducer (Sonos 1500; Hewlett-Packard, Andover, MA).
CPB was conducted with a membrane oxygenator (CobeTM CML; COBE Cardiovascular, Inc., Arvada, CO) and a nonpulsatile flow of 2.2–2.5 L · min-1 · m-2. The circuit was primed with 1500 mL of balanced salt solution, 150 mL of 15% mannitol, and 500 mL of hetastarch. Mean arterial pressure was maintained between 50 and 70 mm Hg. In all patients, moderate hypothermia (rectal temperature, 30°C–32°C) and aortic cross-clamping with cold hyperkalemic antegrade cardioplegia and additional doses of cardioplegia were used at approximately 20-min intervals. For pH management, 
-stat methodology was used, and celite-based activated clotting times (HemochronTM; International Technidyne Corp., Edison, NJ) were maintained at >350 s. After the primary surgery, patients were warmed to a bladder temperature of 36.5°C–37°C. The heart was defibrillated after cardiac reperfusion if sinus rhythm did not resume spontaneously. Epicardial atrioventricular pacing at a rate of 80–90 bpm was used as needed for sinus bradycardia or atrioventricular conduction disturbance.
We randomly assigned 45 patients to an Amrinone, Milrinone, or Placebo group immediately before anesthetic induction. As the aortic cross-clamp was released, we randomly administered a bolus of milrinone 50 µg/kg plus 0.5 µg · kg-1 · min-1 (Milrinone group), a bolus of amrinone 1.5 mg/kg plus 10 µg · kg-1 · min-1 infusion (Amrinone group), or normal saline bolus and infusion (Placebo group). The initial loading dose was administered over 10–15 min, and infusion was continued for 10 h after CPB. The loading dose syringe was covered with aluminum foil to assure blinding because the study protocol required all clinicians to be blinded to drug identity. Patients were separated from CPB by using dopamine 5–10 µg · kg-1 · min-1 and nitroglycerine 0.5–1 µg · kg-1 · min-1 infusions started before weaning to maintain a cardiac index >2.0 L · min-1 · m-2, a systolic blood pressure between 90 and 130 mm Hg, a heart rate at <110 bpm, and a pulmonary-capillary wedge pressure <18 mm Hg. Inhaled anesthetic was not used in any patient after separation from CPB. No vasopressor other than dopamine was used. In the postoperative period, dopamine and nitroglycerine infusion rates and volume transfusion were adjusted to achieve a systolic blood pressure between 90 and 130 mm Hg, a cardiac index >2.0 L · min-1 · m-2, and a pulmonary-capillary wedge pressure <18 mm Hg. For each patient, the total individual doses of dopamine and nitroglycerin administered (in µg · kg-1 · min-1) were recorded, and the mean total dose was calculated for all patients. Patients were weaned from mechanical ventilation when they were hemodynamically stable and alert and were usually discharged from the ICU after extubation and discontinuation of all vasoactive drug infusions.
Hemodynamic measurements (heart rate, mean arterial blood pressure, mean pulmonary artery blood pressure, pulmonary-capillary wedge pressure, cardiac output, and mixed venous oxygen saturation) were obtained after anesthetic induction, before CPB, at 15 and 30 min after CPB, and every hour for the first 24 h after CPB. A venous blood sample was obtained via the pulmonary artery catheter to measure mixed venous oxygen saturation. Cardiac index was determined in duplicate by the thermodilution technique by using 10-mL boluses of ice cold saline injected through a fiberoptic pulmonary artery catheter (PaceportTM used with an OM-2TM optics module and SAT-2TM SAT-2-115; Baxter, Irvine, CA) during the expiratory pause phase of the ventilator cycle. Cardiac index was calculated automatically with each output measurement. In the ICU, cardiac output was measured by means of continuous thermodilution cardiac output measurements (16); the duplicate thermodilution technique described previously was also repeated every 6 h. Hemodynamic indices were calculated from pressure and cardiac output by use of standard formulas (17). An electrocardiographic ischemic episode was evaluated off-line retrospectively, and it was defined as reversible ST depression of 0.1 mV or more from baseline at J + 60 ms or as ST increase of >0.2 mV at the J point lasting for at least 1 min. Possible episodes of ischemia were reviewed and verified by two investigators who were blinded to treatment group assignment. Three or more consecutive ventricular premature beats were recorded as an episode of ventricular tachycardia. Component Central MonitorTM (HP M2360; Hewlett-Packard, Boeblingen, Germany) and Monitoring Full Disclosure Review SystemTM (HP M1251A; Hewlett-Packard) were used to record and review electrocardiograms.
Arterial oxygen and mixed venous oxygen contents, hemoglobin, and lactate levels were measured before and after anesthetic induction, before CPB, and at 30 min and 2, 3, 5, 10, 15, 20, and 24 h after CPB. Oxygen transport index, oxygen consumption index, and oxygen extraction ratio (100 x oxygen consumption index/oxygen transport index; %) were calculated from blood gas analysis and cardiac output results by using standard formulas (17).
Transesophageal echocardiograms were recorded after anesthetic induction, before CPB, at 15 and 30 min, and at 1 and 2 h after CPB. After completion of the study, images were reviewed by experienced intraoperative echocardiographers who were blinded to treatment group assignment. Images were divided into left ventricular anterior, lateral, posterior, septal, and right ventricular wall segments; each segment was divided into base, mid, and apical regions for examination of wall motion abnormalities. Wall motion in each segment was graded according to the following scores: normal or hyperkinesia, 1; mild hypokinesia, 2; severe hypokinesia or akinesia, 3; dyskinesia, 4; and aneurysm, 5. Wall motion index was calculated as (total wall motion scores)/(number of segments) (18). The left ventricular short-axis view was recorded simultaneously with the hemodynamic measurements, and these images were also analyzed postoperatively by trained examiners blinded to treatment assignment. We calculated left ventricular velocity of circumferential fiber shortening (circ/s) and end-systolic wall stress (g/cm2) as described in the previous studies (12,15,19).
Blood samples for laboratory examination were obtained in all patients preoperatively and on Postoperative Days 1, 2, and 3. Laboratory values included those for lactate, creatine kinase, lactate dehydrogenase, aspartate or alanine aminotransferase, creatinine, C-reactive protein, glucose, and platelet count. These laboratory examinations were conducted as routine tests for cardiac surgical patients in the clinical laboratory division of the university hospital and were used for the clinical diagnosis and treatment of general patients. Laboratory examination results have established reliability in the university hospital.
Comparisons of demographic data were made by one-way analysis of variance, followed by the Bonferroni multiple comparison test. Comparisons of hemodynamic and oxygen delivery variables and echocardiographic and laboratory values among the treatment groups were made by analysis of variance with repeated measures in which the within-subject variables were treatment groups and time. After tests on the main effects, multiple comparisons between treatment groups at a specific time were performed by using the Bonferroni procedure adjusted for repeated measures, maintaining an experiment-wise level of 0.01. The number of patients with a postoperative electrocardiographic ischemic episode or ventricular tachycardia and who received allogeneic blood transfusion were analyzed by the 
2 test, supplemented by Fisher’s exact test for pairwise comparisons. All statistical tests were two-sided. Statistical analysis was performed with statistical software (SAS; SAS Institute, Cary, NC). The calculated P values that indicated significance are given in the tables and in the figure legends. All data are expressed as mean ± SD.
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Results |
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The data for hemodynamic variables are shown in Figure 1. The effects of milrinone and amrinone on cardiac index (P = 0.009 and P = 0.005, respectively, for comparison with placebo) and stroke volume index (P = 0.01 and P = 0.0002, respectively) were significantly greater than those of placebo. The effect of milrinone on heart rate was significantly greater than that of placebo (P = 0.011) or amrinone (P = 0.011). Cardiac index at the postoperative nadir in the Milrinone and Amrinone groups was higher (2.5 ± 0.3 L · min-1 · m-2, P < 0.0001; and 2.5 ± 0.2 L · min-1 · m-2, P < 0.0001, respectively, versus 1.9 ± 0.5 L · min-1 · m-2 in the Placebo group), and stroke volume index at the nadir was higher (27.8 ± 4.0 mL · min-1 · m-2, P < 0.0001; and 26.1 ± 3.2 mL · min-1 · m-2, P < 0.0001, respectively, versus 20.4 ± 5.1 mL · min-1 · m-2 per beat in the Placebo group).
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Three patients in the Placebo group (916, 240, and 880 mL), one patient in the Amrinone group (160 mL), and two patients in the Milrinone group (720 and 1010 mL) received allogeneic blood transfusion during surgery, but no patient received blood transfusion postoperatively. There was no significant difference in the number of the patients who received allogeneic blood transfusion among all groups.
Figure 3 displays the data for oxygen transport variables. The effects of milrinone and amrinone on oxygen transport index (P = 0.0012 and P < 0.0001, respectively, for comparison with placebo), mixed venous oxygen saturation (P = 0.004 and P = 0.007, respectively), and oxygen extraction ratio (P = 0.004 and P = 0.009, respectively) were significantly greater than those of placebo. The oxygen transport index at the postoperative nadir in the Milrinone and Amrinone groups was higher than in the Placebo group (354.7 ± 57.8 mL · min-1 · m-2, P = 0.009; and 353.7 ± 91.2 mL · min-1 · m-2; P = 0.009, respectively, versus 283.0 ± 83.9 mL · min-1 · m-2 in the Placebo group).
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We observed larger increases in lactate, creatinine kinase, lactate dehydrogenase, aspartate or alanine aminotransferase, C-reactive protein, and glucose in the Placebo group than in the Milrinone and Amrinone groups (P < 0.01), as shown in Table 3. In the three postoperative days, insulin was administered IV in six patients (67.7 ± 33.6 U, P = 0.82) in the Amrinone group and six patients (62.7 ± 39.6 U, P = 0.44) in the Milrinone group, as compared with six patients (60.0 ± 37.4 U) in the Placebo group.
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Discussion |
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Previous studies have shown that postoperative ventricular dysfunction continues to be common in patients undergoing CPB surgery and that conventional inotropic drugs delay but do not prevent the occurrence of this problem (2–4). This deterioration, associated with postoperative low cardiac output syndrome (20), reduces oxygen transport and increases anaerobic metabolism, and this can lead to organ dysfunction and prolonged ICU stays (6). Patients with congestive heart failure have decreased catecholamine sensitivity and downregulated ß1-adrenergic receptors (7,8), and ß-adrenergic receptor stimulation is less effective in increasing myocardial contractility because of acute desensitization of ß-adrenergic receptors during CPB (9). Impairment of receptor sensitivity to catecholamines may explain why conventional inotropic support with catecholamines fails to prevent ventricular dysfunction. Phosphodiesterase III inhibitors increase ventricular function in patients who receive catecholamine and nitroglycerin therapy immediately after separation from bypass and have a potential to prevent acute ventricular dysfunction in the early postoperative period (13,14). In this study, milrinone and amrinone reduced the deterioration in ventricular function and total necessary doses of dopamine and nitroglycerin. This indicates that milrinone and amrinone are useful in reducing the risk of low cardiac output syndrome after cardiac surgery. A previous report showed that regional wall motion decreased significantly at two hours after cardiac surgery (2). Left ventricular wall motion abnormalities in our study were fewer in the Milrinone and Amrinone groups than in the Placebo group, and milrinone and amrinone prevented deterioration of regional ventricular wall motion after surgery.
There are some important differences between the methods and results of this study and those of previous reports (12–15). First, two previous reports examined the hemodynamic effects of milrinone or amrinone during the initial 10 minutes after separation from CPB and concluded that both milrinone and amrinone can effectively improve hemodynamic status and cardiac function in patients who had already undergone conventional therapy with catecholamines and nitroglycerin (12,15). Other previous studies focused mainly on the postoperative hemodynamic effects of milrinone (13,14). In this study, we investigated the advantages of preemptive use of phosphodiesterase III inhibitors in cardiac surgical patients and found that both milrinone and amrinone can contribute to overcoming the limits of conventional treatment with catecholamines and vasodilators for postoperative ventricular dysfunction and subsequent deterioration of oxygen transport. This study showed another advantage of phosphodiesterase III inhibitors: they attenuate postoperative increases in lactate, cellular enzymes, and glucose levels. Second, in this study we chose the time when the aortic cross-clamp is released as the start point of phosphodiesterase III inhibitor administration and gave a loading dose of the drug for 10–15 minutes, whereas the phosphodiesterase III inhibitors in the previous reports were administered after separation from CPB (12–15). The release of the aortic cross-clamp is the earliest point at which milrinone or amrinone can be delivered to the myocardium to assist in recovery from surgical ischemia-induced reperfusion injury. In addition, because phosphodiesterase III inhibitors decrease arterial pressure because of a potent vasodilatory effect, rapid administration of a loading dose of milrinone or amrinone tends to increase the requirement for additional volume transfusion from a CPB reservoir and the need for incremental doses of catecholamines. Unstable hemodynamic change is detrimental after termination of CPB. The period from release of the aortic cross-clamp to the termination of CPB is usually 15–30 minutes. During this period, we can stabilize the hemodynamics during the administration of milrinone or amrinone by adjusting the catecholamine infusion rate and transfusing blood from the CPB reservoir. Therefore, we consider that starting the administration of phosphodiesterase III inhibitors when the aortic cross-clamp is removed is preferable for minimizing unstable hemodynamic changes.
We previously observed that pulmonary artery pressure increases to undesirable levels during milrinone or amrinone monotherapy combined with phenylephrine and without catecholamine administration in a pilot study. In 10 different patients, 6 men and 4 women (mean age, 65 ± 8 years) undergoing elective coronary artery bypass, we randomly administered milrinone 50 µg/kg plus 0.5 µg · kg-1 · min-1 infusion (n = 5) or amrinone 1.5 mg/kg plus 10 µg · kg-1 · min-1 infusion (n = 5) at removal of the aortic cross-clamp, and we administered no catecholamine. Phenylephrine 0.5–2.0 µg · kg-1 · min-1 infusion and nitroglycerine 0.5–1 µg · kg-1 · min-1 were used to maintain systolic arterial blood pressure between 90 and 130 mm Hg. After CPB, systolic arterial blood pressure was maintained in this range, and cardiac index was 3.3 ± 0.4 and 3.2 ± 0.5 L · min-1 · m-2 in the Milrinone and Amrinone groups, respectively. However, mean pulmonary artery pressure increased to clinically intolerable levels (mean ± SD: 38 ± 5 and 37 ± 6 mm Hg in the Milrinone and Amrinone groups, respectively). Consequently, in all patients, phenylephrine was stopped, and dopamine 5–10 µg · kg-1 · min-1 was started as a substitute for phenylephrine within two hours after CPB, and after one hour of dopamine infusion, mean pulmonary artery pressure decreased significantly to clinically acceptable values (22 ± 3 and 21 ± 5 mm Hg in the Milrinone and Amrinone groups, respectively; P < 0.001). Cardiac index was 3.4 ± 0.5 and 3.3 ± 0.5 L · min-1 · m-2 in the Milrinone and Amrinone groups, respectively. On the basis of this observation, we designed this study to administer milrinone or amrinone in combination with dopamine in the protocol of the study. Although milrinone and amrinone reduce the postoperative requirements for dopamine, these drugs do not replace catecholamines; rather, they supplement catecholamines.
Certain differences in the effects of milrinone and amrinone on cardiac performance deserve attention. In our study, although amrinone did not increase heart rate in the postoperative period compared with placebo, milrinone treatment was associated with significantly faster heart rates than with amrinone or the placebo at 10–20 hours after CPB. This observation is consistent with findings in previous hemodynamic studies (13,14). The mechanism of milrinone-induced tachycardia may be caused by an increase in conduction through the atrioventricular node causing sinus tachycardia (21,22) or to increased peripheral vasodilation, although we found no difference between the Milrinone and Amrinone groups in postoperative systemic vascular resistance index.
Deterioration of ventricular function also decreases tissue blood flow and increases oxygen extraction; a previous study has shown that prolonged stays (more than five days) in ICUs are associated with reduced oxygen transport and an increased oxygen extraction ratio (6). Lower lactate levels and oxygen extraction ratios postoperatively after milrinone or amrinone treatment indicate a reduction in the oxygen demand-supply mismatch and the subsequent anaerobic glycolysis caused by tissue hypoxia. We found that lower systemic vascular resistance was maintained after the administration of milrinone or amrinone and that the vasodilatory effects of phosphodiesterase III inhibitors might contribute to the maintenance of peripheral vascular circulation and oxygen delivery to the tissue. Perioperative administration of small-dose milrinone reduces venous endotoxin and interleukin 6 concentrations in relatively healthy patients undergoing CABG, and milrinone may have antiinflammatory properties, thereby modulating endotoxemia and systemic inflammation and thus alleviating the acute phase of response after CPB (23). In this study, C-reactive protein was significantly low in the Milrinone and Amrinone groups, and this finding may be attributable to the potential of phosphodiesterase III inhibitors for immunomodulation by inhibiting intracellular cyclic nucleotide phosphodiesterase, which increases the intracellular concentration of cyclic adenosine monophosphate.
Postoperative hyperglycemia was attenuated in the Milrinone and Amrinone groups in this study, probably because of reduction of dopamine requirement and subsequent decrease in stimulation of glycogenolysis and gluconeogenesis. Inhibition of phosphodiesterase III increases insulin secretion in islets of Langerhans in the human pancreas (24), and an increase in insulin secretion induced by milrinone or amrinone might contribute to attenuation of postoperative hyperglycemia.
Milrinone or amrinone administration before separation from CPB not only attenuates postoperative deterioration of ventricular function and oxygen transport, but also reduces the necessary doses of dopamine and nitroglycerin and the postoperative increase of lactate, glucose, and certain cellular enzyme levels. These results support a rationale for the use of milrinone or amrinone as a supplement to conventional catecholamine and vasodilatory therapy for maintenance of cardiac function and oxygen transport after CPB. Because we conducted this study in patients with relatively good ventricular function, our findings should not be extrapolated to patients with impaired ventricular function, and further study of the impact on ICU stays, long-term outcome, and cost issues is required.
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Acknowledgments |
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), Amrinone (
), and Placebo (
) groups at baseline and at specified intervals after separation from cardiopulmonary bypass. The effect of milrinone on heart rate was significantly greater than that of placebo (P = 0.011) or amrinone (P = 0.011). Cardiac index at the postoperative nadir in the Milrinone and Amrinone groups was higher (2.5 ± 0.3 L · min-1 · m-2, P < 0.0001; and 2.5 ± 0.2 L · min-1 · m-2, P < 0.0001, respectively, versus 1.9 ± 0.5 L · min-1 · m-2 in the Placebo group), and stroke volume index at the nadir was higher (27.8 ± 4.0 mL · min-1 · m-2, P < 0.0001; and 26.1 ± 3.2 mL · min-1 · m-2, P < 0.0001, respectively, versus 20.4 ± 5.1 mL · min-1 · m-2 per beat in the Placebo group). B1 = after anesthetic induction; B2 = before cardiopulmonary bypass. *P < 0.01, Control versus Amrinone and Milrinone; 
P < 0.01, Control versus Amrinone; 
P < 0.01, Amrinone versus Milrinone; 
P < 0.01, Control versus Milrinone.
