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Ann Thorac Surg 2003;75:1872-1877
© 2003 The Society of Thoracic Surgeons
a Department of Cardiothoracic Surgery, The Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
b The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Accepted for publication December 31, 2002.
* Address reprint requests to Dr Lev-Ran, Department of Cardiothoracic Surgery, The Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel
e-mail: orenlevran{at}hotmail.com
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Abstract |
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METHODS: One-hundred twenty-four insulin-treated diabetics, operated on between April 1996 and December 2001, were compared according to the surgical technique used: BITA (n = 50) or single internal thoracic artery (SITA; n = 74). In the latter, complementary grafts used were saphenous veins and radial arteries.
RESULTS: The groups had comparable risk profiles, with the exception of more neurologic events in the SITA group (21% vs 4%, p = 0.008). There was no significant difference in 30-day mortality (6% vs 4%, p = 0.684), nor in the incidence of neurologic complications (2% vs 8%, p = 0.240). The rate of sternal infection was comparable (4% vs 2.7%, p = 1.000). Use of BITAs was associated with a lower return of angina (4% vs 20%, p = 0.025), less cardiac events (17% vs 38%, p = 0.01), and reduced cardiac mortality (none vs 10%, p = 0.04). Despite the similar 6-year survival (80.5% and 77.4%, p = NS), cardiac-related event-free survival was better in BITA patients (69% vs 23%, p < 0.0001). Multivariate analysis identified use of BITA as a protective factor resulting in less return of angina (p = 0.007) and improved cardiac-related event-free survival (p = 0.001).
CONCLUSIONS: Skeletonized BITA grafting can be performed in insulin-treated diabetics at acceptable risk. This approach may confer improved cardiac outcome. Thus, it should be considered in selected patients.
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Introduction |
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The superiority of the internal thoracic artery (ITA) over other conduits has been established. Comparative histopathologic studies have demonstrated improved ITA resistance to the development of arteriosclerosis, intimal hyperplasia, and medial calcification [3]. This benefit has been further enhanced in diabetics [4]. Similarly, vasoreactive properties, reflected by ITA endothelial function, are better maintained after long-term diabetes [5].
The use of two ITAs in CABG has been associated with decreased risk of death, reintervention, and return of angina [6]. However, despite these advantages, use of multiple ITA grafts in diabetics remains unresolved. Many surgeons are reluctant to use this strategy due to concerns of high rate of sternal complications [7] and subsequent lethal mediastinitis.
Skeletonized ITA mobilization has attenuated the risk of sternal infection following bilateral ITA (BITA) grafting [8]. This has been credited to a lesser reduction in sternal vascularity compared with nonskeletonized ITA harvesting [9]. Although several reports have advocated that BITA grafting may be implemented safely in diabetics [10, 11], thereby bestowing these patients with the long-term benefits of this strategy, the feasibility of this approach in insulin-treated diabetics has yet to be determined.
This study compares the risk of skeletonized BITA grafting in insulin-treated diabetics, and evaluates its impact on long-term outcome.
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Material and methods |
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Patients were eligible for inclusion in the study if they were diagnosed as having type 2 diabetes and treated with insulin protocols for at least 1 year before the index surgery. Insulin treatment had been initiated following failure of maximal oral therapy.
Contraindications to the use of both ITAs were emergency operations and the diagnosis of chronic obstructive pulmonary disease (COPD); a category that included chronic bronchitis, emphysema, and bronchial asthma [8, 10]. Since October 2000 obese diabetic females were also excluded, after midterm analysis revealed a tenfold rate of deep sternal infection in this particular subgroup [10]. The 4 COPD patients included in the BITA subgroup were among the first enrollees who were recruited before established data on the risk of sternal infection appeared. The presence of diabetes mellitus was not considered a contraindication for skeletonized BITA grafting.
Neurologically symptomatic patients or asymptomatic patients 65 years of age or older were screened preoperatively by carotid Doppler assays; those requiring carotid endarterctomy (symptomatic with unilateral stenosis > 70% or asymptomatic with severe bilateral stenosis), were excluded from this study.
Glucose management upon admission included sliding-scale guided intermittent subcutaneous insulin injections aimed to achieve glucose levels of less than 250 mg/dL.
Surgical technique
All operations were performed through a midline sternotomy. Grafting was achieved with cardiopulmonary bypass (CPB) or by off-pump coronary artery bypass (OPCAB) techniques. Myocardial preservation involved intermittent, antegrade, and retrograde blood cardioplegia (30° to 32°C) during CPB and OPCAB was facilitated by use of CTS stabilizers (Guidant, Curpentino, CA) or the Octopus system (Medtronic, Minneapolis, MN).
Skeletonized BITA [8, 10] were used to graft the left coronary artery system, (the left anterior descending [LAD] artery and circumflex systems) [12]. For this purpose T grafts or in situ crossover ITA arrangements were used [12]. The type of ITA configuration used was not related to the patient’s diabetic status but rather to technical considerations [12]. In the BITA group, supplemental grafting the right coronary system was performed with in situ right gastroepiploic artery (RGEA) or saphenous vein graft (SVG).
Use of RA was avoided when the degree of the target coronary stenosis was less than 70% reduction in diameter [13]. The majority of RA were attached proximally on in situ left ITA to form a T-graft configuration.
Postoperative management included high doses of intravenously administered isosorbide dinitrate (4 to 20 mg/hour) for 2 days [12]. A 6-month course of calcium-channel blockers (diltiazem 90 to 180 mg/day orally) were prescribed when RA or RGEAs were used, starting from the second postoperative day. Glucose management was initially aimed to maintain a level of less than 250 mg/dL by sliding-scale guided intermittent subcutaneous insulin injections. However, since late 2000, the Portland protocol was pursued [14]; with continuous intravenous insulin for 1 to 2 days, targeted at glucose less than 200 mg/dL.
Patients’ data were collected and analyzed according to the STS National Cardiac Surgery database guidelines and definitions (http://www.ctsnet.org/doc/4314).
Follow-up was obtained by a telephone questionnaire and ranged between 6 and 70 months (median 55 months).
Statistical analysis
Data are expressed as mean ± standard deviation. The X2 test and Fischer’s exact test were used to compare discrete variables. Multivariable logistic regression analysis was used to evaluate the influence of preoperative and operative variables on early mortality and recurrence of angina.
Cox proportional hazard model was used to evaluate the influence of preoperative and operative variables on late survival, late cardiac mortality, and cardiac-related event-free survival. Postoperative survival was expressed by the Kaplan-Meier method. All analyses were performed by SPSS software (version 9; SPSS, Chicago, IL).
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Results |
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The 30-day mortality was comparable (Table 2). Two patients died of infectious complications (1 patient in each group), and one death resulted from acute renal failure (BITA group). Multivariate analysis did not identify any variable as a predictor for early death. The incidence of deep sternal infections was similar (4% vs 2.7%, p = 1.000). Neurologic complications were more frequent in the SITA group (8% vs 2%); however, this difference was not significant (Table 2).
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Late follow-up was available in 98% of the surviving patients. There were 10 (14%) and 3 (6.4%) late deaths in the SITA and BITA groups, respectively (p = 0.240), with comparable Kaplan-Meier 1- and 6-year survival (92% and 80.5% vs 83% and 77.4% in the BITA and SITA groups, respectively, p = 0.252, log rank test; Fig 1). However, the primary mode of death in the SITA group was cardiac related (7 of 10 patients). The distribution among BITA patients was cancer (2 patients) and complicated pneumonia. Cardiac-related mortality (a category that included late fatal myocardial infarction [MI] and sudden death) was lower in the BITA patients (Table 2).
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Using a Cox regression model with late cardiac death as the censored variable, the only predictor of cardiac mortality was congestive heart failure (CHF; p = 0.015). None of the other explanatory varibles were found to have a significant effect on survival time, including: age (p = 0.125); female gender (p = 0.159); cardiac dysfunction (p = 0.964); preoperative use for intraaortic balloon pump (IABP; p = 0.985); and variables predisposing for microvascular disease, duration of insulin-treatment (p = 0.240), peripheral vascular disease (PVD; p = 0.800), neurologic events (p = 0.340), chronic renal failure (CRF; p = 0.966), hypertension (HTN; p = 0.615), and hyperipidemia (p = 0.413).
Return of angina was higher in SITA patients (p = 0.025; Table 2). The aforementioned variables were assessed by logistic regression. Age (p = 0.208), female gender (p = 0.0.178), cardiac dysfunction (p = 0.285), CHF (p = 0.995), preoperative IABP (p = 0.826), duration of insulin-treatment (p = 0.371), PVD (p = 0.695), neurologic events (p = 0.697), chronic renal failure (CRF) (p = 0.536), hypertension (HTN) (p = 0.411), hyperipidemia (p = 0.572), use of SVG (p = 0.377), and use of RA (p = 0.389) were insignificant. Use of BITA resulted in less return of angina (p = 0.007).
Coronary angiography was performed in 12 (10%) of the survivng patients (average 24 months). Postoperative angioplasty was performed in 7 patients (5.9%). Four procedures were required for non-ITA graft failure, two procedures for progressive disease in nongrafted coronary arteries, and one for occluded ITA graft. Repeat CABG was performed in 1 SITA patient 22-months after the initial operation. Despite even distribution of reinterventions in the groups, ITA grafts (included in both groups) demonstrated 96% patency (25 of 26 anastomoses).
Occurrence of cardiac-related events (return of angina, reinterventions, nonfatal MI, and cardiac death) were significantly lower in the BITA group (p = 0.014).
One-year and 6-year cardiac-related event-free survival (Kaplan-Meier) was significantly better following BITA grafting (98% and 69% in the BITA group, and 82% and 23% in the SITA group, p < 0.00001, log rank test; Fig 2). Cox regression analysis identified CHF as risk a factor for reduced cardiac-related event-free survival (p = 0.006). Age (p = 1.023), female gender (p = 0.784), cardiac dysfunction (p = 0.901), preoperative IABP (p = 0.981), duration of insulin-treatment (p = 0.241), diabetic retinopathy (p = 0.155), PVD (p = 0.979), neurologic events (p = 0.724), CRF (p = 0.514), HTN (p = 0.491), hyperipidemia (p = 0.455), use of SVG (p = 0.744), and use of RA (p = 0.194) did not significantly affect this outcome. However, after adjustment to all variables, use of BITA was found to be a protective factor (p = 0.001). Applying the Cox regression model within the SITA group identified use of SVG as a risk factor for reduced cardiac-related event-free survival (p = 0.039).
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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The 4% rate of sternal infections was not significantly higher in the BITA group, considering that SITA mobilization was associated with a 2.7% risk. To date there is sparse data on this risk; however, the incidence in this cohort is in concert with a recent report of 4.3% (2 patients) among 47 insulin-treated diabetics [15]. Although use of BITA is considered a risk factor for sternal infection [7], this risk appears to be attenuated by skeletonized ITA mobilization [8]. Improved sternal vascularity has been reported by single photon emission computed tomography [9], and probably reflects the preservation of collateral sternal blood supply. The positive effect of BITA skeletonization has also been documented in diabetics [10, 11] with a subsequent similar complication rate to nondiabetics [10, 11].
The important role of perioperative continuous intravenous insulin, aimed at glucose levels of less than 200 mg/dL, has been reported [14]. By applying the Portland protocol in diabetics, several reports [14, 16] were able to reduce the rate of mediastinitis to the range of 0.3% to 0.8%. Stringent observance of glucose values was applied only later in the cohort, nevertheless, did not fully comply with the standards described [14]. Further reduction in sternal infections may be anticipated if this protocol is fully adopted. Continuation of intravenous insulin is of no benefit beyond the second postoperative day [14].
Defining the appropriate patient profile is the third important factor. We have previously delineated the combination of diabetes, obesity, and female sex to be associated with a tenfold rate of sternal infections following BITA grafting [10]. Recently, this risk combination has emerged again; obese diabetics had 7.7-fold increased risk for sternal infection following CABG [17]. Thus, BITA grafting should be avoided in insulin-treated diabetics with BMI more than 29 kg/m2, associated COPD, or undergoing emergency operations [10, 17].
The 30-day mortality was comparable. The 6% BITA mortality was compatible with the expected mortality (5.6%), estimated by the standard Euroscore (http://www.euroscore.org). Use of BITA was not a predictor for early death and the primary mode of death was noncardiac fatal complications. Magee and coworkers [18] determined that avoidance of CPB in diabetics would result in less renal deterioration, nevertheless, the authors could not demonstrate survival benefit. Whether insulin-treated diabetics would further benefit from avoidance of CPB could not be assessed in this study, in face of the limited number of OPCAB procedures.
An alarming fourfold increase in neurologic complications in the SITA group was observed (although statistically insignificant). This may be attributed to preoperative dissimilarities, that is, more prior strokes in this subgroup, but may also result from manipulation of diseased aorta during construction of proximal anastomoses [19]. Epi-aortic ultrasound has been applied since 2001; before this date, detection of atheromatous aorta was based on palpation only.
Lower extremity wound complications emerged as a significant factor of morbidity among this cohort because 7.4% (4 patients) required surgical interventions (Table 2). The reported incidence of this complication ranges from 1% to 24%, and may reach 44% [20]. Although major complications requiring surgical intervention occur in only 0.65% of the patients, risk correlates are female gender, PVD, and diabetes [20]. Avoidance of SVG, or the use of a short segment only, is an inherent benefit of BITA grafting.
Long-term outcome after CABG is related to the severity of diabetes at time of surgery [21]. It may be reasoned that the superior outcome of BITA patients resulted from differences in the severity of diabetic microvascular involvement between the groups. To assess possible bias several variables were evaluated. The presence of diabetic retinopathy has been signified as a marker for microvascular involvement, its severity directly related to the severity and duration of hyperglycemia, and is associated with reduced long-term outcome in diabetics [22]. This marker and other parameters of microvascular disease were entered in a multivariate analysis and were not found to be predictors of cardiac outcome. After adjustment to all explanatory variables, use of BITA was determined as a protective factor associated with improved cardiac-related event-free survival. Although the positive impact of ITA use on late outcome in diabetics has been reported [1, 23], data on BITA grafting in insulin-treated diabetics is sparse. The superior ITA biology [3, 4] and left-sided BITA grafting, a determinant of improved outcome [6], may account for the better outcome in BITA patients.
The low number of postoperative angiographies prevented any conclusions with regard to patency rate of ITAs versus non-ITA conduits. Although the difference in return of angina was not reflected in the reintervention rate (Table 2), it became apparent that patients were advised by their physicians against catheterizations, suspecting deterioration of renal function. Subsequently, this outcome may be biased. Conducting systematic routine angiographic follow-up in insulin-treated diabetics involves an ethical problem.
Lately, the RA has been advocated as the complementary conduit of choice in diabetics [5]. Comparison between BITA and ITA-RA strategies in a study would be invalid due to the small cohort and the fact that follow-up period is not comparable. However, use of RA in severe diabetics may be questioned:
So far, the ITA is the only conduit to positively affect survival in diabetics [1]. The impact on survival of non-ITA arterial grafts, including the RA, awaits confirmation.
Several limitations of this study need to be addressed. In this study, the control group (SITA) included two different supplemental grafts. This was done to enlarge the size of the cohort and improve its statistical power. The study was primarily designed to assess the risk of sternal infection. However, although it is suggested that use of BITA is associated with improved late cardiac outcome and that use of SVG negatively effects these results, the role of complementary RA is not fully resolved. A larger cohort comparing BITA and SITA-RA subgroups would be required to determine the strategy of choice in these diabetics.
It has been demonstrated that skeletonized BITA grafting can be achieved in selected insulin-treated diabetics without increasing the rate of sternal infection. This strategy may result in improved cardiac-related event-free survival.
In conclusion, the results of this study justify questioning the policy of automatically discouraging BITA grafting in insulin-treated diabetics. However, if implemented, skeletonized ITA harvesting, patient selection, and vigilant perioperative glucose management is recommended.
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