Patients undergoing vascular surgery are at risk of myocardial infarction (MI) and cardiac death because of the frequent prevalence of coronary artery disease (CAD) and the severity of the surgical stress (1–4). Aortic abdominal reconstruction involves extensive tissue dissection, large body-fluid shifts, and ischemia-reperfusion injuries. Moreover, neurohumoral and inflammatory responses are associated with prothrombotic conditions and increased metabolic demands (5,6).
Over the last decade, several clinical trials have demonstrated that pretreatment with β-blockers or α2-agonists reduces cardiovascular morbidity and mortality (7). Meanwhile, the American College of Cardiology and the American Heart Association (ACC/AHA) have published guidelines for preoperative cardiac assessment and selected patients who might benefit from preoperative myocardial revascularization and/or perioperative administration of cardioprotective drugs such as β-blockers or α2-agonists (8).
Presently, the effects of implementing ACC/AHA guidelines and cardioprotective drugs have not yet been thoroughly evaluated in noncardiac surgery. A randomized clinical trial comparing a standardized protocol versus routine medical care would be difficult to conduct because of ethical considerations and would be confounded by clinical judgment of the investigators and unwillingness of some patients to be randomized. Observational studies that examine all patients exposed to similar surgical conditions have been proposed as alternatives (9,10).
In this study, we analyzed a local database including all patients who underwent elective aortic abdominal surgery, and we questioned whether the introduction of the ACC/AHA guidelines and the use of sympatholytic drugs could lead to a reduction in postoperative cardiovascular complications.
This study was performed with the permission of our IRB. The Geneva Major Vascular Surgery Registry is a comprehensive, prospectively recorded database including clinical, functional, laboratory, and surgical characteristics of all patients with aortic occlusive disease, aneurysm, or both who have undergone abdominal aortic reconstructive surgery at our academic center since 1993. From January 1993 to December 2000, 475 operations were managed by the same team of cardiovascular surgeons and anesthesiologists with varying experience (minimum 2 yr) in vascular surgery, cardiothoracic anesthesia, and acute postoperative care. Aortic reconstruction was always performed through a transperitoneal approach. Seven patients who participated in the European Mivazerol Study were excluded from the final analysis.
All patients underwent standard intraoperative monitoring, which consisted of five-lead electrocardiography (ECG) with ST segment trend analysis (leads II and V5), pulse oximetry, end-tidal capnography, invasive intravascular pressure monitoring, and measurements of body temperature and urine output. In most patients, a pulmonary artery catheter or a transesophageal echocardiography probe was inserted to assess cardiovascular function and to guide vasoactive treatment and fluid infusion.
After IV anesthesia induction (with thiopental or etomidate and myorelaxants), the trachea was intubated for mechanical ventilation, and anesthesia was maintained with IV opiates and inhaled isoflurane or desflurane (0.5–1.5 minimum alveolar anesthetic concentration). Positive-pressure ventilation with an air/oxygen mixture was adjusted to maintain a Paco2 of 4–5 kPa, an arterial oxygen saturation of ≥96%, and a pH of 7.3–7.4, as assessed by end-tidal CO2 monitoring, pulse oximetry, and blood-gas analysis. Body hypothermia was prevented with a warming water mattress, a forced-air warming device, and heated IV fluids. IV vasoactive drugs, including nitroglycerine, ephedrine, and phenylephrine, were administered to control blood pressure, particularly after aortic clamping and unclamping. A blood salvage device was routinely used, and homologous red blood cell concentrates were transfused to keep the hemoglobin level ≥80–90 g/L. At the end of the surgical procedure, the residual effects of myorelaxants were antagonized; the endotracheal tube was removed after recovery of spontaneous ventilation with adequate neurologic function if the criteria of normothermia and stable hemodynamics were met.
After surgery, the extubated patients were managed in the postanesthesia care unit (PACU), and patients requiring mechanical ventilatory support were transferred to the intensive care unit (ICU) for the first 24–48 h. A 12-lead ECG, chest radiographs, and blood analysis (including hemoglobin, electrolytes, creatinine, and creatine phosphokinase isoenzymes or troponin I [cTn I]) were routinely measured on arrival in the PACU or ICU, on the morning of the next 2 days, before discharge from the hospital, and additionally if required by any clinical change. Pain control regimens were used at the discretion of the anesthesiologists and consisted of IV morphine administered as a continuous infusion or with a patient-controlled analgesia system. Paracetamol was given routinely (2 g IV every 8 h), and after the first 24 h, antiinflammatory nonsteroidal drugs were prescribed, except in patients with unstable hemodynamics, renal dysfunction, or gastroduodenal disorders.
This observational study was designed to evaluate the effect of ACC/AHA guidelines for preoperative cardiac assessment and institutional recommendations for perioperative administration of cardioprotective drugs in high-risk vascular patients.
In 1996, several lectures and meetings were organized at our institution that focused on ACC/AHA guidelines and on the benefits of perioperative antiadrenergic treatments. A consensus was reached among clinicians (cardiologists, internists, surgeons, and anesthesiologists) to support the ACC/AHA recommendations for preoperative cardiac assessment and perioperative administration of α2-agonists (IV clonidine at doses of 150 to 300 μg during surgery) and β-blockers (metoprolol or atenolol, after surgery). In the PACU or ICU, incremental IV doses of β-blockers were titrated to maintain a heart rate less than 80 bpm while preserving an adequate perfusion pressure (systolic arterial blood pressure >100 mm Hg); oral forms of β-blockers were resumed when the patient was transferred to the surgical ward.
Because this new perioperative medical strategy was introduced in January 1997, we compared data of two consecutive 4-yr periods—from January 1993 to December 1996 (control group) and from January 1997 to December 2000 (intervention group)—to evaluate any change in cardiac testing strategy and perioperative outcome, as well as in patients’ preoperative characteristics and surgical conditions.
Dipyridamole thallium scintigraphy with planar acquisition in three standard views was used for assessment of normal myocardial perfusion and detection of fixed and reversible defects. Coronary angiography was performed in patients with positive myocardial imaging (extensive redistribution defect, two or more ischemic areas, or high clinical risk). Revascularization procedures were attempted in the presence of significant coronary stenosis (>50% in the left main trunk or >70% proximal narrowing in at least one artery) and a viable myocardial zone.
In addition to demographic data, cardiac history, comorbid conditions (diabetes, hypertension, congestive heart failure, chronic obstructive pulmonary disease, peripheral arterial disease, smoking, hypercholesterolemia), and current medical treatments, we collected information regarding preoperative cardiac testing (echocardiography, dipyridamole thallium scintigraphy, coronary angiography) and myocardial revascularization procedures (percutaneous coronary angioplasty [PTCA], coronary artery bypass graft surgery [CABGS]). Nursing charts and medical records—including specialty consultations, anesthesia charts, results of investigations, and hospital discharge letters—were also examined.
The diagnosis of CAD was based on the history of MI or angina, typical Q waves on the ECG, positive stress test, or evidence of coronary artery stenosis on the angiogram. Specific cutoff points were selected to define advanced age (≥70 yr), obesity (body mass index ≥30 kg/m2), and renal insufficiency (serum creatinine level >160 μg/L, corrected for age).
During and after surgery, we recorded the amount and type of fluid infused (colloids, crystalloids, homologous blood units, salvaged autologous blood); urine output; and the use of clonidine, β-blockers (metoprolol, atenolol), and other vasoactive drugs (ephedrine, phenylephrine, nitroglycerine). The aortic cross-clamping and total surgical times were noted, as was the duration of hospital stay. Laboratory data included serial measurements of hemoglobin and creatinine concentrations and the highest value of cTn I or creatine phosphokinase and its myocardial band isoenzyme.
Cardiac complications were reported as defined in Appendix 1. Up to 12 mo after hospital discharge, the status of patients was followed up through the central registry, hospital medical files, and telephone calls to the patient’s physician or cardiologist.
Data are presented as mean ± sd, median (range), absolute numbers, or percentages. Differences between the two study periods were examined by using unpaired Student’s t-tests or Mann-Whitney U-tests for continuous variables and Fisher’s exact test for proportions. The Kaplan-Meier method and a corresponding log-rank test was used to compare time until a “hard” end-point (nonfatal MI, myocardial revascularization, or cardiac death).
Potential risk factors for an adverse event were identified by univariate and multivariate logistic regression analysis. To avoid overadjustment by using too many variables in the multivariate model, all variables were subjected to univariate analysis in a first step. Factors with a P value <0.2 were considered as potential risk factors in the forward multivariate model. To control multicollinearity, only one variable in a set of variables with a correlation coefficient more than 0.5 was used in the multivariate analysis. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.
Baseline patient characteristics of our study cohort of 468 patients are shown in Table 1. During the intervention period, there was a more frequent prevalence of documented CAD (43% versus 30% in the control period;P < 0.05) and a more frequent rate of patients with a history of myocardial revascularization (15.9% versus 6.1% in 1993–1996;P < 0.05). Likewise, more patients were chronically treated with angiotensin-converting enzyme (ACE) inhibitors (34.4% versus 23.5% in 1993–1996;P < 0.05), with a trend for lesser prescription of calcium channel antagonists. The proportion of ASA status III and IV was larger during the intervention period, although there was no significant difference regarding the prevalence of cardiac risk factors (hypercholesterolemia, hypertension, diabetes mellitus, smoking, peripheral vascular disease), congestive heart failure, or chronic obstructive pulmonary disease.
As shown in Table 2, the intraoperative doses of opiate were smaller during the intervention period (average reduction of −35% for fentanyl and −38% for sufentanil compared with the control period). Surgical data and the administration of IV fluids, blood components, and vasopressors, as well as diuresis, body temperature, and hematocrit values, were comparable between the two periods.
As shown in Figure 1, implementation of ACC/AHA guidelines was associated with an increased rate of preoperative myocardial scanning and coronary angiogram and with an increasing number of patients who had myocardial revascularization performed 4 to 8 wk before vascular surgery (7.7% versus 0.8% in 1993–1996;P < 0.05). The rates of positive myocardial scanning were similar in both periods for myocardial defects, minor redistribution, and extensive redistribution. No cardiac death or MI occurred among patients selected to undergo PTCA or CABGS before vascular surgery.
During the intervention period, there was an increasing use of intraoperative clonidine (75.6% versus 15.4% in the control period;P < 0.05) and postoperative β-blockers (58.4% versus 8.1%;P < 0.05), which resulted in decreased heart rate on the next morning after surgery (71 ± 4 versus 85 ± 5 bpm in the control period). Immediate extubation at the end of surgery was successful in a larger proportion of patients and was accompanied by a reduction in positive fluid balance on the first postoperative day and fewer admissions to the ICU (Table 3).
The total cardiovascular events rate decreased from 11.3% in the control period to 4.5% in the intervention period (P < 0.01) as a result of a decreased incidence of MI and pulmonary edema (Table 4). As shown in Figure 2, fewer patients had abnormal postoperative peak values of cTn I during the intervention period compared with the control period: 3 versus 16 patients, respectively, had Tn I values >1.5 ng/mL (P < 0.05), and 4 versus 19 patients had cTn I between 0.5 and 1.5 ng/mL (P < 0.05). Notably, fewer cardiovascular complications occurred among patients who had myocardial revascularization (4.6% versus 8.4% patients with no revascularization, P < 0.05) and in those pretreated with α2-agonists and β-blockers (2.7% versus 9.9% in untreated patients, P < 0.05).
The duration of hospital stay (13.7 ± 3.2 days in 1993–1996 versus 13.1 ± 2.9 days in 1997–2000), the overall hospital mortality (1.6% in 1993–1996 versus 2.7% in 1997–2000), and the rate of noncardiac complications remained unchanged (data not shown). Compared with the control period, cardiac event-free survival was improved in the intervention period (91.3% versus 98.2%;P < 0.05) (Fig. 3), and more patients were still treated with β-blockers (22.6% versus 42%;P < 0.05) at 1-yr follow up.
Multivariate regression analysis showed that the combined administration of clonidine and β-blockers was associated with a decreased risk of cardiovascular events (OR, 0.3; 95% CI, 0.1–0.8). Three independent risk factors for cardiovascular complications were identified: moderate renal insufficiency (OR, 2.7; 95% CI, 1.3–5.5), chronic obstructive pulmonary disease (OR, 2.4; 95% CI, 1.1–4.6), and major bleeding (OR, 2.4; 95% CI, 1.1–6.6).
In this eight-year observational study, implementation of ACC/AHA guidelines and perioperative administration of sympatholytic drugs were associated with a marked reduction in early cardiac morbidity and with an increased event-free survival after elective aortic abdominal surgery. In agreement with other studies, chronic obstructive pulmonary disease, preexisting renal dysfunction, and major bleeding were found to be predictive of nonfatal cardiac morbid events (3,11–13). Preoperative expiratory flow limitations, smoking, and small carbon dioxide diffusion capacity are known risk factors for postoperative atelectasis and pneumonias, which may complicate weaning from mechanical ventilation and therefore impose additional cardiac stress. On the other hand, chronic renal dysfunction reflects the severity of systemic atheromatosis associated with long-standing hypertension, hypercholesterolemia, and/or diabetes (14). As expected, patients with CAD or cardiovascular risk factors are more susceptible to develop MI and cardiac failure as a result of compromised myocardial oxygen transport/demand during prolonged or repeated episodes of respiratory failure, sepsis, or uncompensated hemorrhage.
According to the ACC/AHA guidelines (8), we performed noninvasive cardiac testing in patients with intermediate clinical risk factors, poor exercise tolerance, or both. Hence, the rate of myocardial scanning increased from 21% to 49% (1993–1996 versus 1997–2000), and abnormal findings (e.g., fixed defects, redistribution) were found in up to two thirds of these patients. Poldermans et al. (15) reported similar results in vascular patients when at least one intermediate clinical risk factor was present. In contrast, using a modified ACC/AHA algorithm in patients undergoing aortic surgery, Bartels et al. (16) reported a less frequent rate of preoperative thallium scintigraphy (20%); nevertheless, the higher threshold for cardiac testing was associated with a more frequent incidence of postoperative cardiac complications (12.4% versus 4.5% in this study).
Although we observed a frequent prevalence of patients with CAD, <10% of these cases were deemed suitable candidates to undergo percutaneous or surgical revascularization procedures. Despite a smaller incidence of postoperative cardiac complications among revascularized patients, our observations lack statistical power to draw firm conclusions regarding the cardioprotective effects of PTCA and CABGS. An analysis of the Coronary Artery Surgery Study showed that previous CABGS protects from perioperative MI or death for at least six years after revascularization (17,18). Similarly, smaller rates of adverse cardiac outcome have been achieved after successful PTCA if a minimum period of four to six weeks precedes elective surgery (19–21). Currently, no randomized or controlled trial has demonstrated the benefits of prophylactic myocardial revascularization to decrease cardiac risk in noncardiac surgery. The combined risks of angiography and revascularization would possibly outweigh their potential cardioprotective effects, arguing against “prophylactic” invasive interventions (22). Consequently, the decision to proceed to PTCA or CABG surgery should be driven by the same factors as it would be without anticipated noncardiac surgery (i.e., extensive ischemia, impaired ventricular function, viable myocardium).
During the intervention period (1997–2000), in addition to ACC/AHA guidelines for preoperative cardiovascular evaluation, more than 50% of surgical candidates received intraoperative α2-agonists and postoperative β-blockers to keep heart rate less than 80 bpm. Effective and safe cardioprotection was provided through synergistic mechanisms while adverse drug effects were minimized. Sequential administration of cardioprotective drugs was associated with a 65% reduction in cardiac morbidity (MI and congestive heart failure), an effect size similar to that reported in randomized clinical trials testing the efficacy of β-blockers (15,23).
The incidence of myocardial ischemia and MI is increased in patients with CAD and/or impaired vasodilatory reserve when the sympathetic nervous system is activated by perioperative factors such as surgical trauma, anesthesia emergence, fluid shifts, hypothermia, and nociception. Accordingly, preventing the acute changes in platelet hyperaggregability and coronary shear stress associated with sympathetically driven tachycardia and hypertension would likely reduce the risk of intimal plaque disruption and local thrombosis (24,25). In addition, antiadrenergic treatment has been shown to improve subendocardial oxygenation and collateral blood flow in patients with left ventricular hypertrophy and CAD (26,27). Taken together, these mechanisms may explain the large reduction in myocardial ischemia and MI (−30% to 90%) that has been demonstrated in high-risk surgical patients pretreated with bisoprolol, atenolol, clonidine, or mivazerol (15,23,28–32).
Although several studies support that β-blockers should be administered before surgery in all high-risk patients (15,23,28–30), we were concerned that competitive antagonism of β-adrenergic receptors could prevent appropriate resuscitation from sudden hypovolemia and acute heart failure during major surgery (33,34). In contrast, α2-agonists such as clonidine modulate the efferent sympathetic activity from the spinal cord and reduce catecholamine output without interfering with baroreflex-mediated vasoconstriction (35). Hence, we elected to use clonidine during surgery to achieve cardioprotection while preserving the hemodynamic response to hypovolemia (i.e., major bleeding or vasodilatory responses after peritoneal dissection or aortic unclamping) and to vasopressive/inotropic drugs (36).
In addition to its antiischemic effect, clonidine potentiates anesthesia/analgesia and blunts the increased metabolic demand during anesthesia emergence (37,38). Consequently, the increasing use of clonidine was associated with an intraoperative opiate-sparing effect that contributed to facilitating early extubation and to decreasing the need for ICU admission during the intervention period.
After surgery, in addition to optimization of analgesia with IV morphine, our main goal was to control heart rate less than 80 bpm through the administration of incremental doses of β-adrenergic receptor antagonists while avoiding hypotension (<100 mm Hg) and maintaining an adequate oxygen transport to meet metabolic needs. Similar or even lower target heart rate values (60–80 bpm) have been advocated in the early postoperative period (15,24,29,30,39). Our selective treatment regimen takes into account the large interindividual variability in hemodynamic and heart rate response. As reported in other studies, 15%–25% of postoperative patients do not require any treatment because heart rate does not exceed the target values of 60–80 bpm (24,39). However, β-blockers provide little benefit in low-risk patients and are contraindicated in a small subset of patients because of severe bronchospastic disorders, high-grade cardiac conduction abnormalities, or markedly depressed ventricular function (7).
We are mindful of the vulnerability of this observational study to several biases and confounding variables resulting from nonrandom assignment of patients, unblinding of the physicians, and time-related improvement in the management of cardiovascular patients. First, patients with hypertension or ventricular dysfunction were more often treated with ACE inhibitors, whereas the increased number of patients who underwent PTCA/CABGS reflected the potential benefits of revascularization procedures compared with medical treatment (40). However, the larger proportion of ASA status III and IV patients could be explained by better perioperative medical care and greater acceptance of high-risk surgical candidates. Second, advances in scoring and quantification of myocardial scanning improved risk assessment and the predictive value for postoperative cardiac events; hence, closer monitoring and intensive treatment were possibly focused on selected high-risk patients. Third, although the use of transesophageal echocardiography or pulmonary artery catheters did not differ between the two periods, interpretation of hemodynamic data was most useful to tailor antiadrenergic treatments, to adjust the circulatory volume, and to minimize the incidence of drug-related side effects. Finally, adjunctive treatment with antiaggregants or heparin and the duration of postoperative therapy with β-blockers were poorly controlled.
To minimize some residual confounding, we studied a large group of high-risk surgical patients and compared study end-points that were clearly defined with clinical assessments, cardiac markers, chest radiographs, and ECG tracings. It is important to note that the nonfatal cardiovascular event rate in the control period (11.3%) was similar to that reported in the literature (3–4,13,15,16) and decreased by 65% after application of our standardized cardioprotective approach.
In conclusion, implementation of ACC/AHA guidelines and administration of α2-agonists and β-blockers were associated with better cardiac outcome after major vascular surgery. Preoperative cardiac testing was helpful to identify some patients who might benefit from coronary revascularization. Given their effectiveness and safety, sympatholytic treatments might obviate the need to undergo invasive cardiac testing in patients with stable CAD and/or minor to moderate ischemia (13,41). Future studies should address this issue, as well as the cost-effectiveness, the optimal duration, and the benefits of such a cardioprotective strategy in other groups of surgical candidates.
Appendix 1: Definitions of Cardiovascular Complications
- MI: typical increase and decrease of creatine phosphokinase (>120 U/L) and creatine phosphokinase with its myocardial band enzyme ≥6% or troponin I ≥1.5 ng/mL, with at least one of the following criteria: ischemic symptoms, development of pathologic Q waves on the ECG, ST segment elevation or depression (≥1 mm), or coronary artery intervention.
- Arrhythmias: supraventricular and ventricular tachyarrhythmias requiring medications or an electrical cardioversion.
- Congestive heart failure: need for sympathomimetic support, diuretics, or vasodilators consistent with clinical, hemodynamic (pulmonary artery pressure ≥15 mm Hg), and radiological evidence of pulmonary congestion.
- Stroke: focal neurological deficit (transient or permanent).
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