George T. Christakis

Metaanalysis of prophylactic drug treatment in the prevention of postoperative bleeding.

Prophylactic drug treatment is one of several strategies to reduce postoperative blood loss and potentially limit homologous blood use in open heart surgery. A computerized MEDLINE search supplemented with manual bibliography reviews was performed for randomized clinical trials published in peer-reviewed English-language journals from January 1980 to June 1993. A metaanalysis was conducted of trials evaluating desmopressin (group DD, n = 13), epsilon-aminocaproic acid or tranexamic acid (group EA, n = 4), and aprotinin (group AP, n = 16). Eligible studies used placebo controls and administered the drug in a prophylactic manner. The primary study end point was postoperative chest tube loss (mL, mean +/- standard deviation). There was a significant reduction in postoperative chest tube loss detected for each of the active treatments versus the placebo (DD versus controls: percent reduction 0.11, p = 0.0021; EA versus controls: percent reduction 0.30, p < 0.0001; and AP versus controls: percent reduction 0.36, p < 0.0001). Therapy with EA or AP was associated with a greater reduction in chest tube loss than DD (EA versus DD, p = 0.0033, and AP versus DD, p < 0.0001). Secondary study end points were transfusion requirements, chest reexploration, and perioperative mortality. The volume of postoperative red cell transfusion (mean +/- standard deviation) was reduced with EA (p < 0.0001) or AP treatment (p < 0.0001) compared with a placebo or DD, whereas the proportion of patients given transfusions was limited only in the AP-treated patients (odds ratio 0.23; 95% confidence interval, 0.16 to 0.33; p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Predictors of low cardiac output syndrome after coronary artery bypass

The purpose of this study was to identify patients at risk for the development of low cardiac output syndrome after coronary artery bypass. Low cardiac output syndrome was defined as the need for postoperative intraaortic balloon pump or inotropic support for longer than 30 minutes in the intensive care unit to maintain the systolic blood pressure greater than 90 mm Hg and the cardiac index greater than 2.2 L/min per square meter. The preoperative patient characteristics that were independent predictors of low cardiac output syndrome were identified among 4558 consecutive patients who underwent isolated coronary artery bypass at The Toronto Hospital between July 1, 1990, and December 31, 1993. The overall prevalence of low cardiac output syndrome was 9.1% (n = 412). The operative mortality rate was higher in patients in whom low cardiac output syndrome developed than in those in whom it did not develop (16.9% versus 0.9%, p < 0.001). Stepwise logistic regression analyses identified nine independent predictors of low output syndrome (percent frequency in parentheses) and calculated the factor-adjusted odds ratios associated with each predictor: (1) left ventricular ejection fraction less than 20% (27%, odds ratio 5.7); (2) repeat operation (25%, odds ratio 4.4); (3) emergency operation (27%, odds ratio 3.7); (4) female gender (16%, odds ratio 2.5); (5) diabetes (13%, odds ratio 1.6); (6) age older than 70 years (13%, odds ratio 1.5); (7) left main coronary artery stenosis (12%, odds ratio 1.4); (8) recent myocardial infarction (16%, odds ratio 1.4); and (9) triple-vessel disease (10%, odds ratio 1.3). Low cardiac output syndrome is a clinical outcome that may result from inadequate myocardial protection or perioperative ischemic injury. Patients at high risk for the development of low cardiac output syndrome should be the focus of trials of new techniques of myocardial protection to resuscitate the ischemic myocardium.

The Influence of Gender on the Outcome of Coronary Artery Bypass Surgery

BACKGROUND To assess the impact of gender as an independent risk factor for early and late morbidity and mortality following coronary artery bypass surgery. METHODS Perioperative and long-term data on all 4,823 patients undergoing isolated coronary bypass operations from November 1989 to July 1998 were analyzed. Of these patients, 932 (19.3%) were females. RESULTS During the years 1989 to 1998 there was a progressive increase in the percentage of women undergoing coronary artery bypass surgery. The following preoperative risk factors were more prevalent among women than men: age above 70, angina class 3 or 4, urgent operation, preoperative intraaortic balloon pump usage, congestive heart failure, previous percutaneous transluminal coronary angioplasty, diabetes, hypertension, and peripheral vascular disease (all p < 0.05). Men were more likely to have an ejection fraction less than 35%, three-vessel disease, repeat operations, and a recent history of smoking. Women had a statistically significant smaller mean body surface area than men (1.72+/-0.18 versus 1.96%+/-0.26% m2). On average, women had fewer bypass grafts constructed than men (2.9%+/-0.8% versus 3.2%+/-0.9%) and were less likely to have internal mammary artery grafting (76.2% versus 86.1%), multiple arterial conduits (10.1% versus 19.8%), or coronary endarterectomy performed (4.9% versus 8.6%). The early mortality rate in women was 2.7% versus 1.8% in men (p = 0.09). Women were more prone to perioperative myocardial infarction (4.5% versus 3.1% p < 0.05). After adjustment for other risk variables, female gender was not an independent predictor of early mortality but was a weak independent predictor for the prespecified composite endpoint of death, perioperative myocardial infarction, intraaortic balloon counterpulsation pump insertion, or stroke (8.55 versus 5.9%; odds ratio, 1.30; 95% confidence interval, 0.99 to 1.68; p = 0.05) Recurrent angina class 3 or 4 was more frequent in female patients (15.2%+/-4.0% versus 8.5%+/-2.0% at 60 months, p = 0.001) but not repeat revascularization procedures (percutaneous transluminal coronary angioplasty, redo) (0.6%+/-0.3% versus 4.1%+/-0.8% at 60 months). Actuarial survival at 60 months was greater in women then men (93.1%+/-1.7% versus 90.0%+/-1.0%), and after adjustment for other risk variables, female gender was protective for late survival (risk ratio, 0.40; 95% confidence interval, 0.16-0.74; p < 0.005). CONCLUSIONS Perioperative complications were increased and recurrent angina more frequent in women. Despite this, late survival was increased in women compared with men after adjustment for other risk variables

Patient prosthesis mismatch is rare after aortic valve replacement: valve size may be irrelevant

BACKGROUND Although small valve size and patient-prosthesis mismatch are both considered to decrease long-term survival, little direct evidence exists to support this hypothesis. METHODS To assess the prevalence of patient-prosthesis mismatch and the influence of small valve size on survival, we prospectively studied 1,129 consecutive patients undergoing aortic valve replacement between 1990 and 2000. Mean and peak gradients and indexed effective orifice area were measured by transthoracic echocardiography postoperatively (3 months to 10 years). Abnormal postoperative gradients were defined as those patients with mean or peak gradient above the 90th percentile (mean gradient > or = 21 or peak gradient > or = 38 mm Hg). Patient-prosthesis mismatch was defined as those patients with indexed effective orifice area below the 10th percentile (< 0.60 cm2/m2). RESULTS A multivariable analysis identified internal diameter of the implanted valve as the only independent predictor of abnormal gradients postoperatively. However, there was no significant difference in actuarial survival between normal and abnormal gradient groups (7 years: 91.2% +/- 1.5% versus 95.0% +/- 2.2%; p = 0.48). Freedom from New York Heart Association class III or IV (7 years: 74.5% +/- 3.1% versus 74.6% +/- 6.2%; p = 0.66) and left ventricular mass index were not different between normal and abnormal gradient groups. Patients with and without patient-prosthesis mismatch were similar with respect to postoperative left ventricular mass index, 7-year survival (95.1% +/- 1.3% versus 94.7% +/- 3.0%; p = 0.54), and 7-year freedom from New York Heart Association class III or IV (79.3% +/- 6.6% versus 74.5% +/- 2.5%; p = 0.40). In patients with patient-prosthesis mismatch and abnormal gradients, the majority had prosthesis dysfunction owing to degeneration. CONCLUSIONS Severe patient-prosthesis mismatch is rare after aortic valve replacement. Patient-prosthesis mismatch, abnormal gradient, and the size of valve implanted do not influence left ventricular mass index or intermediate-term survival.

Overexpression of Transforming Growth Factor-β1 and Insulin-Like Growth Factor-I in Patients With Idiopathic Hypertrophic Cardiomyopathy

BACKGROUND Idiopathic hypertrophic cardiomyopathy (HCM) is characterized by regional myocardial hypertrophy. To investigate involvement of growth factors on myocardial hypertrophy in HCM patients, we evaluated gene expression and cellular localization of transforming growth factor-beta1 (TGF-beta1), insulin-like growth factors (IGF-I and IGF-II), and platelet-derived growth factor-B (PDGF-B) in ventricular biopsies obtained from patients with HCM (n=8), aortic stenosis (AS) (n=8), or stable angina (SA) (n=8) and from explanted hearts with ischemic cardiomyopathy (TM) (n=7). METHODS AND RESULTS Levels of TGF-beta1, IGF-I, IGF-II, and PDGF-B transcripts were quantified with the use of multiplex RT-PCR. Glyceraldehyde 3-phosphate dehydrogenase was used as an internal standard. Antibodies against TGF-beta and IGF-I were used to localize their peptides within the myocardium. Antisense and sense (control) cRNA probes of TGF-beta1 and IGF-I, labeled with digoxigenin, were used to localize the growth factor transcripts by in situ hybridization. mRNA levels (densitometric ratio of growth factor/glyceraldehyde-3-phosphate dehydrogenase) of TGF-beta1 and IGF-I in HCM (0.75+/-0.05 and 0.85+/-0.15, respectively; mean+/-1 SEM) were significantly (P<.01 for all groups) elevated in comparison with non-HCM myocardium (AS: 0.38+/-0.07, 0.29+/-0.06; SA: 0.32+/-0.04, 0.18+/-0.05; TM: 0.25+/-0.03, 0.15+/-0.03). mRNA levels of TGF-beta1 and IGF-I in the hypertrophic AS myocardium were greater (P=.02, P=.05) than those in the explanted myocardium (TM). Immunohistochemical and in situ hybridization studies showed increased expression of TGF-beta1 and IGF-I in the HCM cardiomyocytes. CONCLUSIONS Gene expression of TGF-beta1 and IGF-I was enhanced in idiopathic hypertrophic cardiomyopathy and may be associated with its development.

A randomized study of the systemic effects of warm heart surgery

The technique of warm heart surgery is defined as continuous warm blood cardioplegia and normothermic cardiopulmonary bypass. Although the systemic effects of traditional myocardial protection are well known, the effects of warm heart surgery are not. In a prospective trial, 204 patients undergoing coronary artery bypass grafting were randomized to the warm heart surgery technique (normothermic group) or traditional intermittent cold blood cardioplegia and cardiopulmonary bypass (hypothermic group). The groups had similar heparin sodium requirement, activated clotting times, urine output, hematocrit, and blood product utilization. There were no differences in hemodynamics immediately after cardiopulmonary bypass. The normothermic patients had a higher incidence of spontaneous defibrillation at cross-clamp removal (84%) than the hypothermic patients (33%) (p less than 0.01). An increase in the flow rate of low K+ cardioplegia was necessary to eradicate electrical activity during aortic occlusion more often in the normothermic patients (20%) than in the hypothermic patients (3%) (p less than 0.01). When low K+ cardioplegia was ineffective, high K+ cardioplegia was necessary to eradicate electrical activity in 31% of the normothermic patients compared with 10% of the hypothermic patients (p less than 0.05). The total cardioplegia volume delivered to the normothermic group (4.7 +/- 1.9 L) was higher than that delivered to the hypothermic group (2.6 +/- 0.8 L) (p less than 0.01). Although urine output was similar in both groups, the serum K+ levels were higher in the normothermic group (5.7 +/- 0.8 mmol/L) than in the hypothermic group (5.3 +/- 0.8 mmol/L) (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Is body size the cause for poor outcomes of coronary artery bypass operations in women

Although small body size and coronary artery diameter are recognized as major contributors to the increased risk of coronary artery bypass grafting in women, few studies have established the independent influence of body size and gender on outcome. We studied 7025 consecutive patients (5694 men, 1331 women) undergoing isolated coronary artery bypass grafting between 1990 and 1994. Women were older, had higher preoperative prevalences of urgent operation because of unstable angina, diabetes, peripheral vascular disease, hypertension, and single-vessel coronary artery disease (p < 0.0001), and a lower prevalence of left ventricular ejection fraction 40% or less (p < 0.0001). The prevalences of operative mortality (men, 1.8%; women, 3.5%), low-output syndrome (men, 6.6%; women, 14.8%), and myocardial infarction (men, 2.8%; women, 5.5%) were higher in women (p < 0.0001). Patients were divided into quartiles for body surface area, weight, height, and body mass index. For both men and women, there was no difference in operative mortality between the highest and lowest quartiles of body size. Women, however, had a higher prevalence of operative mortality than men in the lower quartiles of body surface area, height, and weight and in the higher quartiles of body mass index. Among men, the prevalence of low-output syndrome increased (p < 0.0001) with decreasing body surface area, weight, and body mass index, suggesting that body size did influence the prevalence of low-output syndrome. However, women had a higher prevalence of low-output syndrome than men in every category and quartile of body size (p < 0.0001). Multivariable analysis identified gender as a significant determinant of operative mortality (odds ratio 1.83, 95% confidence interval 1.27 to 2.64) and low-output syndrome (odds ratio 2.52, 95% confidence interval 2.05 to 3.11). When multivariable adjustments were made for body size and preoperative risk factors, gender remained a predictor of both operative mortality and low-output syndrome. Multivariable assessment of risk for men and women separately identified that urgent operation was a predictor of operative mortality (odds ratio 2.52, 95% confidence interval 1.32 to 5.61) and low-output syndrome (odds ratio 1.57, 95% confidence interval 1.14 to 2.17) in women but not men. In conclusion, the increased risk of coronary artery bypass grafting in women may be explained in part by dramatic differences in preoperative risk factors between men and women. In both men and women, small body size did not increase the risk of operative mortality, but may have contributed to the risk of low-output syndrome.(ABSTRACT TRUNCATED AT 400 WORDS)

Are stentless valves hemodynamically superior to stented valves? A prospective randomized trial

BACKGROUND Although stentless aortic bioprostheses are believed to offer improved outcomes, hemodynamic benefits remain unsubstantiated. METHODS Fifty-three patients were randomized to receive the stented C-E pericardial valve (CE) and 46 patients the Toronto Stentless Porcine valve (SPV). Annuli were sized for the optimal insertion of both valve types, such that surgeons were required to commit to specific valve sizes before randomization. Echocardiographic measurements and functional status (Duke Activity Status Index) were assessed at 3 and 12 months postoperatively. RESULTS Although cardiopulmonary bypass times (CE: 118.6+/-36.3 minutes; SPV: 148.5+/-30.9 minutes; p = 0.0001) and aortic cross-clamp times (CE: 95.4+/-28.6 minutes; SPV: 123.6+/-24.1 minutes; p = 0.0001) were significantly prolonged in the SPV group, perioperative morbidity and mortality was similar between groups. Neither valve offered a superior internal diameter for any given annular diameter (mean decrease in left ventricular outflow tract diameter after valvular implantation: SPV: 3.4+/-1.11 mm versus CE: 3.7+/-1.33 mm; p = 0.25). Although labeled mean valve size was significantly larger in the SPV group, the actual mean valve size based on internal valvular diameter was no different between groups (CE: 21.9+/-2.0 mm; SPV: 22.3+/-2.0 mm; p = 0.286). Although effective orifice areas increased, and mean and peak transvalvular gradients decreased in both groups over time, no differences were demonstrated between groups at 12 months. Similarly, although significant regression of left ventricular mass was accomplished in both groups over time, no differences were demonstrated between groups. Finally, Duke Activity Status Index scores of functional status improved in both groups over time; however, no differences were noted between groups at 12 months postoperatively. CONCLUSIONS Although offering excellent outcomes, stentless valves did not demonstrate superior hemodynamic indices in comparison to stented valves up to 12 months after implantation.

Trends in coronary artery bypass surgery results: a recent, 9-year study

BACKGROUND The demographics of patients undergoing coronary artery bypass grafting (CABG) have changed over time and may contribute to differing operative mortality and the combination of mortality and morbidity (M + M). In this study, the trends in results are analyzed and causes are suggested. METHODS Prospectively collected data concerning 4,839 CABG operations was divided into three time cohorts (1990 to 1992, 1993 to 1995, 1996 to 1998) and analyzed by univariate and multivariate techniques. RESULTS Mean age and female gender frequency increased in the later time cohorts (60.7 +/- 9.0 to 63.4 +/- 9.9 years and 16.5% to 21.4%, respectively). The following comorbidities were more prevalent in the later time cohorts: diabetes (26.7% versus 18.6%), renal failure (8.5% versus 2.2%), peripheral vascular disease (20.7% versus 11.0%), previous cerebrovascular accident (6.7% versus 5.0%), urgent procedures (41.5% versus 26.9%), unstable angina (47.8% versus 31.7%), urgent CABG following myocardial infarction (17.1% versus 7.3%), previous percutaneous transluminal coronary angioplasty (8.0% versus 4.5%), ejection fraction less than 35% (20.5% versus 10.4%), (all p < 0.05). Procedurally, increased utilization of the left internal mammary artery, multiple arterial conduits, and warm blood cardioplegia occurred in the later cohorts (91.2%, 22.2%, and 80.4% versus 78.7%, 3.4%, and 38.0%, respectively). The mortality rate was 2.0% and the M + M rate was 15.6% in all 4,839 patients. The mortality and M + M for the three cohorts were 1.6%, 2.0%, and 2.3% and 18.4%, 17.2% and 12.5%, respectively. The risk-adjusted mortality and M + M decreased from 2.4% and 15.9%, respectively, in 1990 to 1992 to 1.8% and 8.4% in 1996 to 1998 (p < 0.001). The difference in adjusted event rates was minimized when the surgical factors were entered into the model. CONCLUSIONS Over time, there has been a trend toward operating on older patients with more comorbidities. Though hospital mortality has been stable, risk-adjusted M + M has been in a constant decline. This decline was associated with an increased use of left internal mammary artery grafts, multiple arterial conduits, and warm blood cardioplegia during the later years of the study.

Hemodynamic benefits of the Toronto Stentless Valve.

We report on 254 consecutive patients (170 male, 84 female) undergoing aortic valve replacement with the Toronto SPV Stentless Valve (St. Jude Medical, Inc., St. Paul, Minn.). Mean age (+/- standard deviation) was 62.1 +/- 11.6 years. Three patients (1%) received sizes 21 or 22 mm, 24 (9%) received size 23 mm, and 227 patients (89%) received sizes 25, 27, or 29 mm. Serial echocardiography was used to assess valve performance during a 3-year follow-up. Mean gradient decreased by 35.8% (p < 0.0001; 95% confidence interval -39.6%, -31.7%) from postoperative values to the 3- to 6-month follow-up and by 6.1% (p = 0.004; 95% confidence interval -10.1%, -2%) at each subsequent interval; effective orifice area increased by 17.2% (p = 0.0001; 95% confidence interval 12.0%, 22.6%) initially and by 4.4% (p < 0.001; 95% confidence interval 1.8%, 7.0%) thereafter. At 2 years of follow-up, mean gradient was 3.3 +/- 2.1 mm Hg and mean effective orifice area was 2.2 +/- 0.8 cm2. Studies on left ventricular mass were carried out on 84 patients. Left ventricular mass decreased by 14.3% (37.8 +/- 57.9 gm; p < 0.0001; 95% confidence interval -53.7, -21.9 gm) and left ventricular mass index decreased by 15.2% (21.1 +/- 30.5 gm/m2; p < 0.0001; 95% confidence interval -29.5, -12.7 gm/m2) from postoperative values to the 3- to 6-month follow-up interval. The reduction in residual gradient and potential regression in left ventricular hypertrophy may have a beneficial prognostic implication. We believe that the unique stentless design of the Toronto SPV Stentless Valve allows this to occur.