Dennis T. Mangano

Effect of Atenolol on Mortality and Cardiovascular Morbidity after Noncardiac Surgery

BACKGROUND Perioperative myocardial ischemia is the single most important potentially reversible risk factor for mortality and cardiovascular complications after noncardiac surgery. Although more than 1 million patients have such complications annually, there is no effective preventive therapy. METHODS We performed a randomized, double-blind, placebo-controlled trial to compare the effect of atenolol with that of a placebo on overall survival and cardiovascular morbidity in patients with or at risk for coronary artery disease who were undergoing noncardiac surgery. Atenolol was given intravenously before and immediately after surgery and orally thereafter for the duration of hospitalization. Patients were followed over the subsequent two years. RESULTS A total of 200 patients were enrolled. Ninety-nine were assigned to the atenolol group, and 101 to the placebo group. One hundred ninety-four patients survived to be discharged from the hospital, and 192 of these were followed for two years. Overall mortality after discharge from the hospital was significantly lower among the atenolol-treated patients than among those who were given placebo over the six months following hospital discharge (0 vs. 8 percent, P<0.001), over the first year (3 percent vs. 14 percent, P=0.005), and over two years (10 percent vs. 21 percent, P=0.019). The principal effect was a reduction in deaths from cardiac causes during the first six to eight months. Combined cardiovascular outcomes were similarly reduced among the atenolol-treated patients; event-free survival throughout the two-year study period was 68 percent in the placebo group and 83 percent in the atenolol group (P=0.008). CONCLUSIONS In patients who have or are at risk for coronary artery disease who must undergo noncardiac surgery, treatment with atenolol during hospitalization can reduce mortality and the incidence of cardiovascular complications for as long as two years after surgery.

Prophylactic atenolol reduces postoperative myocardial ischemia

Background Perioperative myocardial ischemia occurs in 20–40% of patients at risk for cardiac complications and is associated with a ninefold increase in risk for perioperative cardiac death, myocardial infarction, or unstable angina, and a twofold long‐term risk. Perioperative atenolol administration reduces the risk of death for as long as 2 yr after surgery. This randomized, placebo‐controlled, double‐blinded trial tested the hypothesis that perioperative atenolol administration reduces the incidence and severity of perioperative myocardial ischemia, potentially explaining the observed reduction in the risk for death. Methods Two‐hundred patients with, or at risk for, coronary artery disease were randomized to two study groups (atenolol and placebo). Monitoring included a preoperative history and physical examination and daily assessment of any adverse events. Twelve‐lead electrocardiography (ECG), three‐lead Holter ECG, and creatinine phosphokinase with myocardial banding (CPK with MB) data were collected 24 h before until 7 days after surgery. Atenolol (0, 5, or 10 mg) or placebo was administered intravenously before induction of anesthesia and every 12 h after operation until the patient could take oral medications. Atenolol (0, 50, or 100 mg) was administered orally once a day as specified by blood pressure and heart rate. Results During the postoperative period, the incidence of myocardial ischemia was significantly reduced in the atenolol group: days 0–2 (atenolol, 17 of 99 patients; placebo, 34 of 101 patients; P = 0.008) and days 0–7 (atenolol, 24 of 99 patients; placebo, 39 of 101 patients; P = 0.029). Patients with episodes of myocardial ischemia were more likely to die in the next 2 yr (P = 0.025). Conclusions Perioperative administration of atenolol for 1 week to patients at high risk for coronary artery disease significantly reduces the incidence of postoperative myocardial ischemia. Reductions in perioperative myocardial ischemia are associated with reductions in the risk for death at 2 yr.

Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery

OBJECTIVE Inhibition of cyclooxygenase 2 provides analgesia in ambulatory patients. We prospectively evaluated the safety and efficacy of a newly introduced cyclooxygenase 2 inhibitor in patients undergoing coronary artery bypass grafting surgery through a median sternotomy in a randomized clinical trial. METHODS A total of 462 patients with New York Heart Association classes I to III who were less than 77 years of age and were from 58 institutions in the United States, Canada, Germany, and the United Kingdom participated in this multicenter, phase III, placebo-controlled, double-blind, randomized, parallel-group trial. Patients were allocated at a ratio of 2:1 to parecoxib/valdecoxib or standard care (control) groups, respectively. Intravenous study drug (40 mg) was administered within 30 minutes after extubation and every 12 hours for a minimum of 3 days. Subsequently, oral treatment at a dose of 40 mg every 12 hours was initiated and administered for a combined total of 14 days. Patient-controlled analgesia with morphine, oral opioids, or acetaminophen was available as required. Assessment of the analgesic efficacy of the study drug was primarily based on morphine and morphine equivalent use. Additional efficacy evaluations included daily pain intensity, patient and physician global evaluation of study medication, and pain effect on quality of life. Clinical adverse events were assessed by the principal investigator at each site from the time of the first dose through the 30-day postdosing period. RESULTS Patients in the parecoxib/valdecoxib group received significantly less morphine or morphine equivalents than patients in the control group during the 0- to 24-hour (P =.009), 24- to 48-hour (P =.017), 72- to 96-hour (P =.002), 96- to 120-hour (P =.004), and 120- to 144-hour (P =.037) periods. Both patients (P <.001) and physicians (P <.001) evaluated the study medication as significantly better than control therapy. The modified Brief Pain Inventory questionnaire used in the oral dosing period detected significant improvements in the parecoxib/valdecoxib treatment group in 6 of 8 domains tested (eg, current pain, worst pain, and mood) beginning on day 4 and continuing for at least 4 days. Although there were no differences between the groups in overall adverse events, serious adverse events occurred twice as frequently in parecoxib/valdecoxib-treated patients (19.0%, 59/311 patients) than in control patients (9.9%, 15/151 patients; P =.015). Regarding individual serious adverse events, a greater incidence in sternal wound infection was found in the parecoxib/valdecoxib patients (10 [3.2%]) versus control patients (0 [0%]) (P =.035). The incidences of other individual serious adverse events, including cerebrovascular complications, myocardial infarction, and renal dysfunction, were proportionally greater but not significantly different between the groups. CONCLUSIONS In patients undergoing coronary artery bypass grafting surgery, the cyclooxygenase 2 inhibitor combination, parecoxib/valdecoxib, was effective for postoperative analgesia. However, the 14-day treatment regimen also was associated with an increased incidence of serious adverse events overall and sternal wound infections in particular. Therefore our study raises important concerns requiring their comprehensive evaluation in a large-scale trial before these cyclooxygenase 2 inhibitors are used in patients undergoing coronary artery bypass grafting surgery.

Impact of Preoperative Anemia on Outcome in Patients Undergoing Coronary Artery Bypass Graft Surgery

Background— The risk of preoperative anemia in patients undergoing heart surgery has not been described precisely. Specifically, the impact of low hemoglobin per se or combined with other risk factors on postoperative outcome is unknown. Thus, we determined the effects of low preoperative hemoglobin and comorbidities on postoperative adverse outcomes in patients with coronary artery bypass graft in a large comprehensive multicenter study. Methods and Results— The Multicenter Study of Perioperative Ischemia investigated 5065 patients with coronary artery bypass graft at 70 institutions worldwide, collecting ≈7500 data points per patient. In 4804 patients who received no preoperative transfusions, we determined the association between lowest preoperative hemoglobin levels and in-hospital cardiac and noncardiac morbidity and mortality and the impact of concomitant risk factors, assessed by EuroSCORE, on this effect. In patients with EuroSCORE <4 (n=2054), only noncardiac outcomes were increased, whereas patients with EuroSCORE ≥4 (n=2750) showed an increased incidence of all postoperative events, starting at hemoglobin <11 g/dL. Low preoperative hemoglobin was an independent predictor for noncardiac (renal>cerebral; P<0.001) outcomes, whereas the increase in cardiac events was due to other factors associated with preoperative anemia. Conclusions— Anemic patients undergoing cardiac surgery have an increased risk of postoperative adverse events. Importantly, the extent of preexisting comorbidities substantially affects perioperative anemia tolerance. Therefore, preoperative risk assessment and subsequent therapeutic strategies, such as blood transfusion, should take into account both the individual level of preoperative hemoglobin and the extent of concomitant risk factors.

Variability in transfusion practice for coronary artery bypass surgery persists despite national consensus guidelines : A 24-institution study

BACKGROUND An estimated 20% of allogeneic blood transfusions in the United States are associated with cardiac surgery. National consensus guidelines for allogeneic transfusion associated with coronary artery bypass graft (CABG) surgery have existed since the mid- to late 1980s. The appropriateness and uniformity of institutional transfusion practice was questioned in 1991. An assessment of current transfusion practice patterns was warranted. METHODS The Multicenter Study of Perioperative Ischemia database consists of comprehensive information on the course of surgery in 2,417 randomly selected patients undergoing CABG surgery at 24 institutions. A subset of 713 patients expected to be at low risk for transfusion was examined. Allogeneic transfusion was evaluated across institutions. Institution as an independent risk factor for allogeneic transfusion was determined in a multivariable model. RESULTS Significant variability in institutional transfusion practice was observed for allogeneic packed red blood cells (PRBCs) (27-92% of patients transfused) and hemostatic blood components (platelets, 0-36%; fresh frozen plasma, 0-36%; cryoprecipitate, 0-17% of patients transfused). For patients at institutions with liberal rather than conservative transfusion practice, the odds ratio for transfusion of PRBCs was 6.5 (95% confidence interval [CI], 3.8-10.8) and for hemostatic blood components it was 2 (95% CI, 1.2-3.4). Institution was an independent determinant of transfusion risk associated with CABG surgery. CONCLUSIONS Institutions continue to vary significantly in their transfusion practices for CABG surgery. A more rational and conservative approach to transfusion practice at the institutional level is warranted.

PERIOPERATIVE MYOCARDIAL ISCHEMIA IN PATIENTS UNDERGOING NONCARDIAC SURGERY. I, INCIDENCE AND SEVERITY DURING THE 4 DAY PERIOPERATIVE PERIOD

To determine the incidence and characteristics of perioperative myocardial ischemia, the electrocardiographic (ECG) changes consistent with ischemia during the 4 day perioperative period were documented and characterized in 100 patients with or at risk for coronary artery disease undergoing noncardiac surgery. Using continuous two channel ECG monitoring (leads CC5 and CM5), the frequency and severity of ECG ischemic episodes defined by ST segment depression greater than or equal to 1 mm or elevation greater than or equal to 2 mm during the preoperative (up to 2 days), intraoperative and early postoperative (first 2 days) periods were compared. Preoperatively, 28 patients (28%) exhibited 105 episodes of ischemia; intraoperatively, 27 patients exhibited 39 episodes and postoperatively, 42 patients exhibited 187 episodes. There was no difference between the pre- and intraoperative episode characteristics. However, postoperative ischemic episodes were the most severe. The mean ST change was 1.5, 2 and 2.6 mm for pre-, intra- and postoperative episodes, respectively (p less than 0.0001 postoperative versus pre- or intraoperative); duration of ischemic episodes was 69, 45 and 207 min, respectively (p less than 0.005 postoperative versus preoperative, p less than 0.001 versus intraoperative) and area under the ST curve was 88, 74 and 383 mm.min (p less than 0.009 postoperative versus preoperative, p less than 0.005 versus intraoperative). Ninety-four percent of all postoperative ischemic episodes were silent; 80% of all episodes occurred without acute change (+/- 20% of control) in heart rate and 77% of intraoperative episodes occurred without acute change in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Postoperative myocardial ischemia. Therapeutic trials using intensive analgesia following surgery

Recent data suggest that postbypass and postoperative myocardial ischemia are related to adverse cardiac outcome following myocardial revascularization. Therapeutic trials to suppress postoperative ischemia are warranted. Because anesthetics can suppress a variety of physiologic responses to stress as well as myocardial ischemia intraoperatively, we examined whether use of intensive analgesia in the stressful postoperative period could decrease postoperative ischemia. In 106 patients undergoing elective myocardial revascularization, we standardized the anesthetic prior to bypass (sufentanil 5-10 micrograms/kg [induction] and 4.2-6.0 micrograms.kg-1.h-1 [infusion] supplemented with up to 0.5 mg/kg of diazepam). During bypass, patients were randomly assigned to receive either morphine sulfate (group M, n = 54, up to 2 mg/kg) or sufentanil (group S, n = 52, 1 microgram/kg and 1 microgram.kg-1.h-1). In the intensive care unit (ICU), group M received low-dose analgesia (morphine sulfate 1-10 mg intravenously every 30 min, average dose = 2.2 +/- 2.1 mg/h), while group S continued to receive intensive analgesia (infusion of sufentanil at 1 microgram.kg-1.h-1). Both groups received supplemental midazolam in the ICU (group M = 1.1 +/- 1.1 mg/h; group S = 0.6 +/- 0.6 mg/h; P = 0.01). All analgesic and sedative-hypnotic medications were discontinued at 18 hours following myocardial revascularization. Using continuous two-channel electrocardiographic (ECG) monitoring (CC5 and CM5), we documented and characterized ECG changes consistent with ischemia during the preoperative, intraoperative (pre- and postbypass), and postoperative (on- and off-treatment) periods. The total ECG monitoring time was 8,486 h, averaging 81 h per patient. During the prebypass (anesthetic control) period, groups M and S had a similar incidence, but group S episodes were more severe: maximum ST-segment change (median), S versus M: -1.8 mm versus -1.4 mm (P = 0.04). During the postbypass period, both groups had a similar incidence of ischemia, but episodes in group S were less severe: maximum ST-segment change, S versus M: -1.8 mm versus -2.7 mm (P = 0.0005). During the ICU-on-therapy period, the incidence of ischemic episodes was less in group S patients, and the severity was less: area-under-the-ST-time curve, S versus M: -21 mm.min versus -161 mm.min (P = 0.05). After discontinuation of the drug regimen in the ICU, the incidence and severity of ischemic episodes was similar. The incidence of hypotension, hypertension, and tachycardia was similar in both groups in both the intraoperative and ICU periods.(ABSTRACT TRUNCATED AT 400 WORDS)

Cerebral Injury After Cardiac Surgery Identification of a Group at Extraordinary Risk

BACKGROUND AND PURPOSE Cerebral injury after cardiac surgery is now recognized as a serious and costly healthcare problem mandating immediate attention. To effect solution, those subgroups of patients at greatest risk must be identified, thereby allowing efficient implementation of new clinical strategies. No such subgroup has been identified; however, patients undergoing intracardiac surgery are thought to be at high risk, but comprehensive data regarding specific risk, impact on cost, and discharge disposition are not available. METHODS We prospectively studied 273 patients enrolled from 24 diverse US medical centers, who were undergoing intracardiac and coronary artery surgery. Patient data were collected using standardized methods and included clinical, historical, specialized testing, neurological outcome and autopsy data, and measures of resource utilization. Adverse outcomes were defined a priori and determined after database closure by a blinded independent panel. Stepwise logistic regression models were developed to estimate the relative risks associated with clinical history and intraoperative and postoperative events. RESULTS Adverse cerebral outcomes occurred in 16% of patients (43/273), being nearly equally divided between type I outcomes (8.4%; 5 cerebral deaths, 16 nonfatal strokes, and 2 new TIAs) and type II outcomes (7.3%; 17 new intellectual deterioration persisting at hospital discharge and 3 newly diagnosed seizures). Associated resource utilization was significantly increased--prolonging median intensive care unit stay from 3 days (no adverse cerebral outcome) to 8 days (type I; P<0.001) and from 3 to 6 days (type II; P<0.001), and increasing hospitalization by 50% (type II, P=0.04) to 100% (type I, P<0.001). Furthermore, specialized care after hospital discharge was frequently necessary in those with type I outcomes, in that only 31% returned home compared with 85% of patients without cerebral complications (P<0.001). Significant risk factors for type I outcomes related primarily to embolic phenomena, including proximal aortic atherosclerosis, intracardiac thrombus, and intermittent clamping of the aorta during surgery. For type II outcomes, risk factors again included proximal aortic atherosclerosis, as well as a preoperative history of endocarditis, alcohol abuse, perioperative dysrhythmia or poorly controlled hypertension, and the development of a low-output state after cardiopulmonary bypass. CONCLUSIONS These prospective multicenter findings demonstrate that patients undergoing intracardiac surgery combined with coronary revascularization are at formidable risk, in that 1 in 6 will develop cerebral complications that are frequently costly and devastating. Thus, new strategies for perioperative management--including technical and pharmacological interventions--are now mandated for this subgroup of cardiac surgery patients.

Prognostic Importance of Postbypass Regional Wall-Motion Abnormalities in Patients Undergoing Coronary Artery Bypass Graft Surgery

Regional wall motion abnormalities (RWMA) detected by intraoperative transesophageal echocardiography (TEE) are thought to be sensitive markers of myocardial ischemia. To assess the prognostic significance of RWMA as compared with other less costly technologies such as electrocardiography (ECG) and hemodynamic measurements [blood pressure (BP) and pulmonary artery (PA) pressure], 50 patients were prospectively studied who were undergoing elective coronary artery bypass graft (CABG) surgery using continuous TEE, ECG (Holter), and hemodynamic measurements during the prebypass, postbypass, and early postoperative intensive care unit (ICU) periods (first 4 h). Echocardiographic and ECG evidence of ischemia was characterized during each of these three periods and related to adverse clinical outcomes (postoperative myocardial infarction, ventricular failure, and cardiac death). Clinicians were blinded to the TEE and ECG information. The prevalence of myocardial ischemia during the perioperative periods was as follows: prebypass, 20% (TEE) versus 7% (ECG); postbypass, 36% (TEE) versus 25% (ECG); ICU 25% (TEE) versus 16% (ECG). Neither prebypass TEE ischemia nor ECG ischemia occurring in any of the three periods predicted adverse outcome. In contrast, postbypass TEE ischemia was predictive of outcome: six of 18 patients with postbypass TEE ischemia had adverse outcomes versus 0 of 32 without TEE ischemia (P = 0.001). Seventy-three percent of the echocardiographic ischemic episodes occurred without acute change (+/- 20% of control) in heart rate, BP, or PA pressure. The authors conclude that: 1) prebypass myocardial ischemia was relatively uncommon, 2) the incidence of ECG and TEE ischemia was highest in the postbypass period, and 3) postbypass RWMA were related to adverse clinical outcome.

Intraoperative myocardial ischemia: localization by continuous 12-lead electrocardiography

Based primarily on results obtained during exercise treadmill testing, electrocardiographic (ECG) leads II and V5 are the suggested optimal leads for detecting intraoperative myocardial ischemia. However, these recommendations have not been validated in this setting using all 12 ECG leads. Accordingly, the authors studied 105 patients with known or suspected coronary artery disease (CAD) undergoing noncardiac surgery with general anesthesia by continuously recording the 12-lead ECG intraoperatively in all patients. The average duration of monitoring was 8.2 ± 2.7 h (mean ± SD). Ischemic episodes (i.e., ± 1-mm horizontal or downsloping ST depression, ± 1.5-mm slowly upsloping ST depression or ± 1.5-mm ST of 51 ischemic episodes, 45 involved ST depression alone, and the remaining six involved both ST depression and elevation. ST segment changes occurred in a single lead only in 134 episodes, while multiple leads were involved in 37 episodes. Lead sensitivity was estimated assuming that all St segment changes were true positive responses. Sensitivity using a single lead was greatest in V5 (75%) and V4 (61%), and intermediate in II, V3 and V6 (33%, 24%, and 37%, respectively). The remaining seven leads demonstrated very low sensitivity (2–14%) or exhibited no ischemic changes (I and a V1). Combining leads V4 and V5 increased sensitivity to 90%, while the standard clinical combination, II and V5, was only 80% sensitive. Sensitivity increased to 96% by combining II, V4, and V5. The further addition of V2 and V3 (five leads) increased sensitivity to 100%. This study confirms previous recommendations for the routine use of a V5 lead (either uni- or bipolar) in all patients at risk for ischemia. V4 is more sensitive than lead II, and should be considered as a second choice. However, lead II, superior for detection of atrial dysrhythmias, is more easily obtained with conventional monitors. The use of all three would appear to be the optimal arrangement for most clinical needs, and is recommended if the clinician has the capability.