Factors found to be associated with reexploration.
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Dacey LJ, Munoz JJ, Baribeau YR, et al. Reexploration for Hemorrhage Following Coronary Artery Bypass Grafting: Incidence and Risk Factors. Arch Surg. 1998;133(4):442–447. doi:10.1001/archsurg.133.4.442
Copyright 1998 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.1998
To assess mortality and risk factors associated with reexploration for hemorrhage in patients undergoing coronary artery bypass grafting (CABG).
Regional cohort study. Patient characteristics, treatment variables, and outcome measures were collected prospectively.
All 5 centers performing cardiac surgery in Maine, New Hampshire, and Vermont.
A consecutive cohort of 8586 patients undergoing isolated CABG between 1992 and 1995.
Main Outcome Measures
Postoperative hemorrhage leading to reexploration, in-hospital mortality, and length of stay.
A total of 305 patients (3.6%) underwent reexploration for bleeding. In these patients, in-hospital mortality was nearly 3 times higher (9.5% vs 3.3% for patients not requiring reoperation, P<.001) and average length of stay from surgery to discharge was significantly longer (14.5 days vs 8.6 days, P< .001). High rates of reexploration for hemorrhage were observed in patients with prolonged (>150 minutes) cardiopulmonary bypass (39 [11.1] of 351) and in those requiring an intra-aortic balloon pump intraoperatively (12  of 139). In multivariate analysis, older age, smaller body surface area, prolonged cardiopulmonary bypass, and number of distal anastomoses were associated with increased bleeding risks. The use of thrombolytic therapy within 48 hours of surgery was weakly but not significantly associated with the need for reexploration. Factors not significantly associated with reexploration included patient sex, preoperative ejection fraction, surgical priority, history of liver disease, myocardial infarction, prior CABG, renal failure, and diabetes mellitus.
Hemorrhage requiring reexploration after CABG is associated with markedly increased mortality and length of stay. Patients predicted to have increased risks of bleeding may benefit from prophylactic use of aprotinin, aminocaproic acid, or other agents shown to reduce hemorrhage.
HEMORRHAGE necessitating reexploration after coronary artery bypass grafting (CABG) remains a frequent complication with significant adverse consequences. Reexploration for bleeding, which occurs after 2% to 6% of CABG procedures, has been associated with case-fatality rates as high as 22%.1 Patients undergoing reexploration for bleeding also consume considerable resources, including blood products and those related to prolonged intensive care and overall hospital stays.1-4
Efforts to reduce rates of reexploration for bleeding have included use of prothrombotic agents, such as aprotinin and aminocaproic acid. However, because of their potential adverse effects and expense, these agents have generally been reserved for patients considered to be at particularly high risk for postoperative bleeding. Because risk factors for reexploration after CABG are not well established, we performed a prospective, regional study of postoperative hemorrhage in patients undergoing coronary artery bypass in northern New England. This study was performed when aprotinin and aminocaproic acid were used very infrequently in the region.
The Northern New England Cardiovascular Disease Study Group is a voluntary research consortium representing all 5 medical centers in Maine, New Hampshire, and Vermont where CABG surgery is performed. Since 1987, the group has maintained a prospective registry of all patients undergoing cardiac surgery in the region. This analysis was based on 8586 consecutive patients undergoing isolated CABG between January 1, 1992, and July 3, 1995. Data collection, methods and definitions, patient characteristics, and determinants of in-hospital mortality in this group of patients have been described previously in detail.5,6
The following data were recorded prospectively for all patients: patient age and sex, body surface area (BSA), cardiac catheterization results (degree of left main coronary artery stenosis, total number of significantly diseased vessels, left ventricular end-diastolic pressure, ejection fraction), prior CABG, priority of surgery (emergency, urgent, or elective), thrombolytic therapy within 48 hours, use of an intra-aortic balloon pump (IABP), and total time of cardiopulmonary bypass. The ejection fraction results were scored using the method described by Pierpont et al.7 The number of diseased coronary vessels was assessed using criteria established by the National Heart, Lung, and Blood Institute Coronary Artery Surgery Study.8 The left main coronary artery was classified as diseased if any stenosis was greater than or equal to 50% of the luminal diameter. The left anterior descending, left circumflex, right coronary, or posterior descending artery were considered diseased if any stenosis was greater than or equal to 70% of the luminal diameter. In left-dominant coronary anatomy, left main coronary artery disease was equivalent to 3-vessel disease. Coronary artery bypass grafting was defined as emergent when medical factors relating to the patient's cardiac disease dictated that surgery be performed within hours to prevent morbidity or death. Urgent CABG was defined by the presence of clinical factors requiring that the patient stay in the hospital to have the operation before discharge. The remaining cases were defined as elective.
Postoperative hemorrhage was defined as bleeding that resulted in return to the operating room. The decision to reexplore was at the discretion of the individual surgeon. We did not attempt to categorize the specific indication for reoperation, such as excessive chest tube drainage, collection of blood within the chest, or cardiac tamponade. Data on those patients with high chest tube output who did not require reexploration and their outcomes were not collected. In-hospital deaths occurring during the CABG admission were recorded concurrently.
Standard statistical methods (χ2 test for categorical data and t tests for continuous variables) were used to compare the characteristics of patients with and without reexploration. We used multivariate logistic regression analysis to explore the association between hemorrhage and potential risk factors and to adjust for potentially confounding variables.9 The multivariate model was developed by incrementally testing variables found in univariate analysis to be significant at the P<.10 level. The likelihood ratio test was used to compare nested logistic regression models. The Hosmer-Lemeshow goodness-of-fit statistic was calculated. As a measure of test accuracy, the area under the receiver operating characteristic curve, a graphic representation of relation of the true-positive rate (ie, the sensitivity of the test) and the false-positive rate (ie, 1 minus the specificity of the test), was calculated.10 Analysis was performed using STATA software (Stata Corp, College Station, Tex).
Of the 8586 consecutive patients undergoing CABG between 1992 and 1995, a total of 305 (3.6%) underwent reexploration for postoperative bleeding. The in-hospital mortality rate of patients who underwent reexploration was substantially higher than that of those patients without reoperation (9.5% vs 3.3%, P<.001). Also, length of stay from operation to hospital discharge was 6 days longer on average (14.5 days vs 8.6 days, P<.001).
Rates of reexploration for bleeding were significantly associated with age and BSA (Table 1). Patients 75 years or older had reexploration rates 2.6-fold higher than did patients younger than 55 years (P<.001) (Figure 1, A). Smaller patients (BSA <1.6 m2) had reexploration rates 2.3-fold higher than larger patients (BSA ≥2.0 m2 [P<.001]). Stratified by sex, there was a monotonic increase in the risk of bleeding among both men (P for trend, <.001) and women (P for trend, .06) (Figure 1, B).
The risk of reexploration for hemorrhage was not associated with sex, comorbidities, prior CABG (Table 1), or measures of cardiac disease severity (Table 2). The use of thrombolytics within 48 hours of the CABG was slightly associated with higher risks of reexploration, but was not statistically significant (5.0% vs 3.3%, P=.08).
Time on cardiopulmonary bypass, number of distal anastomoses, and the intraoperative insertion of an intra-aortic balloon pump were associated with higher rates of hemorrhage requiring reexploration. Patients on cardiopulmonary bypass more than 150 minutes had a 5-fold higher risk of reexploration than patients on bypass less than 60 minutes (P<.001) (Figure 1, C). Patients requiring 5 or more distal anastomoses had a 1.9-fold higher risk of reexploration than those requiring fewer than 3 anastomoses (P=.002) (Figure 1, D). Patients requiring an IABP intraoperatively had a reexploration rate of 8.0%, as compared with 3.2% in those without an IABP (P<.001). However, preoperative IABP insertion was not a risk factor for reexploration.
In multivariate logistic regression model, only age, BSA, cardiopulmonary bypass time, and number of distal anastomoses were found to be significantly associated with rates of reexploration for hemorrhage. The model had a moderate predictive accuracy (area under the receiver operating characteristic curve=0.66) and good calibration (Hosmer-Lemeshow goodness-of-fit χ2 test=4.84, df=8, P=.77).
In this prospective regional study, 3.6% of patients required reexploration, an incidence rate consistent with findings from other series.1-3 Patients undergoing reexploration had significantly increased rates of in-hospital mortality (9.5% vs 3.3%) as well as prolonged hospital stays (mean, 14 days vs 8.6 days).
Risk factor analysis showed that increased age, lower BSA, prolonged cardiopulmonary bypass, and increasing number of distal anastomoses were associated with higher rates of reexploration for bleeding. Previous work by Moulton et al2 and a prospective multivariate analysis by Despotis et al11 also found age and time on cardiopulmonary bypass to be risk factors for reexploration. Prolonged time on bypass increases the activation of fibrinolysis and induces an inflammatory response. Active plasmin released during bypass may induce platelet activation, which leads to acquired platelet dysfunction and deleterious hemostatic changes.12 We also identified number of distal anastomoses and BSA as risk factors for reexploration after CABG. An increased number of distal anastomoses requires greater time on cardiopulmonary bypass, increases the number of potential bleeding sites, and increases the overall complexity of the procedure. While increased bleeding risks with more distal anastomoses seem plausible on clinical grounds, the reasons why smaller patients have increased risks are unclear but may be the result of dilutional effects. Smaller patients have proportionally smaller circulating blood volumes and therefore decreased total amounts of coagulation factors compared with larger patients. Fluids administered intravenously and in the pump prime will more quickly dilute these factors in smaller patients, and may therefore lead more frequently to coagulopathies.
Rates of reexploration after CABG were not correlated with several variables often considered risk factors for postoperative bleeding in general. For example, recent thrombolytic therapy, urgent or emergent surgery, and prior open heart surgery were not significantly associated with reexploration for hemorrhage. Although one previous study identified chronic renal insufficiency as a risk factor for reexploration,2 our study showed no such association between dialysis-dependent renal failure and higher rates of reexploration. While female sex has been linked with higher rates of postoperative transfusion after CABG,13 our study showed no difference in reexploration rates among men and women (3.5% and 3.6%, respectively). Other authors have noted increased mediastinal drainage and postoperative transfusion rates in patients with an IABP.14 While IABP was associated with reexploration risk in our univariate analysis, this association was not statistically significant in multivariate analysis.
It is important to consider this study's strengths and limitations. Given the large sample size, this study had sufficient power to detect most clinically important predictors of postoperative bleeding requiring reexploration. In addition, data were collected prospectively, limiting the potential for bias in the ascertainment of risk factor and outcome variables. Finally, because this regional study was population-based, our results should be generalizable.
Among the limitations, we did not consider all potentially important risk factors for postoperative bleeding. While we did not have sufficient data to assess the role of preoperative aspirin and heparin use, other studies have not identified these variables as risk factors for clinically important bleeding after CABG.13,15 Preoperative laboratory findings, including bleeding times, have also not been shown to predict reexploration rates.2 This study focused solely on postoperative bleeding sufficient to require reexploration. Other less dramatic but clinically important indicators of postoperative bleeding, such as transfusion rates and mediastinal drainage, were not examined. Also, our analysis focused on mortality. Other studies have shown that reexploration for hemorrhage after CABG also increases rates of nonfatal adverse outcomes, including hemodialysis, atrial arrhythmias, adult respiratory distress syndrome and prolonged mechanical ventilation, and sepsis.1,2 While these outcomes were not specifically examined, they likely are responsible for part of the increased length of stay seen in patients who underwent reexploration.
Efforts to reduce rates of reexploration for bleeding have included use of prothrombotic agents. Among the most commonly used are aprotinin and aminocaproic acid, antifibrinolytic agents that inhibit plasmin and plasmin-induced platelet dysfunction. Several studies have suggested that these agents reduce postoperative bleeding and transfusion requirements with CABG.4,15 However, there remains some concern about potential risks of thrombotic complications and other adverse effects with aprotinin and other antifibrinolytics.11,16 Moreover, because some of these agents (aprotinin in particular) are expensive, few centers are using them routinely in patients undergoing CABG. These agents were not commonly used at the time of our study, and the effects of changes in practice patterns and bleeding trends have yet to be determined.
Identifying patients at high risk for postoperative hemorrhage is important if cardiac surgeons are to adopt cost-effective strategies for bleeding prevention. Our results suggest that surgeons should have low thresholds to initiate aprotinin and aminocaproic acid therapy in patients older than 75 years, small patients, those with potentially prolonged cardiopulmonary bypass, and those requiring higher numbers of distal anastomoses.
Ronald M. Weintraub, MD, Boston, Mass: Several of the findings presented by Dr Munoz were unsurprising and consistent with other reports in the literature. Age and time on bypass were significant risk factors by both univariate and multivariate analysis. The number of distal anastomoses and time on CPB may well be related, of course. Similarly, the need for the intraoperative intra-aortic balloon insertion suggests longer CPB times, more complicated, difficult operations, and technical problems or inadequate myocardial protection. Was intraoperative balloon insertion, as distinct from all balloon insertions, an independent factor by multivariate analysis?
Some of the findings were surprising, however. Surgical priority and prior operation have been risk factors for reexploration in other reports but were not found to be factors here. With respect to liver disease, my own contrary experience raises some questions. How was "liver disease" defined? Were there enough patients with serious disease, for instance, Child class B, to eliminate type II error?
Perhaps of most interest was the authors' finding that the incidence of reexploration was inversely proportional to body size. Though a unique finding, it is perhaps explainable on the basis of hemodilution. In what might be a parallel situation, we conducted a study of postoperative weight gain in cardiac surgical patients at the Beth Israel Hospital between 1990 and 1994. We found that weight gain, like bleeding in the present study, was inversely proportional to body weight. Because this size effect was mitigated by the administration of albumin, we theorized that the greater proportional weight gain was secondary to the abrupt greater dilution of osmotically active molecules by the pump prime in these smaller patients. A similar effect, the dilution of coagulation factors, could be responsible for the greater bleeding in smaller patients.
We reviewed all cardiac operations at the Beth Israel Hospital from 1994 through 1996, finding an incidence of reexploration for bleeding of 1.5%. There was no correlation between BSA and reexploration for bleeding. The average BSA of bleeders was a substantial 1.9 m2. The numbers, however, were relatively small (27 cases of 1800 patients), demonstrating once again the advantage of large multicenter studies. The authors' data appear to be solid and, if confirmed, could lead to processes for reducing perioperative bleeding. Blood sequestration, with or without the use of recombinant hemoglobin, minipump primes, and other methods for reducing hemodilution, could be a pathway for reducing hemorrhage. Do the authors have any other plans for applying their data to the development or process?
Finally, aprotinin became available and fibrinolysis inhibitors became more commonly used during the time frame of the authors' study. Was their use documented, and might this have confounded the study?
The authors are to be congratulated for demonstrating once again the power of a cooperative multicenter registry and for being "poster boys" for outcomes research in this country.
Robert L. Thurer, MD, Boston: I was very impressed as usual by this large study, but I wonder if analysis of the means is confusing the issue. Do we have 2 populations of patients? One might be a group having long pump runs and multisystem disease with many complications, and the other the more routine reoperations on relatively elective straightforward patients. I wonder if the prolonged length of stay and cost was associated with both of those groups or whether it was concentrated on those patients who had the long pump runs. If you looked at patients who had relatively simple operations, was that too associated with a long length of stay and resource utilization?
Dr Munoz: To address Dr Weintraub's questions, the use of the intra-aortic balloon pump was characterized by time of placement. While the use of an intraoperatively placed intra-aortic balloon pump was found to be a statistically significant risk factor in univariate analysis, it was not significant in multivariate analysis.
Liver disease was classified as mild or moderate to severe. Mild liver disease was defined by cirrhosis, chronic active hepatitis, or primary biliary cirrhosis without systemic sequelae. Moderate to severe liver disease was defined by the presence of ascites, esophageal varices, portal hypertension, or hepatic encephalopathy. Since only 2 patients in the entire study group had evidence of liver disease, we were unable to assess this risk factor adequately.
Dr Weintraub mentioned a hypothesis that increased bleeding risks in smaller patients may be related to hemodilution. We do not have detailed information on this issue in our current database.
Similarly, we did not routinely collect data on aprotinin use during the study period, and its use in Northern New England was minimal. However, as the awareness and use of these antifibrinolytics increases, their costs and benefits need to be further evaluated. We are currently initiating an investigation of the cost-effectiveness of pharmacologic interventions, mainly aprotinin and aminocaproic acid, for postoperative bleeding in open heart surgery.
As Dr Thurer noted, postoperative bleeding may represent different processes in different groups of patients. However, rates of bleeding did not vary significantly by surgical priority, severity of cardiac disease, or comorbidities in our analysis.
Presented at the 78th Annual Meeting of the New England Surgical Society, Bolton Landing, NY, September 21, 1997.
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Reprints: Lawrence J. Dacey, MD, MS, Section of Cardiothoracic Surgery, One Medical Center Drive, Lebanon, NH 03756 (e-mail: firstname.lastname@example.org).
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