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Departments of *Anesthesiology and Intensive Care Medicine and
Cardiac Surgery, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany
Address correspondence and reprint requests to Prof. Dr. Joachim Boldt, Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, Ludwigshafen, Germany. Address e-mail to boldtj{at}gmx.net
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Abstract |
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plasma levels), renal function (creatinine clearance, urine concentrations of N-acetyl-ß-D-glucosaminidase), myocardial ischemia (creatine-kinase MB and troponin T plasma levels), inflammation (elastase, interleukin-6 and -8 plasma levels), and endothelial integrity (adhesion molecules plasma levels) were assessed at baseline, before and after cardiopulmonary bypass (CPB), and in the intensive care unit until the first postoperative day. Catecholamine requirements were significantly less in the treated than in the nontreated patients. Heart rate was significantly slower, cardiac index was higher, and gastric-arterial CO2 gap was significantly lower in the treatment group. Troponin T, ß-N-acetyl-ß-D-glucosaminidase, glutathione transferase-, and soluble adhesion molecules increased significantly in the untreated control, but remained almost normal in the esmolol+enoximone patients. Inflammatory responses (elastase/interleukins) were attenuated by esmolol+enoximone. We conclude that, in comparison to an untreated control, the prophylactic use of a combination of esmolol and enoximone in elderly patients undergoing cardiac surgery with cardiopulmonary bypass resulted in overall beneficial effects on postbypass hemodynamic status, organ function, inflammatory response, and endothelial integrity. IMPLICATIONS: Compared with an untreated control group, the prophylactic use of an IV combination of the ß-adrenergic blocker, esmolol, and the phosphodiesterase III inhibitor, enoximone, in elderly patients undergoing cardiac surgery with cardiopulmonary bypass resulted in beneficial effects on postbypass hemodynamic status, splanchnic perfusion, organ function, as well as inflammatory response and endothelial integrity.
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Introduction |
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The complexity of the pathogenesis of postbypass organ failure may offer many opportunities for pharmacological interventions. Prevention of perioperative myocardial ischemia represents an important approach to improve postoperative outcome. At present, use of ß-adrenergic blockers seems to be the most effective regimen to reduce cardiac morbidity and mortality (1–4). Use of ß-receptor stimulating substances (e.g., epinephrine) is often needed in cardiac surgery patients to treat myocardial pump failure and subsequently prevent low output syndrome. Because catecholamines show reduced efficacy in ß-blocked patients, use of phosphodiesterase (PDE) III inhibitors is an interesting alternative to catecholamines in this situation (5). Secondary to their vasodilatory properties, these drugs may also improve organ perfusion and microcirculatory blood flow (6–8).
Increased cyclic nucleotides adenosine monophosphate, guanosine monophosphate related to PDE III inhibition or ß-adrenergic stimulation may be associated with increased incidence of dysrhythmias, especially in ischemic tissues or during reperfusion (9). ß-Adrenergic blockers have been shown to be of benefit in protecting patients from sudden death, but do have considerable negative inotropic effects. This may limit their use in patients who are at risk to develop low output failure. Thus, it seems reasonable that a combination of both approaches (PDE III-induced positive inotropy and ß-receptor blockade) might offer advantages by producing beneficial effects and by compensating each other’s limitations in a complementary manner (10,11). The present study was designed to assess whether the prophylactic use of a combination of the IV ß-adrenergic blocker esmolol with the PDE III inhibitor enoximone before CPB possesses protective properties in elderly patients undergoing cardiac surgery.
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Methods |
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When heart rate (HR) was >70 bpm before anesthesia, the patients were randomly assigned to 2 groups: 21 patients received a combination of IV ß-adrenergic blocker esmolol (aim: HR <70 bpm; Baxter, Unterschleissheim, Germany) plus the PDE III inhibitor enoximone (initial bolus of 0.5 mg/kg followed by a continuous infusion of 2.5 µg · kg–1 · min–1; Myogen, Bonn, Germany) (esmolol+enoximone group). Infusions were started after induction of anesthesia (after baseline measurements had been obtained) and were continued until the morning of the first postoperative day (POD). Another 21 patients received saline solution as placebo (control group).
Weight-related doses of sufentanil, midazolam, and pancuronium bromide were used to induce and maintain anesthesia. Controlled mechanical ventilation was used in all patients. Ventilation patterns were adjusted to keep arterial oxygen saturation >95% (measured by continuous pulse oximetry) and CO2 between 35 and 40 mm Hg (measured by continuous capnometry).
CPB was performed using a nonpulsatile pump and a membrane oxygenator (Optima XPTM; Stöckert Instrumente, Munich, Germany). The (nonheparinized) circuit was primed with 1000 mL of Ringer’s solution plus 500 mL of gelatin. Standard large-dose aprotinin regimen was used in all patients (2 million units as an initial loading dose followed by a continuous infusion of 500,000 U/h). Temperature was kept at almost normothermia (target bladder temperature: 33°–35°C). A flow rate of 2.4 L/min · m2 was maintained continuously. If necessary, norepinephrine was given to keep perfusion pressure during CPB between 50 and 60 mm Hg. Ringer’s solution was added to the circuit to maintain filling volume. When hemoglobin was <7 g/dL, packed red blood cells were administered. As much pump blood as necessary to keep pulmonary capillary wedge pressure (PCWP) between 12 to 15 mm Hg was infused during weaning off bypass. After CPB, the residual blood remaining in the extracorporeal circuit was concentrated using a cell salvage device and the autologous blood was retransfused until the end of the operation. Shed mediastinal blood was not retransfused in the postoperative period.
After surgery, all patients were transferred to the intensive care unit (ICU). Controlled mechanical ventilation was continued for at least 4 h. Tracheal extubation was performed when hemodynamics were stable for 1/2 h, temperature was >36°C, and the patient breathed spontaneously with adequate blood gas analyses. PCWP was kept between 12–15 mm Hg by administrating gelatin. Dobutamine was administered when mean arterial blood pressure (MAP) was <60 mm Hg, cardiac index (CI) was <2.0 L · min–1 · m2, and systemic vascular resistance (SVR) was >1200 dyne · s · cm–5. Target for CI was 2.0–3.0 L · min–1 · m–2. Epinephrine was administered when MAP was <60 mm Hg, CI was <2.0 L · min–1 · m2, and SVR was <1000 dyne · s · cm–5 despite sufficient volume infusion (PCWP 12–15 mm Hg). Target for CI was 2.0–3.0 L · min–1 · m–2. Norepinephrine was administered when SVR was <600 dyne · s · cm–5 and MAP was <60 mm Hg (target for SVR: 600–1000 dyne · s · cm–5). No steroids or nonsteroidal antiinflammatory drugs were given throughout the investigation period.
Patients’ entire perioperative management was performed by anesthesiologists and intensivists who were not involved in the study and blinded to the grouping.
Intra- and postoperative hemodynamic monitoring included continual measurement of HR, MAP, pulmonary artery pressure, PCWP, central venous pressure, and cardiac output (CO, thermodilution technique using a pulmonary artery catheter); derived hemodynamic variables (SVR, CI) were calculated from standard formulas.
Splanchnic perfusion was assessed by monitoring gastric mucosal partial pressure of carbon dioxide (PrCO2) using continuous gas tonometry (TonocapTM; Datex, Helsinki, Finland) and a gastric tonometric TRIP-catheter (Tonometrics; Datex). Difference of gastric PCO2 and arterial PaCO2 difference was calculated (CO2 gap).
Myocardial ischemia was assessed by measuring troponin T plasma levels (normal values: <0.1 ng/mL) and creatine-kinase MB mass (CK-MB; normal <6% from total CK plasma levels) using routine laboratory techniques.
Renal function was assessed by measuring serum and urine creatinine concentrations (Jaffé reaction) and creatinine clearance were calculated (Ucrea x Uvol/Pcrea x duration of urine collection period [Ucrea = urine creatinine concentration, Uvol = urine volume during the collection period, Pcrea = serum creatinine concentration]). Urine concentrations of N-acetyl-ß-D-glucosaminidase (ß-NAG; measured by a spectrophotometric method [Hoffmann La-Roche, Basel, Switzerland; normal values in healthy volunteers: <7 U/L]) were measured to assess tubular integrity. ß-NAG is a sensitive marker of lysosomal tubular damage, it is derived from the proximal tubule, and indicates minor and reversible tubular lesions (12,13). Collection periods of urine were from baseline to end of surgery, from end of surgery to 5 h after surgery, and from 5 h after surgery to 8:00 AM on the first POD.
Glutathione transferase (GST)- (quantitative enzyme immunoassay [Enzyme Immunoassay HepkitTM; Biotrin, Dublin, Ireland], reference range of GST- is 0–7.5 µg/L) plasma levels were measured to assess liver function. GST- has been reported to be more sensitive to evaluate hepatocellular damage than conventional markers for assessing liver function (14).
Endothelial function was assessed by measuring plasma levels of soluble (s) adhesion molecules from arterial blood samples (sE-selectin, normal values: <30 ng/mL; vascular cell adhesion molecule-1 [sVCAM-1], normal values: <550 ng/mL; intercellular adhesion molecules [sICAM-1], normal values: 60 ng/mL). Measurements were done with commercially available solid-phase enzyme-linked immunosorbent assay kits based on the sandwich principle (Diagnostic International, Schriesheim, Germany). All analyses were performed in duplicate according to the instructions of the manufacturer by a single operator who was blinded to the grouping of the patients.
To assess the degree of inflammation, plasma levels of polymorphonuclear (PMN)-elastase (Merck, Darmstadt, Germany) as well as interleukin (IL)-6 and IL-8 were measured in duplicate from arterial blood samples using commercially available solid-phase two-site chemiluminescent enzyme immunometric assays (Diagnostic Product Corporation, Los Angeles, CA). Normal values (measured in healthy volunteers) for PMN-elastase are 29–86 µg/L, for IL-6 <5 pg/mL, and for IL-8 <60 pg/mL.
Measurements were performed after induction of anesthesia before esmolol+enoximone administration was started (T0), immediately before start of CPB (T1; only hemodynamics), 30 min after start of CPB (T2, only hemodynamics), 15 min after CPB (T3; only hemodynamics), at the end of surgery (T4), 5 h after surgery in the ICU (T5), and on the morning of the first POD (T6).
A formal sample-size calculation was performed before start of the study. A previous investigation in cardiac surgery patients (15) was used to evaluate the necessary number of patients. A 50% reduction in the increase of soluble adhesion molecules after CPB by administration of the combination of esmolol and enoximone was considered of relevant importance. Using the standard deviation (SD) of sE-selectin, sVCAM-1, and sICAM-1, an error of 0.05 (two-sided) and a type II error of 0.2, 20 patients per group were determined to be necessary.
All data were expressed as mean and SD unless otherwise indicated. An SPSS/PC+ software package was used for statistical analyses (version 4.0; SPSS, Inc., Chicago, IL). All categorical variables were tested by 
2 test. All normally distributed data (tested by Kolmogorov-Smirnov test) were analyzed using Student’s t-test. One- and two-way analysis of variance (ANOVA) with repeated measures and post hoc Scheffé test were used to determine the effects of group, time, and group-time interaction. Mann-Whitney U-test or the Kruskal-Wallis H test was also used when appropriate. A P value < 0.05 was considered significant.
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Results |
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HR was significantly more rapid in the control than in the treatment group. CI, DO2, and 
O2 increased significantly only in the esmolol+enoximone-treated patients and were significantly higher than in the control group until the end of the study period (Table 2).
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Markers of myocardial ischemia (troponin T, CK-MB) increased in both groups, but control patients showed significantly higher plasma levels after surgery and in the ICU than the esmolol+enoximone-treated patients (control: troponin T from 0.1 ± 0.1 to 0.9 ± 0.7 ng/L 5 h after surgery; treatment group: from 0.1 ± 0.1 to 0.4 ± 0.2 ng/L 5 h after surgery) (Fig. 1).
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plasma levels were within normal range at baseline in both groups (Fig. 3). They increased only in the control patients (from 4.8 ± 1.1 to 15.3 ± 3.0 U/L).
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Discussion |
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Hemodynamic and biochemical markers of myocardial dysfunction and of regional ischemia immediately after surgery and in the ICU portrayed adverse outcome in the elderly cardiac surgery patient. The major results of the present study were that prophylactic IV administration of the ß-adrenergic blocker esmolol and PDE III inhibitor enoximone in our elderly patients resulted in overall beneficial effects on hemodynamics, inflammation, endothelial integrity, and organ function in comparison to an untreated control group.
Our understanding of the inflammatory reactions to CPB has been improved in recent years, enabling the development of novel therapies focused on reducing the inflammatory response (19,20). Cytokines and adhesion molecules have a central role in the inflammatory response in this situation (21). For example, IL-8 attracts and activates PMN leukocytes, it is crucial in the formation of pulmonary and myocardial ischemic-reperfusion injury as well as in proximal tubular injury after CPB. Therefore, pharmacological manipulation of whole body inflammatory response has received some attention in the cardiac surgery patient (22). Many approaches have been tried to selectively block certain cytokines, but most of these specific regimens have failed. We used PDE III inhibitors because they not only provide beneficial hemodynamic effects, but an increase of intracellular cyclic adenosine monophosphate and/or cyclic guanosine monophosphate concentration by inhibition of PDE has also been shown to beneficially modulate inflammatory response (23). These antiinflammatory capabilities may offer another potential mechanism for clinical efficacy of PDE III inhibitors (5,7). In experimental studies, enoximone inhibited FMLP (methionyl-leucyl-phenylalanine)-stimulated neutrophil oxygen radical production indicating oxygen free radical scavenging (24). In septic shock patients, treatment with the PDE III inhibitor enoximone (2.5–10 µg · kg–1 · min–1) resulted in increased hepatosplanchnic O2, increased indocaine metabolism, and decreased release of hepatic tumor necrosis factor- indicating improved hepatosplanchnic function and antiinflammatory properties (25). Administration of enoximone (5 µg · kg–1 · min–1) started before CPB and continued for the following 24 hours diminished endotoxin levels in liver venous blood indicating beneficial effects on tissue damage and barrier function of the gut (26).
PDE III inhibitors, however, may increase myocardial oxygen consumption and may have (fatal) dysrhythmogenic effects, especially during myocardial ischemia or reperfusion (27). Because ß-adrenergic blockers have important antiarrhythmic properties and may reduce apoptic myocardial cell death (28), a combination of both substances in this situation may be useful. In our elderly patients, markers of myocardial ischemia (troponin T, CK-MB) in the postbypass period were significantly less increased in esmolol+enoximone-treated patients than in the untreated control group. This myocardial protective effect may be attributed to the use of the ß-adrenergic blocker, but the PDE III inhibitor may have also contributed to this effect because an increase in (myocardial) blood flow has been shown with this agent (6–9).
The beneficial effects of ß-adrenergic blocking substances is primarily related to HR reduction. Aside from this cardioprotective effect of ß-adrenergic blockers, this class of compounds may produce additional cellular effects by inhibition of protein kinases. By this mechanism, ß-adrenergic blockers affect endothelin synthesis, neutrophil chemotaxis, inflammation, nitric oxide synthesis, and other functions (29,30). In a retrospective database analysis covering approximately 2500 patients undergoing coronary artery bypass graft surgery, perioperative use of ß-adrenergic antagonists was associated with a substantial reduction in the incidence of postoperative neurological complications (31). These results indicated a potential neuroprotective effect of ß-adrenergic blockers in cardiac surgery patients aside from their myocardial properties.
Not only the heart and macrocirculation have profited from the prophylactic use of esmolol+enoximone in our study. Kidney and liver function were also preserved from the negative influence of CPB. This beneficial effect on organ function may mainly be attributed to the effects of PDE III inhibitors on (micro-) perfusion. Despite similar loading conditions (similar PCWP and central venous pressure) - and ß-receptor agonists were needed in several of our control patients to improve myocardial performance and to guarantee perfusion pressure in the postbypass period. Catecholamines, however, may have negative effects on organ perfusion. PDE III inhibitors increase CO through combined positive inotropic and vasodilative effects ("inodilators"). Because altered microperfusion is an important mechanism for deteriorated organ function in the postbypass period, maintenance of adequate blood flow by the PDE III inhibitor may be an important maneuver.
The microvasculature is a key battleground for inflammatory processes, and there is evidence of a central role for the endothelium in modulating inflammation. The endothelium is not only an inert cellular layer; endothelial cells actively and reactively participate in inflammation and hemostasis (32). Both leukocytes and endothelial cells express particular adhesion molecules that are responsible for the cell-cell interactions. Trafficking and migration of leukocytes across the vascular endothelial barrier into tissues is modulated by this cell-cell interplay. The release of soluble adhesion molecules into the circulation correlated with the degree of trauma depending on the associated ischemia/reperfusion injury (33). An increased expression of adhesion molecule L-selectin (of more than double of baseline values) was seen after CPB (34). In an experimental study using human umbilical vein endothelial cells, the expression of ICAM-1 increased by 300% ± 41% in the presence of lipopolysaccharide and hypoxic conditions (35). It is widely accepted that CPB is associated with the risk of large increase in lipopolysaccharide plasma levels and tissue hypoxia (26). Plasma levels of all measured circulating adhesion molecules were significantly lower in our treated than in the control patients, indicating less endothelial injury in the esmolol+enoximone group. This may have been attributed either to the reduced inflammatory response as proinflammatory cytokines induced expression and release of adhesion molecules (36) or to improved (micro-) circulation that attenuated development of tissue hypoxia (35).
Organ protection should start as early as possible preoperatively and should be continued during the entire perioperative period (26). Thus, we started administration of esmolol+enoximone immediately after induction of anesthesia, more than one hour before the start of CPB. Because the decrease in CO by ß-adrenergic blockers may limit their use in patients with reduced myocardial function, we selected esmolol as the ß-adrenoceptor antagonist because of its short half-life that facilitates control of ß-blocking effects.
The beneficial, organ-protective effects of the combination of ß-adrenergic blockers and PDE III inhibitors in our elderly cardiac surgery patients have been confirmed in noncardiac surgery patients: long-term use of the ß-adrenergic blockers carvedilol and metoprolol in patients with chronic heart failure inhibited the favorable hemodynamic effects of dobutamine, whereas administration of the PDE III inhibitor enoximone resulted in improved hemodynamics in these patients (10,11).
No beneficial effects on outcome of the prophylactic use of the combination of esmolol and enoximone have been shown in our elderly patients. The study population was too small to detect significant differences in outcome (mortality), and outcome was not the major focus of this study. The beneficial effects on postbypass morbidity (e.g., organ function, endothelial integrity, inflammatory response), however, revealed some promising effects of this combination.
We conclude that the combination of the IV ß-adrenergic blocker esmolol and the PDE III inhibitor enoximone showed organ-protective properties (myocardium, kidneys, liver) in elderly patients undergoing cardiac surgery using CPB. Inflammatory response was attenuated and endothelial integrity and organ function were improved by administration of the combination of esmolol and enoximone. Large prospective randomized trials will be required to determine whether this approach improves outcomes.
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Footnotes |
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