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Departments of *Anesthesiology and Intensive Care Medicine and Surgery, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany
Address correspondence and reprint requests to Dr. Stefan Suttner, Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen, Germany. Address e-mail to suttner{at}gmx.de.
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Introduction |
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Much of the ischemia during the pre-, intra-, and postoperative periods has been described as being asymptomatic and not associated with increased levels of traditional serum markers of myocardial injury, such as creatine kinase MB fraction or cardiac troponin (5,6). The entire spectrum of ischemic heart disease, including stable and unstable angina without myocyte necrosis is characterized by activation of the natriuretic peptide system (7,8). Natriuretic peptides are produced by the heart and regulate arterial blood pressure, electrolyte balance, and fluid volume (8). Atrial natriuretic peptide (ANP) is synthesized and secreted by the atrial myocardium in response to atrial stretch (9). Brain natriuretic peptide (BNP) is released almost exclusively by the ventricular myocardium in response to increased left ventricular wall tension and volume (7,8). A number of studies in nonsurgical patients with or without symptomatic cardiac disease have demonstrated the diagnostic and prognostic value of these cardiac hormones (7,10–12). The role of the cardiac natriuretic peptides in patients undergoing major surgery and anesthesia has been less extensively studied (13,14).
In this prospective study, we hypothesized that blocking afferent nociceptive inputs by continuous intra- and postoperative TEA would decrease plasma concentrations of BNP in patients requiring major abdominal surgery who were at risk for, or had, CAD.
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Methods |
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Patients were eligible for the study if they 1) were scheduled for major abdominal surgery, 2) could sign informed consent before surgery, and 3) had documented CAD or risk factors for CAD. The presence of CAD was defined as a previous myocardial infarction, typical angina, or atypical angina with a positive stress test. A patient was considered at risk for CAD if they had at least 2 of the following cardiac risk factors: age >65 yr, hypertension, current smoking, a serum cholesterol >240 mg/dL, and diabetes mellitus was present (1).
Exclusion criteria were 1) severe alteration of left ventricular function (ejection fraction <30%), 2) symptomatic mitral or aortic valvular disease, 3) liver dysfunction (alanine aminotransferase, aspartate aminotransferase >40 U/L), 4) renal insufficiency requiring hemodialysis, 5) known allergies to the study drugs, 6) contraindications to dural puncture (chronic back pain or previous lumbar spinal surgery in the area of puncture, localized infection; therapy with antiplatelet drugs <3 days before surgery), and 7) abnormal blood coagulation tests (activated partial thromboplastin time >40 s, international normalized ratio >1.25, fibrinogen concentration <1 g/L, platelet count <150·109/L).
A total of 28 patients received either combined general anesthesia with continuous TEA (n = 14; TEA) or general anesthesia followed by IV patient-controlled analgesia (n = 14; IV PCA). The study was conducted in an open manner because the performance of a sham epidural insertion was considered unethical, given the risk of epidural hematoma formation. Therefore, neither the anesthesiologists nor the nurses taking the measurements were blinded to the patients’ treatment.
Before the study, all patients underwent a routine clinical evaluation that included a detailed medical history, physical examination, laboratory tests, chest radiography, 12-lead electrocardiogram (ECG), and transthoracic echocardiographic examination. Preoperative cardiac medications were continued until the day of surgery. One hour before surgery, all patients were premedicated with oral midazolam 7.5 mg. In the TEA group, after arrival in the operating room and before induction of general anesthesia, an epidural catheter was inserted between the level T2 and T7 using a median approach and loss-of-resistance technique. To exclude placement of the epidural catheter in the intrathecal space, a test dose of 3 mL of mepivacaine 2% was used. Epidural blockade was established with an initial bolus of 10–12 mL of 1.25 mg/mL bupivacaine with 20 µg of sufentanil, depending on patient size and catheter placement. The somatosensory blockade was evaluated by touching the skin with ice and performing the pinprick test. A 20%–30% decrease in systolic blood pressure and heart rate was interpreted as a further sign of effective epidural blockade. The extent of the epidural blockade was recorded. A patient-controlled epidural analgesia pump (Graseby 9300 Ambulante; Smiths Medical, Kirchseeon, Germany) was started to provide a continuous mixture of 1.25 mg/mL bupivacaine and 1 µg/mL sufentanil epidurally (constant rate of 4 mL/h) throughout the operation. Anesthesia in all patients was then induced using weight-related doses of thiopental (3–5 mg/kg), fentanyl (3 µg/kg), and atracurium (0.5 mg/kg). After intubation of the trachea, the lungs were ventilated with 50% O2 in nitrous oxide. Ventilation was controlled with a tidal volume of 8–10 mL/kg and a positive end-expiratory pressure of 5 mm Hg. The ventilatory rate was adjusted to maintain an arterial partial pressure of carbon dioxide (Paco2) of 32 to 42 mm Hg and arterial pH between 7.35 and 7.45. Anesthesia was maintained with isoflurane (0.5–1 minimum alveolar concentration) and additional bolus injections of atracurium. Intraoperative analgesia in both groups was achieved with additional bolus injections of IV fentanyl (0.1 mg) at the discretion of the attending anesthesiologist. Doses for anesthetics were adjusted to provide optimal anesthetic (lack of movement, lacrimation, sweating) and surgical conditions, while maintaining hemodynamic stability. IV ß-adrenergic antagonists were administered intraoperatively and postoperatively to aid in controlling arterial blood pressure and heart rate (target heart rate <90 bpm) and to provide prophylaxis against myocardial ischemia. The administration and dosing of IV ß-adrenergic antagonists were left to the discretion of the attending anesthesiologist. Indications for the use of IV ß-adrenergic antagonists did not differ for patients assigned to the IV PCA group or TEA group. Urinary and evaporative losses were replaced with lactated Ringer’s solution and blood losses were compensated by equal volumes of gelatin (4% modified gelatin, GelafundinTM; B. Braun, Melsungen, Germany). A hemoglobin concentration <8.5 g/dL was defined as the transfusion trigger and mandated the transfusion of 1 U of allogeneic packed red blood cells. Perioperative monitoring included pulse oximetry, continuous monitoring of leads II and V5 of the ECG and automated ST segment analysis, and continuous invasive measurement of mean arterial (MAP) and central venous pressure; pulmonary artery catheters were not used.
Tracheal extubation was planned to occur in the intensive care unit (ICU), and not in the operating room. After surgery, all patients were transferred to the ICU and stayed for at least 24 h. On postoperative days (PODs) 1–3, all patients were visited at least twice daily and on demand by a physician of the acute pain service, who adjusted pain medications in the case of inadequate analgesia. The analgesic regimen in both groups was adjusted to achieve a visual analog scale (VAS; scale from 0 = no pain to 10 = worst pain) pain score <4 during rest and a dynamic pain score (i.e., scoring pain during movement, coughing, or taking deep inspirations) of <6. If necessary, repetitive small IV bolus injections of piritramid (3.75–7.5 mg), a synthetic pure µ receptor agonist with a potency 0.8 times that of morphine, or rectal paracetamol (1 g, 4 times daily) was given on request for additional pain relief in both groups.
Patients in the IV PCA group received IV bolus injections of piritramide—up to 0.1–0.2 mg/kg—until a clear decrease of pain was reached (VAS <4 at rest). After this initial treatment, patients were connected to a PCA pump (Injektomat; Fresenius AG, Oberursel, Germany), which was set to deliver a 2-mg IV bolus of piritramid per demand with a lockout time of 10 min and a maximal dose of 25 mg in any 4-h period, without continuous background infusion. If necessary, bolus doses of piritramid were increased to a maximum of 4 mg but the lockout interval was kept constant. Patients in the TEA group received a continuous 3–5 mL/h infusion of 1.25 mg/mL bupivacaine and 1 µg/mL sufentanil via the epidural catheter for 72 h. Additional bolus doses of 2 mL of 1.25 mg/mL bupivacaine and 1 µg/mL sufentanil, lockout time of 10 min, for on-demand self-administration were set in the bedside pump’s program. The patient-controlled setting in both groups could be further adjusted during the daily visits of the physicians from the acute pain service to optimize analgesia whereas minimizing side effects such as sedation, respiratory depression, nausea, pruritus, or hemodynamic instability.
Venous blood samples were obtained preoperatively (T0), 90 min after skin incision (T1), at arrival in the ICU (T2), and in the morning of the first (T3), second (T4), and third (T5) POD; they were stored at –30°C until analysis. The following variables were determined using commercially available laboratory kits: BNP (CIS Bio International, Gif-Sur-Yvette Cedex, France), for which values >80 pg/mL are indicative of neurohormonal activation in patients with acute coronary syndromes (7,8); ANP (Nichols Institute, Diagnostika GmbH, Bad Nauheim, Germany), for which normal values are 10–70 pg/mL in healthy men <65 yr (9); and cardiac troponin T (cTnT) (Troponin T Enzyme Immunoassay; Boehringer Mannheim, Germany), for which normal range is up to 0.1 µg/L. Measurement of plasma catecholamines (epinephrine/norepinephrine) was performed by using a reverse-phase high-performance liquid chromatography assay on an isocratic liquid chromatograph interfaced with an electrochemical detector. Standard biochemical assays (serum creatinine, alanine aminotransferase/aspartate aminotransferase) and arterial blood gas analyses were performed before surgery and in the morning of PODs 1–3.
The primary objective was to evaluate whether continuous intra- and postoperative TEA would decrease plasma concentrations of BNP in patients requiring major abdominal surgery. The number of patients to be studied was determined using a power analysis according to data from a previous study on BNP plasma concentrations in patients with acute coronary syndromes (7). A 40% difference in BNP plasma concentrations between groups was considered to be of clinical significance. The approximate standard deviation (sd) of plasma BNP has been found to be 40% of the means (7). The 
error was set at 0.05 (two-sided) and type II error was at 0.2. Based on the above assumptions, the projected sample size was 14 patients per group. A MedCalc 4.30 (MedCalc Software, Mariakerke, Belgium) software package was used for statistical analyses. Data were presented as either mean ± sd or median (25th percentile; 75th percentile). The assumption of normality was checked using the Kolmogorov-Smirnov test. Continuous, normally distributed data were compared using paired and unpaired Student’s t-test or analysis of variance for repeated measures. When multiple comparisons were made, the Bonferroni correction was applied. Continuous, non-normally distributed data were compared using the Wilcoxon test. Binominal data were compared using 
2 analysis and Fisher’s exact test. Pearson’s correlation coefficients, simple linear regression analyses, and forward stepwise regression analyses were used to compare associations between continuous variables. Associations between continuous and categorical variables were examined with a Mann-Whitney ranked sum test. All tests were two-sided and were performed at a corrected = 0.05 level unless otherwise specified.
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Discussion |
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This controlled study of surgical patients with or at risk for CAD was designed to evaluate two different perioperative analgesia regimens, incorporating TEA, for their ability to ameliorate this neurohormonal stress response as measured by circulating levels of cardiac natriuretic peptides. Our working hypothesis was that continuous perioperative TEA would modulate the release of BNP, which is reported to be the biochemical marker of choice for evaluating the acute risk of nonsurgical patients with cardiovascular conditions ranging from asymptomatic myocardial ischemia without ST segment elevation to acute transmural myocardial infarction (7,8). The major result of our study was that continuous thoracic epidural administration of local anesthetics and opioids attenuated BNP release in patients undergoing major abdominal surgery.
Both cardiac natriuretic peptides act as counter-regulatory hormones to the increased sympathoadrenal and neurohormonal activation in response to ischemic myocardial injury (16). These physiologic effects result in improved loading conditions of the heart after transient or permanent myocardial dysfunction. The most recent attention has focused on BNP, because increased plasma levels of this cardiac hormone have been shown to reflect the extent and severity of an ischemic insult, as well as the degree of left ventricular dysfunction resulting from myocardial ischemia even when myocyte necrosis has not occurred (7,12). In patients with cardiovascular conditions such as hypertension, congestive heart failure, and acute coronary syndromes, larger concentrations of ANP, and especially BNP, are associated with increased cardiovascular and overall mortality, independent of age, New York Heart Association functional class, previous myocardial infarction, and left ventricular ejection fraction (7,10–12). The significantly larger plasma BNP concentrations in our patients receiving IV PCA may have been the result of brief episodes of myocardial dysfunction and increased left ventricular wall stress secondary to transient myocardial ischemia. Conversely, this finding suggests that the use of continuous TEA for perioperative pain management in patients with CAD may produce antiischemic actions via modulation of neurohormonal-mediated pathways, which ultimately translates into less reversible myocardial ischemia.
The exact mechanism by which TEA exerts this beneficial effect is unclear, but may be related to pain relief that is superior to conventional therapy with parenteral opioids and to perioperative sympatholytic effects (3,17–19). In nonsurgical patients with severe ischemic chest pain refractory to standard anti-anginal therapy, continuous epidural blockade of the upper five thoracic segments with bupivacaine had a beneficial effect on the major determinant of myocardial oxygen demand, as it reduced heart rate, without affecting MAP or coronary perfusion pressure (18). In patients undergoing coronary artery bypass surgery, Kirnö et al. (19) demonstrated that TEA completely blocked the cardiac sympathetic efferent activity at the time of sternotomy as cardiac norepinephrine spill-over was reduced to below that of the presurgical level. Loick et al. (17) demonstrated an attenuated catecholamine response and reduced myocardial ischemia in patients receiving high TEA in addition to IV sufentanil for cardiac surgery.
Very similar results to ours were obtained by Berendes et al. (14), who showed that reversible cardiac sympathectomy and pain therapy by high TEA significantly improved regional left ventricular function and reduced postoperative ischemia after coronary artery bypass grafting. The reduction of overall sympathetic activation by TEA results in less stress placed on potentially ischemic myocardium and thereby an attenuated BNP release. It is conceivable that the smaller plasma BNP concentrations observed in our patients receiving continuous TEA might be attributed to similar mechanisms. This assumption is supported by the fact that the use of TEA in our study was associated with less pain and sympathetic stress, as indicated by significantly lower pain scores, plasma epinephrine levels, and slower heart rates in the morning of the first and second PODs. It should be acknowledged, however, that the diagnostic and prog-nostic value of increased plasma ANP and BNP levels as a surrogate of myocardial ischemia and dysfunction is established only in nonsurgical patients. It is unclear whether an increase of these peptides after surgery indicates myocardial ischemia in the absence of symptoms and, if so, what magnitude of increase is predictive of myocardial injury.
To determine the prognostic value of BNP in acute coronary syndrome, de Lemos et al. (7) studied 2525 patients with a broad range of ischemic symptoms. Patients with a BNP level of >80 pg/mL were significantly more likely to die or have a new or recurrent myocardial infarction than those with a level of 
80 pg/mL (7). Although we could demonstrate a significant increase in BNP after surgery above this cutoff point, no patient in either group died or had a major cardiac event during the study period. This might be because our study was designed with sufficient power to detect differences in perioperative plasma BNP concentrations, but not differences in serious adverse cardiac outcomes, such as myocardial infarction and cardiac death, or other important in-hospital clinical outcome. Assuming an 8%–15% incidence of adverse cardiac outcomes and a 40% reduction of this incidence rate with continuous intra- and postoperative TEA, enrollment of >900 patients would have been necessary to achieve an 80% chance of detecting this reduction at a significance level of 0.05. Therefore, such adverse outcome events could not be assessed in the current study. We did not find a significant increase within groups or a difference between groups with respect to plasma concentrations of cTnT, which is a highly specific biochemical marker for myocardial cell necrosis. The observation that cTnT levels and BNP release did not parallel each other supports the concept that increase of BNP is a general indicator of reduced cardiac performance rather than a specific indicator of structural myocardial damage (7,20).
There are several limitations to the present study. First, plasma concentrations of the natriuretic peptides may also reflect transient volume overload caused by vigorous perioperative fluid management. To control for this confounding variable, a strict anesthesia and volume replacement scheme with predefined hemodynamic goals was followed in all patients during the entire study period. Second, the different behavior of both natriuretic peptides may also have been caused by the different sites and mechanisms of release. It is important to know that ANP and BNP are released continuously from the heart, but the rate of the release increases in response to appropriate stimuli. Several endogenous vasoactive factors, neurotransmitter, proinflammatory cytokines, and hormones directly stimulate ANP and BNP secretion. However, myocyte stretch is regarded as the central regulator of ANP and BNP release (21). Third, this study only evaluated immediate intra- and postoperative effects of continuous TEA. Therefore, we can only speculate on potential beneficial long-term effects of this treatment.
In summary, we found that continuous intra- and postoperative TEA using opioids and local anesthetics attenuated the release of BNP in patients undergoing major abdominal surgery who have, or are at risk for, CAD. Large studies must be undertaken to evaluate the prognostic importance and to define the role of ANP and BNP as a surrogate measure of adverse cardiac outcomes in the general surgical population.
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