Booth, John V. MBChB, FRCA*; Ward, Erin E. BS*; Colgan, Kelly C. BS‡; Funk, Bonita L. BS*; El-Moalem, Habib PhD*; Smith, Michael P. BS*; Milano, Carmelo MD†; Smith, Peter K. MD†; Newman, Mark F. MD*; Schwinn, Debra A. MD*
Despite improvements in cardiac surgical and anesthesia techniques, myocardial dysfunction is still common after coronary artery bypass graft (CABG) surgery. Depressed myocardial function can result in difficulty in separation from CPB, the need for inotropic drugs, and increased morbidity and cost (1). Cardiac surgery requiring cardiopulmonary bypass (CPB) results in significant impairment of β-adrenergic receptor (βAR) function and is one of the causes of depressed myocardial function after cardiac surgery (2). Possible mechanisms underlying impaired βAR function include myocardial ischemia-reperfusion injury (3–5), hibernating and stunned myocardium (6,7), and acute myocardial βAR desensitization (8–10). Previous studies have indicated that a major mechanism behind acute βAR desensitization is the markedly increased catecholamine levels found during cardiac surgery (8,11,12) resulting in agonist-induced desensitization. We have previously demonstrated that acute administration of βAR blocker during CPB in an animal model of CABG surgery attenuates βAR desensitization (13), whereas chronic oral β-adrenergic blocker therapy in patients undergoing CABG surgery does not protect patients from acute βAR desensitization (8). We now propose to test whether acute IV administration of βAR blocker in humans during CABG surgery can reduce acute myocardial βAR desensitization. Our hypothesis is that IV metoprolol, administered immediately before CPB, results in the attenuation of acute myocardial βAR desensitization. In addition, we examined a number of secondary clinical end-points potentially affected by βAR antagonists, such as incidence of supraventricular arrhythmias (SVA) and postoperative inotropic drug use.
Patients were enrolled after IRB approval and informed consent from the patient population undergoing primary CABG surgery at Duke University Medical Center. Exclusion criteria included history of severe hepatic dysfunction (βAR antagonists are metabolized predominately by the liver), history of bronchospasm requiring daily bronchodilator therapy, pregnancy, preoperative inotropic drug use, or off-pump coronary surgery. Two separate and consecutive studies were performed. First, a randomized placebo-controlled trial (n = 72 patients) was performed whereby patients were administered either IV metoprolol 10 mg or placebo given immediately before initiation of CPB. Myocardial atrial samples were obtained just before metoprolol or placebo administration and immediately before termination of CPB; myocardial samples were analyzed for evidence of βAR desensitization. This study had sufficient power to detect a 20% difference in βAR desensitization between groups. From this study it was clear that 10 mg metoprolol did not prevent acute myocardial βAR desensitization. Therefore, a second dose-finding study was conducted. We chose the dose-finding methodology as opposed to a randomized-controlled trial because the effective dose of metoprolol required to prevent desensitization was not known. In this study, 2 consecutive groups of patients (n = 20 each) were given 20 mg or 30 mg of metoprolol. At 20 mg of metoprolol, adenylyl cyclase assays were performed to test whether acute βAR desensitization had been attenuated as evidenced by a decrease of cyclic adenosine monophosphate (cAMP) response of 10% or less. If this end-point was not achieved, the dose was increased to 30 mg. We did not feel comfortable using doses larger than 30 mg in the setting of CPB as the literature was devoid of safety data on larger doses and we had no clinical experience of using doses larger than 30 mg. In addition, if serious adverse events were reported to the principal investigator (Dr. Schwinn), the study would be suspended while the data would be reviewed. The study was performed on an intention-to-treat basis with identical primary and secondary outcomes.
IV, radial artery, and pulmonary artery (PA) occlusion catheters were placed in all patients. Induction and maintenance of anesthesia was accomplished with midazolam (2–5 mg), fentanyl (1000–1500 μg), pentothal (200–400 mg), and isoflurane (0.5%–1.5%) followed by placement of a transesophageal echocardiography (TEE) probe. All patients underwent non-pulsatile CPB, cooling to 32°C–34°C before rewarming. Data collection occurred as follows (schematic in Fig. 1):
1. Pre-CPB: ejection fraction (EF) determined from TEE immediately before initiation of CPB followed by a biopsy of the right atrium on atrial cannulation.
2. CPB initiation: administration of study drug or placebo over 1 min on initiation of CPB.
3. CPB termination: atrial biopsy immediately before separation from CPB (carefully obtained so that ischemic areas from the suture lines and distal were not included) before any inotropic drug administration.
4. Post-CPB: EF via TEE 10 min postcompletion of protamine administration with central venous pressure and PA diastolic pressures carefully matched to pre-CPB levels.
Atrial biopsies were each immediately snap-frozen in liquid nitrogen and stored at −80°C until assayed. Atrial biopsies were collected rather than ventricular biopsies for ethical reasons. There are a many studies supporting a similar response to agonist in atrium and ventricle (14–16), as well as in circulating lymphocytes (12,17).
Before separation from CPB, patients were rewarmed to a nasopharyngeal temperature of at least 36°C and the heart rate was optimized with epicardial pacing as needed. Hematocrit was maintained ≥0.25. Preload and afterload were optimized by fluid administration and vasoactive drugs. Inotropic drugs were added if clinically indicated to maintain a cardiac index more than 2.0 L/min/m2. If inotrope use was deemed necessary by the attending anesthesiologist, dopamine was instituted at 5 μg · kg−1 · min−1 as a first-line drug, followed if necessary by epinephrine as second-line treatment; milrinone or intraaortic balloon counterpulsation were classified as third-line interventions. Only dopamine doses larger than 2.5 μg · kg−1 · min−1 were defined are inotropic (18,19). Hemodynamic data (heart rate, rhythm, mean arterial blood pressure [MAP], PA diastolic pressure, cardiac output and index) were collected at the following intervals: before anesthetic induction (baseline), immediately before commencement of CPB, after separation from CPB, on arrival in the intensive care unit (ICU), and at 4 h, 8 h, 16 h, and 24 h after admission to the ICU. Patients receiving preoperative β-adrenergic blockers had their therapy reinstituted on the first day postoperatively as per standard Duke protocol for heart rate >60 bpm and MAP >70 mm Hg. Supraventricular tachycardia were documented by 12-lead ECG.
Atrial membrane adenylyl cyclase activity was assessed using the method of Salomon et al. (20), as modified and described previously (2). Briefly, 20 μL atrial membranes were incubated in triplicate with either water (basal), 100 μM isoproterenol (ISO-MAX), 500 ηM isoproterenol (ISO-EC50), 100 μM zinterol (a selective β2AR agonist), 10 mM sodium fluoride (mixed in a glass tube), or 5 mM manganese for 15 min at 37°C in a 50-μL reaction mixture. The reaction mixture contained the following final drug concentrations: 30 mM Tris, 5 mM MgCl2, 0.8 mM EDTA, 0.12 mM adenosine triphosphate, 0.06 mM guanosine triphosphate, 2.8 mM phosphoenol-pyruvate, 50 μg/mL myokinase, 0.1 mM cAMP, 10 μg/mL pyruvate kinase, and 1 μCi α[32P]adenosine triphosphate. The reaction was stopped with 1 mL stop buffer (360 μm adenosine triphosphate, 285 μM cAMP, and 25,000 cpm/mL [3H]-cAMP). [32P]cAMP was isolated by sequential chromatography over Dowex columns using 1 mL alumina, and individual column recovery was normalized based on the recovery of a known amount of [3H]cAMP added to the stop buffer; routine recovery is approximately 75%–80%. Samples were eluted off alumina columns with 0.1 M imidazole into 15 mL scintillation cocktail and counted with a dual-channel liquid scintillation counter (Wallac Inc., Gaithersburg, MD). This resulted in a linear accumulation of [32P]cAMP with respect to time, protein, and temperature. Final results were reported as pmol cAMP/mg total protein/15 min.
βAR density was determined using standard single point ligand binding techniques and as described previously (8). A single concentration of antagonist was used because of limitations in sample size. Briefly, assays were performed in triplicate with a saturating concentration (275 pM) of [125I]-cyanopindolol (Dupont, Boston, MA). Propranolol (1 μM; Sigma Chemical, St. Louis, MO) was used to determine nonspecific binding.
The primary end-point of this study was determined prospectively to be βAR signaling (isoproterenol-stimulated adenylyl cyclase activity), with major clinical end-points being inotropic support and SVA. Inotropic support was measured as cumulative dose sums, inotrope hours, and percentage of patients receiving inotropes. Other comparisons are considered descriptive, including hemodynamic variables and baseline pre-operative characteristics.
Data were tested for normal distribution, then either Wilcoxon’s two-sample rank sum test or Student’s t-test was used to test differences between different metoprolol doses and placebo in continuous demographic data, ISO-stimulated cAMP production, serum creatinine levels, hours in ICU, βAR receptor expression, cardiac output at each time point, inotrope hours, length of hospital stay, and hours intubated. Fisher’s exact test was used to study the unadjusted association between group and the binary variables, including percentage of patients on inotropes, SVAs, 5% reduction of ISO-stimulated adenylyl cyclase activity, 10% reduction of ISO-stimulated adenylyl cyclase activity, and gender. Logistic regression was used to model inotrope hours and SVAs at each time point separately as a function of group and other covariates that included gender, age, race, congestive heart failure (CHF), body surface area (BSA), EF, aortic cross-clamp time, CPB time, hypertension, and diabetes mellitus. Generalized estimating equations logistic regression was used to study the rhythm response at the different time points as a function of group and covariates mentioned above. SAS software version 8.2 (SAS, Cary, NC) was used to analyze the data. A P value < 0.05 was considered significant. Data are presented as mean ± sd.
To determine whether groups were similar with regard to preoperative and intraoperative characteristics, general characteristics such as age, BSA, gender, perioperative EF, and creatinine were examined; all were similar between groups (Table 1). In addition, comorbities such as diabetes, congestive heart failure (CHF), and hypertension, as well as preoperative use of βAR antagonists and angiotensin converting enzyme (ACE) inhibitors, were similar. In terms of intraoperative characteristics, all groups showed similar CPB times, aortic cross-clamp times, and number of coronary artery distal grafts (Table 2).
To confirm hemodynamic effects of acute administration of β-adrenergic blockers in this setting, relevant clinical outcomes such as cardiac output and inotrope use were measured. Cardiac output remained similar in each group throughout the intraoperative and postoperative period, demonstrating no detrimental effect of β-adrenergic blockers on this variable (Table 2 and 3). In addition, the percentage of patients in each group receiving inotropes was not statistically different between groups, although there was a tendency for more inotropic drug use in the metoprolol 20 and 30 mg groups (Table 2).
To test the primary hypothesis of attenuated βAR desensitization, we tested whether maximal or sub-maximal ISO-stimulated adenylyl cyclase activity was altered between groups. When examined as a continuous variable, all groups showed similar percentage decreases in ISO-stimulated adenylyl cyclase activity, i.e., percentage desensitization (percentage change from baseline: placebo, −18% ± 8%; metoprolol 10 mg, −24% ± 8%; metoprolol 20 mg, −13% ± 17%; metoprolol 30 mg, −21% ± 9%;Table 2). Figure 2 plots the percent βAR desensitization between placebo and each metoprolol group. In addition, when βAR desensitization was examined as a dichotomous variable, all groups were similar with regard to percentage of patients with >10% βAR desensitization (Table 2). Mean myocardial βAR density was 51 ± 19 fmol/mg protein and percent change in βAR density (Pre-CPB to End-CPB) was not significant in any group of patients (placebo, −9%; metoprolol 10 mg, −8%; metoprolol 20 mg, −6%; and metoprolol 30 mg, −8%).
The incidence of SVA was different among groups. Specifically, there was a dose-dependent effect in that those patients receiving metoprolol 20 or 30 mg had significantly less SVAs in the 24 h postsurgery than those receiving metoprolol 10 mg or placebo (placebo, 10%; metoprolol 10 mg, 15%; metoprolol 20 mg, 0%; metoprolol 30 mg, 5%;Table 3). The study was not specifically powered for this outcome. Other outcomes such as length of stay in the ICU, number of hours intubated, and length of hospitalization were also similar among groups (Table 3).
The results from this human study are surprising. We expected some degree of attenuation of myocardial βAR desensitization based on our previous animal work (13). However, the main results from this study contrast with our previous dog study in that metoprolol does not appear to attenuate myocardial βAR desensitization in humans during CABG surgery.
Myocardial βAR desensitization (also called “dampened βAR signal transduction”) can occur as a result of changes in the receptor, changes in proteins involved in the signal transduction pathway, or both. Three mechanisms are involved in βAR desensitization at the receptor level (21): uncoupling (disruption of receptor/G protein complex) (22,23), sequestration (movement of receptor from the cell surface to intracellular compartments) (24,25), and down-regulation (complex interplay between depressed receptor synthesis and destruction of sequestered receptors) (24). These processes are thought to result from receptor phosphorylation by various kinases (second messenger stimulated kinases, protein kinase A and protein kinase C) as well as G protein-coupled receptor kinases (22,23). Elegant work over the last two decades examining mechanisms underlying βAR desensitization suggests that sympathetic activation leads to increased transmyocardial concentrations of norepinephrine and dampened βAR signal transduction (21,24). Thus our hypothesis: prevention of sympathetic activation of myocardial βARs using βAR antagonists would attenuate myocardial βAR desensitization.
Perioperative changes in βAR function could result form a number of etiologies including ischemia and desensitization. Several studies have examined mechanisms underlying the effect of isolated myocardial ischemia on βAR signal transduction. The capacity of βAR agonists to stimulate adenylyl cyclase activity is enhanced during the first 15 minutes of myocardial ischemia because of acutely increased cell surface βAR density (26,27). With sustained ischemia, however, ISO-stimulated adenylyl cyclase activity decreases to less than control values, although βAR density remains increased (28). During CABG surgery, aortic cross-clamp placement induces a reversible functional impairment of βAR signaling in myocardium in vivo, and we have previously demonstrated acute reduction in left ventricular myocardial βAR responsiveness at CPB termination despite stable βAR density in both dogs and humans (2,8,9). In these studies ISO (β-receptor level), sodium fluoride (Gs level), and manganese (adenylyl cyclase level) stimulated adenylyl cyclase activity was dampened; therefore, impaired myocardial βAR responsiveness to agonists during CPB is attributable to heterologous desensitization because the dampening included impairment of nonreceptor components of the signal transduction cascade (29).
A study by Ungerer et al. (30) provides a possible mechanism for βAR dysfunction in the setting of acute myocardial ischemia. This study, using isolated perfused rat hearts, demonstrates time-dependent (10–15 minute) increased βARK activation (βARK is a βAR specific kinase responsible for receptor phosphorylation and desensitization) corresponding to functional inactivation of the βAR system occurring within the 15th to 30th minute of isolated ischemia. In the same time frame, other serine/threonine kinases, such as protein kinase C, have been shown to be activated during myocardial ischemia (31). Ungerer et al. also found that norepinephrine, perfused through the heart, increases membrane βARK activity during normoxia, implying that receptor activation itself triggers translocation of the enzyme. Furthermore, in perfusion of ischemic hearts treated with desipramine before ischemia (desipramine suppresses ischemic nor-epinephrine release by almost 75%) (32), βARK activity was suppressed compared with ischemic untreated hearts. Thus agonist occupation of cardiac βARs during ischemia leads to induction and intracellular translocation of βARK to the cell membrane.
In adult humans, βAR dysfunction after cardiac surgery occurs in the clinical setting of significant acute myocardial ischemia resulting in increased (2–20 fold) catecholamine concentrations (2,8,9,11,33). Recently, Lee et al. (34) demonstrated that a single dose of 37.5 mg intrathecal bupivacaine prevents acute myocardial βAR desensitization and is associated with reduced plasma catecholamine levels (45). These data, together with the study of Ungerer et al. (30), indicate that increased myocardial catecholamine concentrations may, at least in part, be the stimulus for myocardial hyporesponsiveness seen during cardiac surgery. In support of this, blockade of βARs with small dose βAR antagonist therapy has been shown to improve myocardial function in CHF (35–37), a clinical setting wherein attenuation of chronic βAR desensitization has been postulated as a possible mechanism. In addition, Cork et al. (38) demonstrated improved early intermediate outcomes (such as cardiac output) immediately post-CPB in patients receiving an intraoperative β-adrenergic blocker.
The primary hypothesis of this study was to investigate whether intraoperative metoprolol attenuates myocardial βAR desensitization. We demonstrated that ISO-stimulated adenylyl cyclase activity is reduced similarly post-CPB in all groups; thus, βAR desensitization was not attenuated by intraoperative administration of metoprolol. Our previous work demonstrated that chronic βAR antagonists did not prevent acute myocardial βAR desensitization (8). An explanation for this finding might be that clinically effective doses of preoperative βAR antagonists may not be present in sufficient concentration during CPB to prevent binding of extremely large concentrations of myocardial catecholamines generated during aortic cross-clamp, especially as cold inactivates monoamine oxidase and catechol-O-methyltransferase (33,39), further increasing myocardial catecholamine levels. Therefore, all patients, regardless of administration of preoperative βAR antagonists, appear to be at risk for acute intraoperative myocardial βAR dysfunction.
These findings are in contrast to our previously published animal model (13). A possible explanation of our findings is that we were unable to provide a sufficient concentration of β-adrenergic blocker to antagonize adrenergic receptors on the myocardium. We limited the maximum metoprolol dose to 30 mg because of our concern that larger doses might be associated with bradycardia and negative inotropic effects that would continue into the post-CPB period. We were cognizant of the potential dose-response aspect of metoprolol; thus we designed our study in a dose-finding method to demonstrate clinical effect, biological effect, and also to ensure the safe use of β-adrenergic blockers in the intraoperative period. In fact, an increased requirement for intraoperative epicardial pacing for slow ventricular rate was seen in patients receiving 30 mg of metoprolol, preventing us from escalating to a larger dose of β-adrenergic blocker. We chose metoprolol for this study because it is relatively β1AR selective and high lipophilic, has a moderate duration of action, and is readily available. Both lipophilicity and selectivity of βAR blockers have been shown to confer survival benefit over nonselective and poorly lipid soluble drugs such as propranolol and atenolol in CAD patients (40).
One possible explanation for the failure of metoprolol to attenuate βAR desensitization after CABG with CPB is that βAR stimulation by increased catecholamines may not be the only cause of impaired βAR signaling. Non-catecholamine mediators have been implicated in the etiology of impaired βAR signaling after cardiac surgery (41), whereas others have shown that proinflammatory cytokines can induce acute βAR desensitization (42). In addition, myocardial ischemia itself impairs adenylyl cyclase activity (27,28,31). Although prevention of catecholamine activation by spinal anesthesia has been shown to prevent βAR desensitization after CABG surgery, the prevention of indirect pathway activation could be responsible for the attenuation of βAR desensitization in this setting (34). Therefore, it is likely that multiple mechanisms are involved in acute heterologous myocardial βAR desensitization in humans after CABG.
It is interesting that in this present research, and in our previous human study describing the occurrence of acute myocardial βAR desensitization (13), there seemed to be widespread variation in βAR response to CPB. That is, some patients had very little or no desensitization whereas the majority had significant desensitization. Indeed describing the population as a single entity may not adequately reflect βAR desensitization biology. Six functionally important single nucleotide polymorphisms (SNPs) have been identified in the human β1AR (2 SNPs) and β2AR (4 SNPs) genes. SNPs are base-pair changes that occur reasonably frequently (>1%) in the DNA sequence of an individual. Many SNPs have no functional consequence, although some can alter expression or function of a protein. βAR SNPs include changes that alter receptor down-regulation and desensitization in response to agonist stimulation; clinically, these βAR polymorphisms predispose patients to (or protect them from) hypertension, CHF, and asthma. It is therefore possible that specific βAR SNPs influence acute myocardial βAR desensitization pathways during cardiac surgery. In fact, it may be that βAR antagonist therapy is helpful in some patients with particular βAR SNPs and not in others of a different genotype. Such genetic issues may be a reason why βAR antagonists work to prevent βAR desensitization in dogs and not humans.
Our secondary outcomes included the effect of a single dose of metoprolol on postoperative SVAs. We demonstrate that a single intraoperative dose of metoprolol (20 mg or 30 mg) reduces the incidence of SVAs by 75% compared with placebo up to 24 hours postoperatively. This effect appears to be dose-dependent, in that 20 mg or 30 mg of metoprolol reduces the incidence of SVAs, but 10 mg of metoprolol does not reduce this morbidity. There are perhaps more questions raised by the finding than there are answers. We do note that our incidence of SVAs is relatively small in the control group (10%). This may be attributable to our measurement of SVAs ending 24 hours postoperatively. In addition, our study was inadequately powered to investigate the effect of β-adrenergic blockers on postoperative SVAs. Also, our institutional practice is to commence oral β-adrenergic blocker therapy on the first postoperative day, thus data beyond 24 hours would be difficult to interpret. The peak incidence of SVAs is around the third postoperative day; this may explain the relatively small incidence of SVAs reported in our study compared with other publications (43,44). Overall, it is difficult to clinically interpret the relevance of this finding. Previous studies have noted that β-adrenergic blockers may reduce intraoperative or postoperative arrhythmias; however, there has been concern that a β-adrenergic blocker-induced reduction in postoperative arrhythmias may also result in decreased cardiac output (45,46). In our present study we note that there was no decrease in cardiac output associated with the use of up to 30 mg of metoprolol pre-CPB.
In conclusion, in contrast to our previous animal model of CABG surgery, acute administration of intraoperative β-adrenergic blocker did not attenuate myocardial βAR desensitization. Further work is required to investigate the discrepancy between the animal model and humans undergoing CABG surgery.
The authors graciously thank Ms. Zarrín T. Brooks for expertise in manuscript and figure preparation.
Members of the Duke Heart Center Perioperative Desensitization Group include Robert W. Anderson, MD, Mark P. Anstadt, MD, Joseph E. Arrowsmith, MD, MRCP, FRCA, Beatrice I. Baldwin, CRNA, Harmuth B. Bittner, MD, Fiona M. Clements, MD, Narda D. Croughwell, CRNA, Duane Davis, MD, J. Micheal DiMaio, MD, Francis Duhaylongsod, MD, Joseph M. Forbess, MD, Donald D. Glower, MD, Katherine P. Grichnik, MD, Hilary Grocott, MD, FRCPC, Steven C. Hendrickson, MD, James Jaggers, MD, Robert H. Jones, MD, Bruce J. Leone, MD, James E. Lowe, MD, James R. Mault, MD, Cary H. Meyers, MD, Michael G. Mythen, MD, MBBS, FRCA, Mark F. Newman, MD, Clarence H. Owen, MD, Davis S. Peterseim, MD, Joseph G. Reves, MD, Corey T. Sawchuk, MD, Lynne K. Skaryak, MD, Robert N. Sladen, MB, ChB, Peter K, Smith, MD, Barbara E. Tardiff, MD, Mark Tedder, MD, Christopher M. Watke, MD, Blake E. Wendelburg, MD and Walter G. Wolfe, MD.
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