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Anesth Analg 2001;92:1377-1383
© 2001 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Inhibition of Phosphodiesterase Type III Before Aortic Cross-Clamping Preserves Intramyocardial Cyclic Adenosine Monophosphate During Cardiopulmonary Bypass

Gregory M. Janelle, MD*, Felipe Urdaneta, MD*, Mark L. Blas, MD*, John Shryock, MD{dagger}, Yeong-Shiuh Tang, MD*, Tomas D. Martin, MD{ddagger}, and Emilio B. Lobato, MD*§

Departments of *Anesthesiology, {dagger}Medicine, and {ddagger}Cardiothoracic Surgery, University of Florida College of Medicine; and §Anesthesiology Service, Department of Anesthesiology, Veterans Affairs Medical Center, Gainesville, Florida

Address correspondence and reprint requests to Emilio B. Lobato, MD, Department of Anesthesiology, University of Florida College of Medicine, Box 100254, Gainesville, FL 32610-0254. Address e-mail to lobato{at}anest2.anest.ufl.edu


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Inotropes are often used to treat myocardial dysfunction shortly after cardiopulmonary bypass (CPB). ß-Adrenergic agonists improve contractility, in part by increasing cyclic adenosine monophosphate (cAMP) production, whereas phosphodiesterase type III inhibitors prevent its breakdown. CPB is associated with abnormalities at the ß-receptor level and diminished adenyl cyclase activity, both of which tend to decrease cAMP. These effects may be increased in the presence of preexisting myocardial dysfunction. We tested the hypothesis that inhibition of phosphodiesterase type III before global myocardial ischemia and pharmacologic arrest results in the preservation of intramyocardial cAMP concentration during CPB. Twenty adult patients undergoing coronary artery bypass grafting with CPB were studied. After CPB was instituted, a myocardial biopsy was obtained from the apex of the left ventricle. Patients were randomized to receive either placebo or milrinone (50 µg/kg) through the bypass pump 10 min before aortic cross-clamping. Another myocardial biopsy was performed adjacent to the left ventricular apex just before weaning from CPB. Myocardial cAMP concentration was determined by radioimmunoassay. Myocyte protein content was determined by the Bradford method by using a commercial kit. There were no significant demographic differences between the groups; however, patients in the Milrinone group had a lower left ventricular ejection fraction than placebo (41% ± 13% vs 53% ± 7%; P < 0.05). Patients who received milrinone had larger cAMP concentrations at the end of CPB compared with placebo (21 ± 12.5 pmol/mg protein versus 12.8 ± 2.2 pmol/mg protein; P < 0.05). The administration of milrinone before aortic cross-clamping is associated with increased intramyocardial cAMP concentration at the end of CPB.

Implications: The administration of a single dose of milrinone before aortic cross-clamping resulted in significantly larger intramyocardial cyclic adenosine monophosphate concentration in myocardial biopsy specimens compared with controls.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Patients undergoing cardiac surgery often exhibit myocardial dysfunction after cardiopulmonary bypass (CPB) (1,2). The etiology is multifactorial, with possible causes including incomplete myocardial protection, effects of cardioplegia solutions, global ischemia, and reperfusion (3). The severity and duration of cardiac depression after CPB correlates with the duration of ischemia (3). Clinical and experimental data have demonstrated that the heart exhibits acute ß-adrenergic receptor (ßAR) desensitization during CPB; this results in decreased cyclic adenosine monophosphate (cAMP) production after stimulation of the ßARs (4–6). Thus, large doses of ßAR agonists may be required to improve contractility, leading to increased myocardial oxygen consumption and the risk of myocardial ischemia and arrhythmias (7).

Milrinone is a bipyridine agent that increases intramyocardial cAMP because of inhibition of the enzyme phosphodiesterase type III (PDEIII) (8–11). In models of regional and global ischemia, PDEIII inhibition before the ischemic insult improves myocardial function without an increase in myocardial oxygen consumption, both before and after reperfusion (12–15). This phenomenon is thought to occur as a result of the decrease in left ventricular (LV) wall stress caused by peripheral arteriolar vasodilation, LV preload reduction, positive lusitropic effects, and direct coronary vasodilation, and it may be of particular benefit, specifically in patients with limited coronary flow reserve (16–18). Milrinone in patients with angiographically demonstrated coronary artery disease and stable angina significantly reduces exercise-induced angina severity and duration when compared with a Control group (17). Milrinone has proved effective when administered before surgery as a bridge to cardiac transplantation in patients with end-stage ischemic cardiomyopathy, who are probably at increased risk of negative sequelae from inotropic drugs that increase myocardial oxygen consumption (18). Notably, PDE inhibitors reduce myocardial ischemia extent and infarct size in isolated rabbit hearts (19). However, the effects of PDEIII inhibition on cAMP concentrations under conditions of ischemia or reperfusion during CPB are not known. The purpose of this study was to investigate whether the administration of milrinone before aortic cross-clamping preserved intramyocardial cAMP concentration and to establish a clinical correlation with improved hemodynamics during separation from CPB.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval of the local IRB and signed informed consent, 20 adult patients undergoing elective coronary artery bypass graft (CABG) surgery were studied. Two patients were eventually excluded because of inadequate myocardial biopsy specimens. Demographic data were recorded. Digoxin was withheld on the day of surgery for patients previously on this therapy, but all other preoperative medications were continued until the time of surgery. All patients received premedication with IV midazolam. The anesthetic technique consisted of sodium thiopental (2–4 mg/kg), fentanyl (total dose of 20–25 µg/kg), and pancuronium, supplemented with isoflurane in an oxygen/air mixture. After the induction of anesthesia and the institution of mechanical ventilation, hemodynamic monitors were placed, including radial and pulmonary artery catheters and a transesophageal echocardiography probe (HP Omniplane; Hewlett-Packard, Andover, MA). All operations were performed with heparin-induced anticoagulation targeted to maintain an activated clotting time longer than 480 s. After heparin administration and placement of an ascending aortic cannula and a two-stage right atrial cannula, CPB was instituted with a nonpulsatile pump primed with 1500 mL of Normosol and 25 g of mannitol. A coronary sinus catheter was placed via the right atrium. The aorta was cross-clamped, and the cardioplegic solution was delivered via the aortic root and the coronary sinus to achieve electromechanical arrest. The crystalloid cardioplegic solution—25 g/L dextrose, 100 mEq/L sodium chloride, 20 mEq/L potassium, and 2 mEq/L magnesium—was administered at regular intervals. Moderate hypothermia was used in all the cases (nasopharyngeal temperature of 28°C). All patients received an internal mammary artery graft to the left anterior descending artery. The distal coronary anastomoses were performed first, and after rewarming with the heart beating spontaneously or artificially paced, the proximal anastomoses were completed with the aid of an aortic side-clamp. Patients were then weaned from CPB after normothermia (bladder temperature 37.5°C) was achieved and mechanical ventilation reinstituted. Hemodynamic variables were measured and calculated with standard formulae before the administration of protamine. Epinephrine was used as the inotrope of choice by the treating physicians; however, the dose was left to the discretion of the treating physicians.

After patients were placed on CPB, a transmyocardial biopsy was obtained from the apical anterior wall of the LV in an area supplied by the left anterior descending artery. The average sample contained approximately 100–200 µg of muscle. Patients were then randomized in a blinded fashion via a computer-generated table to receive either a dose of milrinone (50 µg/kg) or placebo, diluted in 20 mL of normal saline and infused via a syringe pump directly into the CPB pump over 10 min. The drug was supplied directly by the pharmacy to maintain blinded randomization. Approximately 10 min after the study drug administration, the aortic cross-clamp was applied. Immediately before separation from CPB, a second transmyocardial biopsy was taken from the apical anterior wall of the LV from a site adjacent to the first biopsy.

Immediately after the biopsy, the myocardial specimen was kept in a buffered medium of 50 mM HCl and frozen at -70°C for cAMP preservation. Subsequently, it was centrifuged at 30,000 rpm for 5 min to separate and quantify the protein content of the sample. Cyclic AMP contents of the acid extracts of cells were measured by radioimmunoassay. Cellular extract (100 µL), antibody to cAMP, and a 125I-labeled succinyl cAMP tyrosyl methyl ester (%sim;20,000 disintegrations per minute) were mixed and incubated in glass tubes overnight at 2°C. Hydroxyapatite (75 µL; 50:50 vol/vol in water) was then added to each sample, and the mixtures were incubated for 10–30 min at 2°C. An assay was terminated by vacuum filtration of samples and collection of bound radioactivity on filter paper, by using a Brandel cell harvester. The radioactivity of antibody bound 125I-labeled cAMP ester adsorbed to hydroxyapatite and trapped on filter paper was quantified by a {gamma} counter. Cyclic AMP content of sample extracts was estimated by comparison of sample results with results of parallel assays of standards of known cAMP content (0.6–8 pmol). Protein content of cellular extracts was determined according to the Bradford method by using a commercially available kit (BioRad, Richmond, CA) (20). Albumin was used as a standard. The results were reported in picomoles per milligram of protein.

Demographic and CPB data were analyzed with {chi}2 (or Fisher’s exact test) and paired Student’s t-tests. Differences in cAMP concentrations and hemodynamic data, both within the same group and between groups, were analyzed with analysis of variance. All results are reported as mean ± SD. When statistical significance was identified, the Student-Newman-Keuls method was used where appropriate. A P value <0.05 was considered significant.


   Results
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 Introduction
 Methods
 Results
Discussion
 References
 
Demographic characteristics were similar between groups (Table 1) with the exception of the preoperative ejection fraction (41% ± 14% in the Milrinone group versus 53% ± 7% in the Placebo group; P < 0.05), which was determined either by cardiac catheterization or echocardiography. Preoperative use of digoxin was also more frequent in the Milrinone group (six patients versus none in the Placebo group). Length of CPB, aortic cross-clamp time, number of grafts, minimal temperature, number of patients weaned from CPB with epinephrine, and the dose range of epinephrine used were not significantly different.


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  		Table 1. Demographic and Procedural Data
 
Hemodynamic comparisons are represented in Table 2. There were no significant differences in cardiac index between groups either before or after CPB. Heart rate was significantly increased after CPB in both groups (from 67 ± 19 bpm at baseline to 101 ± 7 bpm in the Placebo group [P < 0.05] and from 73 ± 17 bpm at baseline to 99 ± 13 bpm in the Milrinone group [P < 0.05]). Systemic vascular resistance was significantly lower after CPB in both the Placebo group (from 1247 ± 283 mm Hg · s · cm-5 at baseline to 791 ± 312 mm Hg · s · cm-5 after CPB; P < 0.05) and the Milrinone group (from 1242 ± 355 mm Hg · s · cm-5 at baseline to 875 ± 341 mm Hg · s · cm-5 after CPB; P < 0.05). Post-CPB pulmonary vascular resistance was lower in the Milrinone group but failed to reach statistical significance (P = 0.07 compared with the Placebo group after CPB).


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  		Table 2. Hemodynamic Variables
 
Baseline cAMP levels were similar in both groups (16.0 ± 12.5 pmol/mg protein in the Milrinone group versus 15.9 ± 9.4 pmol/mg protein in the Placebo group). Patients who received milrinone had larger cAMP levels at the end of CPB (21 ± 12.5 pmol/mg protein; P < 0.05 from baseline) compared with the Placebo group (12.8 ± 2.2 pmol/mg protein; P < 0.005 compared with the Milrinone group) (Fig. 1). Individual values are shown in Figures 2 and 3. Percentage of deviation from baseline levels between groups is shown in Figure 4.



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  		Figure 1. Cyclic adenosine monophosphate (cAMP) levels before and after cardiopulmonary bypass (CPB). *P < 0.05 compared with the Placebo group; {dagger}P < 0.05 compared with baseline. M = Milrinone group; P = Placebo group.

 


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  		Figure 2. Milrinone group: individual cyclic adenosine monophosphate (cAMP) values before and after cardiopulmonary bypass. Ao X-clamp = aortic cross-clamp.

 


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  		Figure 4. Average deviation from baseline cyclic adenosine monophosphate levels. *P < 0.05 compared with Placebo group.

 


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  		Figure 3. Placebo group: individual cyclic adenosine monophosphate (cAMP) values before and after cardiopulmonary bypass. Ao X-clamp = aortic cross-clamp.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The main finding in our study is that the inhibition of PDEIII before global ischemia and after reperfusion was associated with preservation of intramyocardial cAMP concentrations. Upon initial consideration, it would seem that increasing cAMP could be counterproductive during global ischemia, because arrhythmias can occur because of increased influx of calcium (21). Tse et al. (14) have shown that increased activity of ßARs occurs during transient global ischemia, most likely because of large concentrations of myocardial catecholamines (4,22–24). Thus, during the early stages of global ischemia, cAMP production is stimulated (25). With prolonged ischemia, however, ßAR desensitization occurs, resulting in decreased adenylyl cyclase activity (26).

Unlike models of transient ischemia, the effect of CPB on ßAR-induced cAMP production is more complex. Stimulation of ßARs occurs during initiation of CPB because of a 2- to 20-fold increase of serum catecholamines (4,27). In addition, other factors, such as the systemic release of inflammatory mediators, as well as cardioplegia, hypothermia, and increased local concentrations of catecholamines during aortic cross-clamping, are likely to affect ßAR function (28–30). Thus, a unique phenomenon occurs during extracorporeal circulation that has a profound effect on cAMP production. Although the number of ßARs remains relatively unchanged or slightly decreased (29), the activity of adenylyl cyclase is significantly diminished because production of cAMP by direct activators (i.e., manganese) is unhindered (4).

Abnormalities in the ßAR pathway during CPB have been described in patients with normal ventricular function undergoing CABG (4) and valve surgery (22) and in children with congenital heart repairs (29). Experimental studies suggest that in animals with normal preoperative ventricular function subjected to normothermic CPB and cardioplegic arrest, the ßAR pathway recovers shortly after CPB (31). There are no published data, however, regarding the duration of ßAR desensitization in humans. Similarly, the degree of desensitization and recovery in patients with preexisting ventricular dysfunction is unknown.

Although many patients undergoing CABG surgery with short CPB times and normal ventricular function will tolerate this acute desensitization, others may incur significant abnormalities in cardiac function, which may impede separation from CPB. In this situation, larger doses of ßAR agonists, along with their associated untoward effects, may be required (7). Similarly, PDEIII administered during separation from CPB may produce excessive vasodilation and consequent hypotension (32).

Milrinone acts by diffusing through the sarcolemmal membrane and inactivating cAMP breakdown by preventing its hydrolysis. Evidence suggests that for milrinone to exert significant inotropic effects, the cell must maintain the ability to generate cAMP (33). Thus, although milrinone has complex effects on the myocyte independent of the production of cAMP, its primary mechanism of action is caused by increased cAMP (10). In cases in which cAMP production is impaired, the ability of milrinone to increase contractility is significantly diminished (11,34). Unlike ßAR agonists, milrinone does not rely on a G-protein second messenger, effectively bypassing any abnormalities of the ßAR-cAMP production cascade (8,10). Milrinone improves ventricular function during and after separation from CPB (35–38). In addition, it exerts beneficial effects on native and grafted coronary blood flow (39,40), thus improving myocardial energetics through a combination of inotropic, vasodilatory, and lusitropic effects (41,42).

Recognition of ßAR desensitization during CPB may have therapeutic implications. The first logical step would be to arrest, retard, or at least minimize the degree of ßAR desensitization. Although therapeutic doses of long-acting ßAR-blocking drugs do not appear to be protective (4), preliminary data from animals suggest that large-dose ßAR-blockade may preserve adenylyl cyclase activity.1 Warm-blood cardioplegia also may improve ßAR protection (43).

The results of this study suggest that the preemptive administration of milrinone in the early stages of CPB significantly increases post-CPB cAMP tissue concentration. The clinical significance of these findings is somewhat less obvious, because systemic hemodynamic measurements and the degree of inotropic intervention during separation from CPB were similar between the Milrinone and Placebo groups.

Possible explanations for lack of significant differences in hemodynamic variables between groups after CPB include

  1. 1. The absence of any clinically discernible effect on the myocyte despite the increase in cAMP content. Although total myocyte cAMP concentrations were increased, not all cAMP participates in the regulation of contraction and relaxation, but rather in selected amounts from specific locations within the cell (e.g., forskolin significantly increases cAMP with minimal changes in contractility) (44–47). Perhaps overall preservation of cAMP may be irrelevant to issues of systolic or diastolic myocardial performance. We do not believe that to be the case because the degree of PDEIII inhibition bears a linear relationship to levels of cAMP and contractility (10,11).
  2. 2. Perhaps a more plausible explanation stems from analyzing the patient population. The patients in the Milrinone group had worse ventricular function before surgery, as evidenced by a lower LV ejection fraction and more frequent use of digoxin. A lower preoperative LV ejection fraction is a significant predictor for inotropic requirements after CPB (48). The fact that there were no differences in the hemodynamic profiles and use of inotropes between a healthier group of patients in the Placebo group and those in the Milrinone group suggests a protective effect. In addition, we did not measure indices of contractility, but rather systemic hemodynamic variables. Any association between cAMP levels and contractile function would be better served with load-independent indices of contractility obtained by pressure-volume loops, such as the end-systolic pressure volume relationship or preload recruitable stroke work index.

A potential confounding variable is the recognition that six patients in the Milrinone group were on digoxin therapy before surgery. Doses of digoxin were withheld on the morning of surgery in these patients, as is done routinely at our institution. It has been suggested by Nagai et al. (49) that digoxin reduces both basal and stimulated adenylyl cyclase activity and blunts the increase in cAMP after dobutamine infusion in vivo. This observation would lead to the conclusion that patients receiving preoperative digoxin potentially would have smaller pre-CPB levels of cAMP and further reductions after CPB than those in the Placebo group; however, neither of these assumptions became evident. Contrary to these assumptions, there was no statistical difference between intramyocardial cAMP concentrations before CPB, despite the use of digoxin in more than half of the Milrinone patients. Similarly, the administration of milrinone resulted in larger post-CPB cAMP levels in this group whether or not they received preoperative digoxin. One explanation for this finding is that the dose of digoxin administered to rabbits in the Nagai et al. (49) study was 0.3 mg/kg over five minutes (49). This represents a 10-fold increase over the usual recommended loading dose in humans over a 24-hour period. Additionally, this supramaximal dosing regimen was not evaluated in a human model.

In conclusion, this study showed that the administration of milrinone at the initiation of CPB increases myocardial cAMP and suggests that it may facilitate recovery of ventricular function after aortic cross-clamping. Additional evidence is required to determine whether or not the concept of synergistic up-regulation of cAMP with the combination of ßAR agonists and PDE-III inhibitors facilitates weaning from CPB, as previously suggested by Levy et al. (35) Likewise, further studies are necessary to address whether incrementally increased intramyocardial cAMP concentrations at the end of CPB correlate with improved hemodynamics and decreased need for conventional inotropes.


   Acknowledgments
 
Supported in part by the I. Heermann Anesthesia Foundation.


   Footnotes
 
Presented in part at the 21st annual meeting of the Society of Cardiovascular Anesthesiologists, Chicago, IL, April 24–28, 1998, and the International Anesthesia Research Society 74th Clinical and Scientific Congress, Honolulu, HI, March 10–14, 2000.

1Booth J, Chesnut L, White W, et al. Acute myocardial ß-adrenergic receptor desensitization in a canine model during CPB: mechanisms and therapeutic implications [abstract]. AnesthAnalg 1997;84:SCA1. Back


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Accepted for publication February 7, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press