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Eur J Cardiothorac Surg 2007;32:560-566. doi:10.1016/j.ejcts.2007.01.071
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
a Division of Thoracic and Cardiovascular Surgery, Hannover Medical School, Carl-Neuberg-Street 1, 30625 Hannover, Germany
b Center of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
Received 25 October 2006; received in revised form 21 January 2007; accepted 29 January 2007.
* Corresponding author. Tel.: +49 511 532 2153; fax: +49 511 532 5404. (Email: goerler.adelheid{at}mh-hannover.de).
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Key Words: Fibrin glue • Coronary artery bypass grafting • Myocardial infarction
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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We started our data collection in July 1999, because at that time computer based documentation has been introduced in the operating room. Since that time information about the use of fibrin glue has been easily available. We excluded all patients after off-pump surgery (n = 238), because extracorporeal circulation has a major influence on mortality, postoperative bleeding, organ dysfunction and complement activation after cardiac surgery. Thus, 160 patients after minimal invasive direct coronary artery bypass (MIDCAB) and 78 patients after off-pump coronary artery bypass (OPCAB) have been excluded. Moreover, all patients with beating heart surgery without aortic cross clamping have been excluded (n = 33), because we considered aortic cross clamp time an important parameter for statistical analysis. Thirteen patients were lost to follow-up. These patients were all foreigners, who did not live in Germany. In 544 patients no information about 30-day mortality was available in the patient records. We contacted these patients by phone. When we were informed about a patient's death, we verified that information by contacting the registration office. If patients could not be reached under the phone number or address documented in the hospital records, we contacted the registration office, in order to receive information about the current status of the patient.
2.2 Patient characteristics
Patient characteristics are presented in Table 1
. Relevant concomitant diseases and preoperative state were documented according to the European System for Cardiac Operative Risk Evaluation (EuroScore) [5,6]. The EuroScore variables were adapted according to the conventional logistic EuroScore attributing a weight of zero to the variables ‘ventricular septal rupture’ and ‘thoracic aortic surgery’, which were not documented in this study. Additionally, we documented other preoperative parameters, e.g., coronary risk factors, such as arterial hypertension, hyperlipoproteinemia and diabetes.
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2.5 Intra-operative data
Intra-operative data were subdivided into parameters, that cannot be influenced by fibrin glue and parameters that may conceivably be influenced by fibrin glue according to Table 3
. The following intra-operative data were recorded: aortic cross clamp time, bypass time, number of anastomoses, use of fibrin glue and amount of fibrin glue. Moreover, intra-operative complications, such as re-institution of cardiopulmonary bypass (CPB), low cardiac output and implantation of an intra-aortic balloon pump (IABP) was documented.
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2.6 Postoperative data
Postoperative complications such as resuscitation, ventricular fibrillation, IABP implantation, re-operation, angiography and myocardial infarction were documented as shown in Table 4
. Furthermore maximal creatine kinase (CK) and creatine kinase myocardial band (CKMB) values were recorded within the first postoperative days. We considered CK values above 500 U/l and CKMB values above 50 U/l as significant elevation, indicating myocardial ischemia.
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2.7 Statistical analysis
The primary endpoint for the study was the 30-day all-cause mortality rate in the Tissucol® Duo S treated group compared to the 30-day mortality in the control group.
Summary measures (mean, standard deviation, median, minimum and maximum for quantitative data, and counts and percentages for categorical data) were used to describe the distribution of patient characteristics as well as intra- and postoperative variables in either group. Fisher's exact test and Wilcoxon rank sum test were used for comparing two patient groups with respect to binary and (at least) ordinal-scaled variables, respectively. Differences between survival curves were assessed by means of the log rank test. Quantitative data that were potential confounders of the Tissucol® Duo S effect (e.g., age, aortic cross clamp time, number of anastomoses) were dichotomized by using cut-off points determined in a preliminary analysis described below.
The main objective of modeling was neither prediction of individual survival nor a ‘ranking’ of prognostic factors, but rather adjustment for potential confounding [7–9].
The analysis proceeded in two steps.
2.7.1 Step 1: Screening for potential confounding variables and interaction
For all variables that could not conceivably be causally influenced by the use of fibrin glue (including the surgeons performing the operation) both the association with the outcome and with the use of fibrin glue was analyzed by estimating odds ratios (OR) with 95% CI and using Fisher's exact test for non-independence.
2.7.2 Step 2: Multivariable modeling
Model building was done alternatively using a 3% and a 5% criterion for confounding with the Tissucol effect (i.e., the basic multivariable model contained T along with the variables the inclusion of which resulted in a 
3% (5%) change of the estimated model parameter for T in the logistic regression models of Step 1.
2.7.3 Additional analyses
2.7.4 General remarks
All statistical tests were two-tailed. The level of significance was 
= 0.05. No adjustment for multiple testing was done. Statistical analysis was performed using the SAS and the SPSS statistics software.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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3.1 Part I: Tissucol® Duo S group versus control group
3.1.1 Patient characteristics
Patients in the control group were older than in the Tissucol® Duo S group (67.3 vs 65.6 years, p
< 0.001) (Table 1). As for the EuroScore variables, more patients in the Tissucol® Duo S group had previous cardiac surgery (15.5 vs 8%, p
< 0.001), more patients suffered from active endocarditis (1.7 vs 0.6%, p
= 0.014), and more patients underwent combined surgical procedures (37.1 vs 28.0%, p
< 0.001). The EuroScore was not statistically different between both patient groups. As mentioned above, patients in the control group were older than in the Tissucol® Duo S group (age >70; 42.4 vs 36.3%, p
= 0.005).
With regard to the other preoperative parameters, e.g., coronary risk factors, there was no significant difference between both groups.
3.1.2 Surgical procedures
More patients in the control group underwent isolated CABG surgery (72.0 vs 62.9%, p
< 0.001). In the Tissucol® Duo S group more patients received additional aortic valve replacement (17.7 vs 14.0%, p
= 0.021) and other combined operations (13.3 vs 8.7%, p
= 0.001) (Table 2).
3.1.3 Intra-operative data
As shown in Table 3 there were significant differences between the two groups with respect to intra-operative parameters. Aortic cross clamp time was significantly longer in the Tissucol® Duo S group (69.7 vs 55.3 min, p
< 0.001). Bypass time was also longer in this group (126.5 vs 97.3 min, p
< 0.001). Intra-operative low cardiac output, implantation of IABP and re-institution of cardiopulmonary bypass occurred significantly more often in the Tissucol® Duo S group (p
< 0.001).
3.1.4 Postoperative data
Thirty-day-mortality was 5.5% in all patients, 8.5% in the Tissucol® Duo S group and 3.5% in the control group, giving a crude odds ratio of 2.60 (95% CI: 1.77–3.81) and a crude relative risk of 2.46 (1.71–3.54) (Table 4). Thus 30-day-mortality in the Tissucol® Duo S group was significantly higher than in the control group. Causes of deaths were: cardiac failure (85 patients, 71.4%), sepsis (14 patients, 11.8%), multi-organ failure (8 patients, 6.7%), bleeding, pulmonary embolism and others (each 2 patients, 1.7%). In 12 patients autopsy was performed. One patient of the control group died because of bypass graft occlusion and severe myocardial infarction during emergency re-operation. Cumulative survival in both groups is presented in Fig. 1
(p
< 0.0001). Fig. 2
shows the mortality rates by the amount of fibrin glue used. According to this figure there was a dose dependent increase of mortality. The odds ratios for death increased with the amount of fibrin glue used. In the postoperative course more patients in the Tissucol® Duo S group underwent re-operation (6.7 vs 4.3%, p
= 0.019). Elevated CK and CKMB values occurred significantly more often in the Tissucol® Duo S group.
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Primary endpoint for this study was the 30-day all-cause mortality rate in the Tissucol® Duo S treated group compared to the 30-day mortality in the control group. The major issue of this study was the investigation of the safety of the use of Tissucol® Duo S in cardiovascular surgery. We found an increased 30-day mortality in the Tissucol® Duo S group compared to the control group (8.5 vs 3.5%, p < 0.001). In order to determine if and to what extent the apparent fibrin glue effect might be due to confounding effects from covariates, a careful adjustment for confounding was done. This included a variety of multivariable models taking into account all variables that proved to have a relevant confounding effect in bivariate analysis. No adjustment was done for any intra- or postoperative variables that might conceivably be causally influenced by the use of fibrin glue. Thus, the elevated apparent fibrin glue risk was indeed reduced by multivariate adjustment, but it was not eliminated.
In other words, mortality risk after isolated or combined CABG surgery was significantly increased in patients who received fibrin glue intra-operatively. And although we identified several cofactors reducing the risk of fibrin glue, such as prolonged aortic cross clamp time, the mortality risk still remains significantly elevated compared to the control group.
As these results are contradictory to our clinical experience, we have been looking for explanations.
First, this study is based on a retrospective data collection. As such, it is limited to the variables that are documented in the patient charts. According to our statistical analysis, none of the documented cofactors reduced the fibrin glue effect on mortality below an odds ratio of 2.2. Nevertheless, it cannot be excluded that important variables have been omitted. The EuroScore which was used in this study for predicting operative mortality does not include intra-operative findings such as coronary anatomy and operative difficulties. However, most surgeons would agree that these intra-operative variables have a significant impact on operative morbidity and mortality. Unfortunately, the information provided in the operative reports depends very much on the individual surgeon and could therefore not be considered for our analysis. Instead of the missing intra-operative variables we included some surrogate parameters which reflect the complexity of the operation like aortic cross clamp time, number of anastomoses and LV dysfunction. In a prospectively conducted data acquisition exact documentation of these intra-operative parameters would of cause be mandatory.
The same methodical problem applies to the indication for the use of fibrin glue, i.e., haemostasis in most patients. Neither the exact localization of bleeding nor the application site of fibrin glue has been specified in the majority of operative reports. Therefore, the only reproducible parameter we included in our analysis was the amount of fibrin glue used. Referring to haemostasis the following parameters have a major impact on surgical outcome: intra- and postoperative amount of bleeding, intra- and postoperatively administered blood products and clotting factors as well as the coagulation status of the patient. None of these variables has been documented in this study.
Secondly, the mechanism of the supposed deleterious fibrin glue effect remains unclear. One hundred nineteen patients (5.5%) died within the first 30 days after the operation. Among them 85 patients (71.4%) died because of cardiac reasons; other causes of death were sepsis, multi-organ failure, bleeding, pulmonary embolism and other reasons. Bypass graft occlusion has been proven in only one patient of the control group. Autopsy has been performed in 12 of deceased patients (1%). According to our data, the difference of myocardial infarction rate between the Tissucol® Duo S group and the control group was not statistically significant, although there was a tendency towards an increased rate of myocardial infarction in the fibrin glue group.
Provided that fibrin glue causes bypass graft occlusion by activation of clotting factors or penetrating of the thrombin component through the wall of the vein graft, it has to be administered directly on the bypass graft on proximal or distal anastomoses. However, in our patients the application sites were varying. Fibrin glue was not only used directly on the bypass graft, but also for epicardial bleeding in redo-operations, aortic sutures in combined aortic surgery and severe bleeding from the sternum. Moreover, antibiotic sealing of valve prostheses was another indication for fibrin glue which is not related to haemostasis. Unfortunately, as mentioned above, the application sites of fibrin glue have not been specified in the majority of operation records. The same applies to the way of administration. Fibrin glue can be administered directly by the application system that consists of two syringes that can be used with and without additional needle, but it can also be administered by spray-application. In this case, compressed air is used to spread the glue over a large area with diffuse bleeding. With this method it is theoretically possible that small amounts of fibrin glue are squeezed into the vein graft at the anastomotic site between the stitching wholes by inadequate air pressure or distance of the spray device. Another possible source of incorrect application of fibrin glue may be caused by insufficient mixture of both components by incomplete thawing. However, literature reports dealing with safety concerns in connection with the use of Tissucol® are mainly associated with immunogenicity of components of the product and its consequences in pre-sensitized patients [3,4], as mentioned above. Kjaergard and Fairbrother reviewed 24 controlled clinical studies of fibrin sealant in cardiothoracic surgery. They found that in none of the studies fibrin glue had any negative effect. They concluded that when applied properly fibrin glue is safe and effective therapeutic tool in cardiothoracic surgery [10]. We learned from this analysis that we pay increased attention to the correct preparation of fibrin glue, i.e., complete thawing and mixture of the components. Moreover, we avoid spray-application directly on bypass graft anastomoses. Routine applications of fibrin glue in CABG surgery such as sealing of the anastomosis in MIDCAB surgery should probably be reconsidered.
In sum, the underlying clinical situation which led the surgeon to the usage of fibrin glue is not specified exactly. For further clarification of the negative effect of fibrin glue on mortality after CABG surgery some distinctive variables have to be defined which describe the intra-operative course including the anatomy, surgical difficulties and the complexity of the procedure. Moreover, further haemostasis related information should be provided like preoperative coagulation status of the patients and peri-operatively administered blood products. According to our experience the use of Tissucol® Duo in cardiac surgery is a predictor not a cause for increased postoperative 30-day mortality. The same applies to the dose-dependent effect of fibrin glue. A comparison may be drawn with one of the most effective drugs in cardiac surgery, i.e., adrenalin: It is obvious that patients who received adrenalin have a significantly higher risk to die compared to those patients who never received this drug. The same applies to the dose dependent mortality risk of adrenalin: The more adrenalin a patient receives, the higher is his risk to die. But, would anybody therefore accuse adrenaline of being harmful to the health of our patients?
Although the apparent increase of mortality risk associated with the use of fibrin glue could not be eliminated by the applied statistical means, we consider Tissucol® Duo S fibrin glue a safe and effective therapeutic tool in patients undergoing coronary artery bypass grafting based on long-term clinical experience.
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Footnotes |
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References |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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