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Ann Thorac Surg 1999;68:1661-1667
© 1999 The Society of Thoracic Surgeons

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Original Articles

Inhibitory effect of milrinone on cytokine production after cardiopulmonary bypass

^a Department of Surgery, Kurume University, Fukuoka, Japan

Address reprint requests to Dr Hayashida, Department of Surgery, Kurume University, 67 Asahi-machi, Kurume, Fukuoka, 830-0011 Japan

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. It has been suggested that cyclic adenosine monophosphate-elevating agents suppress cytokine production. To evaluate the effects of milrinone, a phosphodiesterase III inhibitor, on cytokine production after cardiopulmonary bypass, we conducted a prospective randomized study.

Methods. Twenty-four patients undergoing coronary artery bypass grafting were randomized to receive either milrinone treatment (milrinone, n = 12) or no milrinone treatment (control, n = 12). Administration of milrinone (0.5 µg · kg^-1 · min^-1) was started after induction of anesthesia and was continued for 24 hours. Blood samples for determination of plasma cyclic adenosine monophosphate, tumor necrosis factor-, interleukin-1ß, interleukin-6, and interleukin-8 levels were collected perioperatively.

Results. No significant differences were observed in tumor necrosis factor- and interleukin-8 levels between the groups. Interleukin-1ß and interleukin-6 levels after cardiopulmonary bypass were significantly (p < 0.05) lower in the milrinone group than in the control group. Plasma levels of cyclic adenosine monophosphate increased significantly (p < 0.05) after the administration of milrinone and the levels correlated inversely (r = -0.55, p < 0.01) with interleukin-6 levels.

Conclusions. The results indicate that milrinone suppresses cytokine production by elevating cyclic adenosine monophosphate levels in patients undergoing cardiopulmonary bypass. With its positive inotropic and vasodilator activities, milrinone may have antiinflammatory effects.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
It has been well documented for many years that cardiopulmonary bypass (CPB) produces a systemic inflammatory response syndrome attributable to the release of proinflammatory mediators, such as complement and cytokines [1–3]. Of these mediators, tumor necrosis factor- (TNF-), interleukin-1ß (IL-1ß), IL-6, and IL-8 are a class of endogenous proteins that exert influences on immune, hematologic, and metabolic responses to injury [1–3]. The degree of release of the mediators is thought to be associated with the incidence of postoperative organ failure and mortality [4].

Milrinone, a phosphodiesterase (PDE) III inhibitor, has been reported to have positive inotropic and vasodilatory effects and to be beneficial in patients with chronic congestive heart failure or with low cardiac output after cardiac operation [5, 6]. The mechanism of action appears to be mediated by inhibition of the cyclic adenosine monophosphate (cAMP) phosphodiesterase, resulting in an increase in intracellular cAMP. Therefore, the regimen would increase intracellular calcium availability [5]. In recent reports, it was suggested that elevation of intracellular cAMP by PDE inhibitors reduced cytokine production in lipopolysaccharide (LPS)-stimulated human mononuclear cells [7–10]. However, it is unknown whether PDE inhibitors have the potential to decrease the production of proinflammatory cytokines in patients undergoing CPB.

The purpose of this study was to evaluate the effects of milrinone administered before CPB on cytokine production in patients undergoing coronary artery bypass grafting.

	Patients and methods

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Between September 25, 1997, and January 24, 1998, a prospective randomized study was performed on 24 consecutive patients undergoing primary isolated coronary artery bypass grafting by one surgeon (TK). All patients signed a consent form approved by the Human Experimental Committee of Kurume University. Exclusion criteria for the study were impaired organ function other than myocardial ischemia, the presence of active inflammatory disease, and acute myocardial infarction. Six patients were receiving aspirin or a nonsteroidal antiinflammatory drug before the operation. Administration of these platelet-active drugs was stopped at least 7 days before the operation. None were receiving corticosteroids preoperatively. The patients were randomized into two groups by means of a computer-generated randomization table. The control group received no milrinone treatment (n = 12); the milrinone group (n = 12) received continuous infusion of milrinone (Yamanouchi Seiyaku Inc, Tokyo, Japan) immediately after anesthesia induction at a rate of 0.5 µg · kg^-1 · min^-1 for 24 hours. To avoid the risk of hypotension as a result of synergistic vasodilator effect of both anesthetic and milrinone, a bolus infusion was not used in this study. The demographic data are shown in Table 1.

Cytokine and cyclic adenosine monophosphate levels
Blood was collected from the patient’s peripheral arterial lines or the arterial side of CPB circuit immediately after induction of anesthesia, 5 minutes after initiation of CPB, at the end of CPB, and 1 hour, 3 hours, and 12 hours after completion of CPB. All blood samples were drawn in precooled red-top vacuum tubes for determination of cytokines and precooled vacuum tubes containing disodium ethylenediaminetetraacetic acid (1.5 mg/mL) for determination of cAMP. The samples were immediately centrifuged (1,500 g for 10 minutes) at -4°C. The plasma was transferred to a sterile polypropylene test tube and stored at -80°C until assayed. Tumor necrosis factor- was measured in plasma by means of enzyme-linked immunosorbent assays (Human TNF- ELISA kit, Nihon Koutai Kenkyusho Inc, Tokyo, Japan). Interleukin-8 was measured in plasma by means of enzyme-linked immunosorbent assays (Human IL-8 ELISA kit, Toray Inc, Tokyo, Japan). Interleukin-1ß was measured in plasma by means of radioimmunoassay (Human IL-1 IRMA kit, Medgenix Diagnostics, Fleurus, Belgium). Interleukin-6 was measured in plasma by means of chemiluminescent enzyme immunoassay (Human IL-6 CLEIA kit, Fuji Rebio Inc, Tokyo, Japan). Cyclic adenosine monophosphate was measured in plasma by means of radioimmunoassay (YAMASA RIA kit, YAMASA Shoyu, Choshi, Japan). No adjustment was made for hemodilution. The sensitivity was 5 pg/mL for TNF-, 5 pg/mL for IL-1ß, 4 pg/mL for IL-6, and 12.5 pg/mL for IL-8. Reference range of plasma cAMP was 11 to 21 pmol/mL.

C-reactive protein and MB isoenzyme of creatinine kinase levels
Blood samples for the determination of C-reactive protein (CRP) and isoenzyme of creatinine kinase (CK-MB) levels were also collected from the patient’s peripheral arterial lines immediately after induction of anesthesia, 1, 3, 12, 24, and 48 hours after completion of CPB. The CRP levels were measured with a turbidimetric immunoassay and the reference range was 0 to 0.4 mg/dL. The CK-MB levels were measured with a chemiluminescent immunoassay and the reference range was 6 to 28 IU/L. Integration of the area under the time–concentration curve for CK-MB within the first 48 hours postoperatively allowed calculation of the total CK-MB release, expressed as international units times hours per liter.

Hemodynamic measurements
Heart rate (HR), mean arterial blood pressure (MAP), mean pulmonary artery pressure (MPA), mean right atrial pressure (RAP), and pulmonary capillary wedge pressure (PCWP) were measured. Cardiac output (CO) was measured in triplicate by the thermodilution technique (model 744H-7.5F; Edwards Swan-Ganz, Baxter Healthcare Corp, Irvine, CA). Derived hemodynamic indices were calculated as follows: rate–pressure product = HR x systolic blood pressure (mm Hg/min; cardiac index (CI) = CO/body surface area (L · min^-1 · m^-2); stroke index (SI) = CI/HR (mL · min^-1 · m^-2); left ventricular stroke work index (LVSWI) = SI x (MAP - PCWP) x 0.0136 (g · m/m²); right ventricular stroke work index (RVSWI) = SI x (MPA - RAP) x 0.0136 (g · m/m²); pulmonary vascular resistance (PVR) = (MPA - PCWP)/CI x 80 (dyne · s^-1 · cm^-5); and systemic vascular resistance (SVR) = (MAP - RAP)/CI x 80 (dyne · s^-1 · cm^-5). These hemodynamic variables were measured immediately after induction of anesthesia, 5 minutes before CPB, 1, 3, 6, and 12 hours after cessation of CPB. Postoperative volume repletion and intensive care unit care followed the standard protocol of this institute.

Statistical analysis
Statistical analysis was performed with SPSS statistical software (SPSS Inc, Chicago, IL). All data are expressed as a mean ± standard error of the mean. One-way or two-way repeated measures analysis of variance was used to test the effect of group and time on the levels of cytokines, cAMP, CRP, CK-MB, and hemodynamic measurements. When analysis of variance indicated a significant effect of group or time (p < 0.05), the differences were specified with Sheffé’s test for within-group comparison and unpaired Student’s t test for between-group comparison. The Pearson’s correlation coefficient test was used to explore the correlation between cytokine levels and cAMP levels. Unpaired Student’s t test was used to compare other continuous variables. Categoric data were analyzed using the ² test or Fisher’s exact test where appropriate. Statistical significance was assumed at a probability level of less than 0.05.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Clinical and operative data for the two patient groups are shown in Table 1. No significant differences were noted in the clinical and operative data.

Cytokines and cyclic adenosine monophosphate levels
The levels of cytokines and cAMP are shown in Figure 1. Plasma TNF- was not detectable at any time in all patients. The two-way analysis of variance indicated a significant effect of group (p = 0.04) and the time (p = 0.01) in IL-1ß levels. The IL-1ß level increased significantly (p = 0.01 by one-way analysis of variance, p < 0.05 by Sheffé’s test) at the end of CPB in the control group, whereas the levels remained constant (p = 0.35 by one-way analysis of variance) in the milrinone group. The level at the end of CPB in the control group was significantly (p < 0.05 by unpaired Student’s t test) greater than that in the milrinone group. Although IL-6 levels increased significantly (p = 0.0001 by one-way analysis of variance, p < 0.05 by Sheffé’s test) at the end of CPB and the increase persisted until 3 hours after CPB in both groups, the levels were significantly (p < 0.05) lower in the milrinone than those in the control group 1 hour and 3 hours after CPB. The IL-8 levels increased significantly (p < 0.05) 3 hours after CPB in both groups and no significant differences were found between the groups at any time. A marked increase (p < 0.05) in plasma cAMP levels was found in the milrinone group after milrinone administration, whereas the levels remained essentially constant (p = 0.40) in the control group. Plasma cAMP levels were significantly (p < 0.05) greater in the milrinone group than those in the control group 5 minutes after initiation of CPB, at the end of CPB, and 1 hour after CPB. Plasma cAMP levels at the end of CPB correlated inversely (r = -0.56, p < 0.01) with IL-6 levels 3 hours after CPB (Fig 2).

View larger version (21K): [in this window] [in a new window]   Fig 1. Cytokine and cyclic adenosine monophosphate (cAMP) levels. Interleukin-1ß (IL-1ß) levels at the end of cardiopulmonary bypass (CPB) and interleukin-6 (IL-6) levels 1 and 3 hours after cardiopulmonary bypass were significantly lower in the milrinone group than those in the control group. Cyclic adenosine monophosphate levels were significantly greater in the milrinone group than those in the control group 5 minutes after initiation, at the end, and 1 hour after cardiopulmonary bypass. (Control = control group; IL-8 = interleukin-8; Ind = induction of anesthesia; Milrinone = milrinone group; NS = not significant; Off = at the end of cardiopulmonary bypass; On = 5 minutes after initiation of cardiopulmonary bypass.)

View larger version (19K): [in this window] [in a new window]   Fig 2. Relationship between the plasma cyclic adenosine monophosphate (cAMP) and interleukin-6 (IL-6) levels. Plasma cyclic adenosine monophosphate levels at the end of cardiopulmonary bypass correlated inversely (r = -0.56, p < 0.01) with interleukin-6 levels 3 hours after cardiopulmonary bypass. (Control = control group; Milrinone = milrinone group.)

Hemodynamic measurements
The hemodynamic measurements are summarized in Table 2. There were no significant differences in MAP, MPA, RAP, PCWP, HR, rate–pressure product, PVR, and RVSWI between the groups at any time. Cardiac index was significantly (p < 0.05) greater in the milrinone group than that in the control group 1, 3, 6, and 12 hours after CPB. Left ventricular stroke work index was also significantly (p < 0.05) greater in the milrinone group 6 hours after CPB. Systemic vascular resistance decreased significantly (p < 0.05) after CPB in both groups; however, the value was significantly (p < 0.05) lower in the milrinone group than that in the control group 1, 3, and 6 hours after CPB.

	Comment

Top Abstract Introduction Patients and methods Results Comment References

 
Heart operations with CPB causes a systemic inflammatory response characterized by activation of the compliment, neutrophils, coagulation, fibrinolytic, and kallikrein cascades, and the synthesis of proinflammatory cytokines [1–4]. The response has been reported to be associated with the incidence of postoperative organ failure and mortality [4]. In recent years, the release of proinflammatory cytokines, such as TNF-, IL-6, and IL-8, has been reported to play an important role in altering cardiac function [2, 11]. Finkel and associates [11] noted a negative inotropic effect of TNF- and IL-6, which was mediated through a myocardial nitric oxide synthase. Hennein and colleagues [2] have also demonstrated that left ventricular wall motion abnormalities were associated with both IL-6 and IL-8 levels after uncomplicated coronary revascularization. Therefore, if cytokine production could be reduced during and after CPB, some postoperative organ failure, such as cardiac dysfunction and respiratory distress syndrome, might be avoided. To date, a number of therapeutic interventions to minimize the cytokine response, including pharmacologic agents, heparin-coated circuits, or hemofiltration, have been investigated.

Milrinone, a peak III PDE inhibitor, has been reported to produce enhanced contractility, vasodilation, and accelerated diastolic relaxation [5, 6, 12]. Several studies have shown milrinone to have beneficial hemodynamic and clinical effects in patients with congestive heart failure or with low cardiac output syndrome after cardiac operation [5, 6]. The mechanisms of action appear to be mediated by an increase in intracellular cAMP level, resulting in an increase in intracellular calcium availability [5]. Monrad and colleagues [12] reported that therapy with milrinone resulted in a greater decrease in PCWP and a lower oxygen consumption than that with dobutamine in patients with congestive heart failure. Moreover, it produced an equivalent hemodynamic response to nitroprusside with less concomitant hypotension. In the present study, milrinone improved left ventricular function (CI and LVSWI) without increasing the rate–pressure product and it decreased SVR significantly. The results were consistent with the previous report [6], which investigated the hemodynamic effects of milrinone in patients with postoperative low cardiac output syndrome. A marked increase in plasma cAMP levels was also found in patients receiving milrinone, whereas the levels remained constant in the control group. As suggested by Konstam and Cody [5], the increases in intracellular cAMP levels by milrinone administration may play a central role in the hemodynamic improvement. However, because the cAMP levels were measured in plasma in the present study, the levels may not have directly reflected the intracellular levels. Imai and colleagues [13] demonstrated in isolated perfused heart model that cAMP can pass relatively freely across the cell membrane and the released cAMP levels correlated strongly with cardiac function and coronary vasodilation, whereas intracellular levels did not. Therefore, we believe that the plasma cAMP levels are substantially relevant to its functional levels.

Recently, the nonspecific PDE inhibitors theophylline and pentoxifylline were reported to decrease TNF- production from endotoxin-induced monocytes [8, 14]. Specific PDE inhibitors, including amrinone and milrinone (PDE III inhibitors) and rolipram and nitraquazone (PDE IV inhibitors) have also been suggested to inhibit TNF- and IL-1ß production from human mononuclear cells or rat cardiac tissue [7, 9, 10]. Although the mechanisms of action of PDE inhibitors in inhibiting cytokine production are still not clear, increases in intracellular cAMP levels may play a central role in reducing cytokine generation [15, 16]. Verghese and colleagues [17] have demonstrated that cAMP depressed the accumulation of TNF- mRNA by inhibiting the transcriptional processes. The processes contrast with the action of steroids that block cytokine production at the translational level. With regard to IL-1ß production, Yoshimura and colleagues [10] showed that PDE inhibitors and dibutyryl cAMP, a cAMP analog, suppressed IL-1ß production by LPS-stimulated human mononuclear cells. The reported mechanism of the action is that cAMP reduces the amount of secreted IL-1ß from LPS-stimulated monocytes without affecting steady state mRNA levels and that cAMP interferes with the secretion of IL-1ß rather than with other steps in the biosynthetic pathway [16, 17]. In the present study, we also found a marked increase in plasma cAMP levels and a suppression of IL-1ß production at the end of CPB in patients receiving milrinone. The results of our study and previous studies [10, 16] suggest that the inhibitory effect of the PDE inhibitor on IL-1ß production is through an increase in cAMP. The regulation of IL-6 production by cAMP is still a matter of controversy. The cAMP-elevating agents were considered as inducing enhanced IL-6 production, whereas they suppressed TNF- production by LPS-stimulated monocytes [18]. Zabel and colleagues [19] demonstrated that pentoxifylline did not affect the endotoxin-induced increase in IL-6. In contrast, Matsumori and colleagues [20] showed a slight inhibitory effect of PDE III inhibitor on IL-6 production by LPS-stimulated human blood. Because the majority of the reports have concentrated on the effects of PDE inhibitors on cytokine production in vitro, little is known regarding their effects in vivo. Moreover, the effect of PDE III inhibitors on cytokine production has not yet been studied in patients undergoing CPB. In the present study, the administration of milrinone markedly suppressed IL-6 production after CPB and the effect correlated with the cAMP levels. Therefore, our results suggest that cAMP modulates IL-6 production as well as IL-1ß production in patients undergoing CPB. In recent reports, myocardium was proposed as a source of TNF- and IL-6 after ischemic stress [21] or after CPB [3]. It was also suggested that cAMP-elevating agents reduced cytokine production from the myocardium itself [9]. Moreover, the PDE inhibitor was reported to have an inhibitory effect on myocardial reperfusion injury [22]. Therefore, the possibility exists that the lesser IL-6 levels after CPB in the milrinone group are attributable to the inhibitory effect of the regimen on cytokine production, not only by activated monocytes but also by ischemic myocardium. However, because we measured cytokine levels only in peripheral arterial blood, the present study could not define the tissue source of cytokines. Therefore, further investigations are required to assert whether milrinone suppresses cytokine production by monocytes or by myocardium. Interleukin-8 is a potent neutrophil chemotactic and activating factor, whereas TNF- and IL-1ß are nonchemotactic cytokines. Because IL-8 production is induced by TNF- and IL-1ß [23], it is expected that the production is suppressed by decreasing TNF- or IL-1ß. However, several studies have shown that PDE inhibitors had no inhibitory effect on IL-8 production, whereas they suppressed TNF- and IL-1ß levels by LPS-stimulated human mononuclear cells [8, 10]. The present study also demonstrated no direct effect of milrinone on IL-8 production, whereas it suppressed IL-1ß production. Yoshimura and colleagues [8] showed that theophylline, a nonselective PDE inhibitor, potentiated IL-8 production by recombinant human IL-1ß-stimulated human mononuclear cells. Therefore, they suggested that the phenomenon might offset the inhibitory effect of theophylline on IL-8 production as a result of the suppression of TNF- and IL-1ß production.

In the present study, minimal-dose aprotinin (1 x 10⁶ KIU added to the pump prime) was administered to all patients to improve hemostasis [24]. Because aprotinin has been documented to abrogate the inflammatory response to CPB [25], the possibility exists that its use may skew the present results. However, recent reports have clearly demonstrated that low-dose aprotinin has little influence on cytokine production after CPB [26, 27]. Because the dose used in the present study was almost half of the low dose used in those studies, we believe that aprotinin used in this study has few effect on cytokine production.

Because the number of patients involved in the present study was small and preoperative patient’s risks were relatively low, no differences in clinical outcomes were found. However, we believe that the inhibitory effect of milrinone on cytokine production may contribute to a decrease in the prevalence of organ dysfunction after CPB in high-risk patients. Further investigations involving more patients and high-risk patients are required to assert that milrinone can be a potent pharmacologic agent for the treatment of systemic inflammatory response after CPB.

In conclusion, administration of milrinone suppressed cytokine production after CPB. The effect appears to be mediated by increases in cAMP levels. With its positive inotropic and vasodilator activities, milrinone may have antiinflammatory effects in patients undergoing CPB.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

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