Off-Pump Coronary Artery Bypass Grafting With Skeletonized Bilateral Internal Thoracic Arteries in Insulin-Dependent Diabetics

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1 Off-Pump Coronary Artery Bypass Grafting With Skeletonized Bilateral Internal Thoracic Arteries in Insulin-Dependent Diabetics Masashi Kai, MD, Michiya Hanyu, MD, PhD, Yoshiharu Soga, MD, PhD, Takuya Nomoto, MD, PhD, Jota Nakano, MD, Takehiko Matsuo, MD, Eitaro Umehara, MD, Masahide Kawato, MD, and Hitoshi Okabayashi, MD, PhD Department of Cardiovascular Surgery, Kokura Memorial Hospital, Fukuoka; and Department of Cardiovascular Surgery, Iwate Medical University Memorial Heart Center, Iwate, Japan Background. We evaluated the effects of coronary artery bypass with off-pump skeletonized bilateral internal thoracic artery grafting in patients with insulin-dependent diabetes. Methods. One hundred eighty-five consecutive patients with insulin-dependent diabetes who underwent isolated coronary artery bypass grafting with bilateral internal thoracic grafts were retrospectively compared according to surgical technique, ie, off-pump grafting with skeletonized internal thoracic artery (n 162) or on-pump grafting with pedicled internal thoracic artery (n 23). Results. The on-pump group was younger ( versus years; p 0.02) and had fewer distal anastomoses ( versus ; p 0.02) than the off-pump group. No 30-day mortality occurred in either group. The incidence of deep sternal infection was significantly lower in the off-pump group than in the on-pump group (0.6% versus 13.0%; p 0.01). The early angiographic results did not differ between the two groups. The median duration of follow-up was 3.4 years (range, 0.1 to 9.9 years). Rates of survival, freedom from cardiac mortality, and freedom from cardiac-related events (including cardiac-related death, myocardial infarction, percutaneous coronary intervention, repeat coronary artery bypass grafting, and congestive heart failure) did not differ between the two groups. Dialysis, peripheral vascular disease, ejection fraction less than 0.40, and age were independent risk factors of late death. Conclusions. Overall, our results support the surgical management of coronary artery bypass grafting in insulin-dependent diabetics using off-pump skeletonized bilateral internal thoracic artery grafting. (Ann Thorac Surg 2007;84:32 7) 2007 by The Society of Thoracic Surgeons The current evidence suggests that diabetics have better survival with coronary artery bypass grafting (CABG) than with percutaneous coronary interventions [1, 2]. Internal thoracic artery (ITA) grafts are important because the higher survival rate in diabetics after CABG is limited to patients who receive ITA grafts. Recently, bilateral internal thoracic artery (BITA) grafting was applied to gain further beneficial long-term results. Several reports have indicated that BITA grafting gives better survival rates and higher rates of freedom from cardiac-related events in diabetics than does single ITA grafting, although no randomized trials have been published [3 6]. Patients with insulin-dependent diabetes also benefit from BITA grafting in long-term studies [7]. However, from early results it has been commonly recognized that BITA grafting should be avoided in diabetics and particularly in insulin-dependent diabetics. The reason for avoiding BITA grafting is evidence that Accepted for publication Feb 28, Address correspondence to Dr Okabayashi, Department of Cardiovascular Surgery, Iwate Medical University Memorial Heart Center, Chuodori 1-2-1, Morioka, Iwate, , Japan; cardiovascsurg@siren.ocn.ne.jp. BITA grafting is accompanied by increasing rates of deep sternal wound infection [8, 9]. Recently, it was reported that skeletonized harvesting of ITAs was associated with a lower incidence of sternal infection than occurs with pedicled harvesting [10, 11]. In addition, the advantage of off-pump CABG versus the conventional CABG in high-risk patients has been reported in several studies [12 14]. We have been actively performing BITA grafting by using these techniques skeletonization and off-pump grafting in selected patients with insulin-dependent diabetes who we believe will gain the most beneficial long-term results from BITA grafting. The purpose of our study was to investigate the effects of off-pump, skeletonized BITA grafting in insulin-dependent diabetics. Patients and Methods Between January 1996 and December 2005, 802 consecutive patients with diabetes underwent isolated CABG with BITA grafting at Kokura Memorial Hospital. Among them, 185 patients (23.1%) treated with insulin were retrospectively analyzed. The insulin-dependent diabet by The Society of Thoracic Surgeons /07/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg KAI ET AL 2007;84:32 7 OFF-PUMP CABG IN TYPE 1 DIABETES Table 1. Patients Characteristics and Operative Data Characteristic Skeletonized Pedicled (N 162) (N 23) p Value Age (y), mean SD Female, 70 (43.2%) 12 (53.2%) Comorbidity Hypertension, 104 (64.2%) 12 (52.2%) Hyperlipidemia, 86 (53.1%) 14 (60.9%) Peripheral vascular 42 (25.9%) 5 (21.7%) disease, Dialysis, 21 (13.0%) 3 (13.0%) Cerebrovascular disease, 35 (21.6%) 6 (26.1%) Previous PCI, 73 (45.1%) 7 (30.4%) Previous myocardial 78 (48.1%) 10 (43.5%) infarction, Unstable angina, 29 (17.9%) 3 (13.0%) Ejection fraction 0.40, 31 (19.1%) 5 (21.7%) Left main trunk disease, 56 (34.6%) 8 (34.8%) Three-vessel disease, 135 (83.3%) 17 (73.9%) Emergent, 10 (6.2%) 0 (0.0%) Redo, 0 (0.0%) 1 (4.3%) Preoperative IABP, 7 (4.3%) 0 (0.0%) No. of distal anastomoses, mean SD Y composite grafting, 40 (24.5%) 3 (13.0%) IABP intraaortic balloon pump; PCI percutaneous coronary intervention; SD standard deviation. ics were subdivided into two groups, off-pump ITA grafting group (n 162) and on-pump ITA grafting group (n 23). Internal thoracic arteries were harvested in a skeletonized manner in the off-pump group and in a pedicled manner in the on-pump group in accordance with the hospital protocols at the time (see below). The two groups were compared with regard to operative mortality, morbidity, early angiographic results, and late results. Permission to use the appropriate database was obtained from the review board of Kokura Memorial Hospital, and informed consent was obtained from each participant. The preoperative characteristics of the patients and the operative data are summarized in Table 1. Surgical Technique Before January 2000, ITAs were harvested in a pedicled manner and cardiopulmonary bypass was used routinely. Thereafter, the skeletonized technique and offpump grafting was introduced as another option and used in isolated CABG cases as a first choice. Pedicled ITAs were harvested by the standard technique. Skeletonized ITAs were dissected as isolated arteries with an ultrasonic scalpel (Harmonic Scalpel, dissecting-hook type; Ethicon Endo-Surgery, Cincinnati, OH). Internal thoracic arteries were harvested from the subclavian vein level to about 5 cm distal to the bifurcation of the musculophrenic and superior epigastric arteries. Our basic strategy was in situ BITA grafting for left-sided revascularization (left ITA to left anterior descending artery, right ITA routed through the transverse sinus to major branches of the circumflex artery) and either gastroepiploic artery or saphenous vein grafting for right-sided revascularization. However, in cases in which the in situ right ITA did not reach the major branches of the circumflex artery, a Y graft was constructed by attaching the free right ITA proximally to the left ITA in an end-to-side manner. Since 2001, before closing the chest we had routinely removed the xiphoid process: we had seen some cases in which the xiphoid process had become necrotic possibly because of ischemia and had become a source of infection after BITA harvesting. For blood glucose control in the early postoperative period, we used intravenous insulin injections every 3 to 6 hours in a directed attempt to maintain blood glucose levels less than 200 mg/dl. If it was difficult to control glucose levels by the above method, we used continuous insulin injection protocols [15]. Postoperative angiography was performed approximately 2 weeks after surgery (before discharge) for graft evaluation. All the anastomoses were performed by one experienced surgeon. Definition Deep sternal wound infection was defined according to the guidelines of the Centers for Disease Control and Prevention, with patients meeting at least one of the following criteria: (1) isolation of an organism from culture of mediastinal tissue or fluid; (2) evidence of mediastinitis during sternal reexploration; or (3) chest pain, sternal instability, or fever present in combination with purulent discharge from the mediastinum or isolation of an organism from blood or tissue cultures. Statistical Methods Data are expressed as mean standard deviation. Unrelated two-group comparisons were done with unpaired, two-tailed Student s t tests for continuous Table 2. Early Results Variable Skeletonized Pedicled (N 162) (N 23) p Value Mortality 30-day, 0 (0.0%) 0 (0.0%) N/A In-hospital, 2 (1.2%) 0 (0.0%).999 Morbidity Deep sternal infection, 1 (0.6%) 3 (13.0%) Reexploration, 0 (0.0%) 1 (4.3%) Intraoperative stroke, 1 (2.4%) 0 (0.0%) Blood transfusion, 77 (47.5%) 16 (69.6%) N/A not applicable. 33 CARDIOVASCULAR

3 34 KAI ET AL Ann Thorac Surg OFF-PUMP CABG IN TYPE 1 DIABETES 2007;84:32 7 Table 3. Early Angiographic Results Variable Fitzgibbon A Fitzgibbon B Occlusion Patency Rate (%) skeletonized LITA (n 137) RITA (n 137) GEA (n 66) SVG (n 58) pedicled LITA (n 23) RITA (n 23) GEA (n 7) SVG (n 12) GEA gastroepiploic artery; LITA left internal thoracic artery; RITA right internal thoracic artery; SVG saphenous vein graft. Fig 2. Freedom from cardiac-related mortality (p 0.985). (ITA internal thoracic artery.) variables and the 2 or Fisher s exact test for categorical data. Survival curves, curves of freedom from cardiac mortality, and curves of freedom from cardiac events were estimated by the Kaplan Meier method. Statistical significance was calculated by the log-rank test. Cox proportional hazard models were used to determine the influence of patients characteristics and operative data on late survival. Hazard ratios, 95% confidence intervals, and levels of statistical significance (p values) were calculated. In all statistical tests a two-sided probability value less than 0.05 was considered significant. All data were analyzed with Stat- View version 5.0 (SAS Institute, Inc, Cary, NC). Results Patient Characteristics and Operative Data The off-pump, skeletonized group was significantly older and had more distal anastomoses (Table 1). Early Results Table 2 shows early results. No 30-day mortality occurred in either group. The off-pump, skeletonized group had a significantly lower incidence of deep sternal infection. Of the 4 patients with deep sternal infection, 2 were dialysis patients. Early Angiographic Results Twenty-three patients (100%) in the on-pump, pedicled group and 137 patients (84.6%) in the off-pump, skeletonized group underwent early angiography (Table 3). The Fitzgibbon classification was used for graft evaluation [16]. Only Fitzgibbon A was considered to be patent. All of the 4 patients with occluded ITA grafts (2 left ITAs and 2 right ITAs) subsequently underwent percutaneous coronary intervention for revascularization of the branches of the coronary arteries in which the bypass failures had occurred. Fig 1. Kaplan Meier survival (p 0.130). (ITA internal thoracic artery.) Fig 3. Freedom from cardiac-related events (including cardiac-related death, myocardial infarction, percutaneous coronary intervention, redo coronary artery bypass grafting, and congestive heart failure; p 0.709). (ITA internal thoracic artery.)

4 Ann Thorac Surg KAI ET AL 2007;84:32 7 OFF-PUMP CABG IN TYPE 1 DIABETES Table 4. Cox Proportional Hazard Model for Death at Long- Term Follow-Up Variable HR 95% CI p Value Age Female Dialysis Peripheral vascular disease Hypertension Cerebrovascular disease Hyperlipidemia Unstable angina Previous myocardial infarction Previous PCI Left main trunk disease Ejection fraction Emergent CI confidence interval; HR hazard ratio; PCI percutaneous coronary intervention. Late Results The median duration of follow-up was years (range, 1 month to 9.9 years). Kaplan Meier 5-year survivals were 68.6% 5.5% in the off-pump, skeletonized group and 78.3% 8.6% in the on-pump, pedicled group (excluding hospital deaths; Fig 1). The difference between the two groups was not significantly different (p 0.130, log-rank). There were 30 late deaths in the off-pump, skeletonized group. Nine were attributed to cardiac causes: congestive heart failure (n 5) and sudden death (n 4). The other 21 deaths had noncardiac causes: cerebrovascular disease (n 5), sepsis (n 4), renal failure (n 2), liver cirrhosis (n 2), cancer (n 2), and others (n 6). There were 8 late deaths in the on-pump, pedicled group. Six were attributed to cardiac causes: sudden death (n 4), congestive heart failure (n 1), and ventricular fibrillation (n 1). The other 2 deaths were related to noncardiac reasons: cancer and pneumonia. We examined the rates of freedom from cardiacrelated mortality (Fig 2). The 5-year cardiac-related mortality-free rate was 86.1% 5.1% in the off-pump, skeletonized group and 87.0% 7.0% in the on-pump, pedicled group (excluding hospital deaths; Fig 1). This difference was not significant (p 0.985, log-rank). We examined the rates of freedom from cardiacrelated events (including cardiac-related death, myocardial infarction, percutaneous coronary intervention, redo CABG, and congestive heart failure; Fig 3). The 5-year rate of freedom from cardiac-related events was 77.7% 5.7% in the off-pump, skeletonized group and 73.7% 9.2% in the on-pump, pedicled group (excluding hospital deaths; Fig 1). This difference was not significant (p 0.709, log-rank). Cox proportional hazard models (Table 4) were used to assess the effect of confounding factors on late death. Significant predictors of late death were dialysis, peripheral vascular disease, ejection fraction less than 0.40, and age. Comment The most dreaded complication when using BITA grafting in insulin-dependent diabetics is deep sternal infection. Patients who experience deep sternal infection have a 300% increase in hospital mortality rates [8]. However, insulin-dependent diabetics are believed to benefit the most from BITA grafting in the long run. Recently, because of its conservation of sternal blood flow, skeletonized BITA grafting has been reported to result in a lower incidence of deep sternal infection in diabetics than pedicled grafting [10, 11]. Our study demonstrated that a higher risk group, insulin-dependent diabetics, can benefit from skeletonized BITA grafting. We believe that a 0.6% risk of deep sternal infection is acceptable. This result supports our ongoing use of BITA grafting in insulin-dependent diabetics. One recent article reported a 3.2% incidence of deep sternal infection after BITA grafting in insulin-dependent diabetes patients higher than in their single ITA grafting group (1.2%; not significant) [17]. These researchers used a pedicled technique with low electrocautery settings and ligation of the arterial branches. We believe that use of a skeletonized technique with an ultrasonic scalpel is more beneficial in terms of preservation of sternal vascularity and reduces the incidence of deep sternal infection. Indeed, improved sternal vascularity after skeletonized harvesting has been reported by single photon-emission computed tomography [18, 19]. The major concern with off-pump grafting and skeletonization is poor long-term clinical outcome. This could occur because of suboptimal anastomosis quality and incompleteness of revascularization [20]. Potential endothelial damage of the harvested ITAs and poor late clinical results are other concerns when the skeletonized technique is used [21, 22]. However, our study showed that the off-pump, skeletonized group was comparable to the conventional group in terms of early angiographic results and late cardiac results. The longterm survival of the conventional group tended to be better, but the conventional group was significantly younger. We think that this is a primary factor that explains the above phenomenon and also the limitations of this study. Indeed, our Cox proportional hazard model demonstrated that age was an independent risk factor for late death. Thus, we believe that optimal anastomosis and complete revascularization are possible in off-pump grafting. Furthermore, we believe that the ITAs were harvested safely by the skeletonized technique. This was a retrospective study and was not randomized because the off-pump technique was introduced after the on-pump one. The on-pump group was smaller and younger, as we mentioned above. These are primary limitations of our study, although it is still one of the largest to have assessed the effects of off-pump, skeletonized BITA grafting in patients with insulin-dependent diabetes. In conclusion, the incidence of deep sternal infection was reduced by use of the off-pump, skeletonization technique in patients with insulin-dependent diabetes. 35 CARDIOVASCULAR

5 36 KAI ET AL Ann Thorac Surg OFF-PUMP CABG IN TYPE 1 DIABETES 2007;84:32 7 Early angiographic and late clinical results were similar between the two groups. These results support our surgical management of patients with insulin-dependent diabetes by off-pump grafting with bilateral skeletonized internal thoracic arteries. References 1. Brooks MM, Jones RH, Bach RG, et al. Predictors of mortality and mortality from cardiac causes in the Bypass Angioplasty Revascularization Investigation (BARI) Randomized Trial and Registry. Circulation 2000;101: Stent or Surgery Trial Investigators. Coronary artery bypass surgery versus percutaneous coronary intervention with stent implantation in patients with multivessel coronary artery disease (the Stent or Surgery Trial): a randomized controlled trial. Lancet 2002;360: Stevens LM, Carrier M, Perrault LP, et al. Single versus bilateral internal thoracic artery grafts with concomitant saphenous vein grafts for multivessel coronary artery bypass grafting: effects on mortality and event-free survival. J Thorac Cardiovasc Surg 2004;127: Lytle BW, Blackstone EH, Loop FD, et al. Two internal thoracic artery grafts are better than one. J Thorac Cardiovasc Surg 1999;117: Toumpoulis IK, Anagnostopoulos EC, Balaram S, et al. Does bilateral internal thoracic artery grafting increase long-term survival of diabetic patients? Ann Thorac Surg 2006;81: Rizzoli G, Schiavon L, Bellini P. Does the use of bilateral internal mammary artery (IMA) grafts provide incremental benefit relative to the use of a singe IMA graft? A metaanalysis approach. Eur J Cardiothorac Surg 2002;22: Lev-Ran O, Mohr R, Amir K, et al. Bilateral internal thoracic artery grafting in insulin-treated diabetics: should it be avoided? Ann Thorac Surg 2003;75: Borger MA, Rao V, Weisel RD, et al. Deep sternal would infection: risk factors and outcomes. Ann Thorac Surg 1998; 65: Grossi EA, Esposito R, Harris LF, et al. Sternal would infections and use of internal mammary artery grafts. J Thorac Cardiovasc Surg 1999;102: Peterson MD, Borger MA, Rao V, Peniston CM, Feindel CM. Skeletonization of bilateral internal thoracic artery grafts lowers the risk of sternal infection in patients with diabetes. J Thorac Cardiovasc Surg 2003;126: De Paulis R, Notaris S, Scaffa R, et al. The effect of bilateral internal thoracic artery harvesting on superficial and deep sternal infection: the role of skeletonization. J Thorac Cardiovasc Surg 2005;129: Cleveland JC, Shroyer AL, Chen AY, Joseph C, Peterson E, Grover FL. Off-pump coronary artery bypass grafting decreased risk-adjusted mortality and morbidity. Ann Thorac Srug 2001;72: Plomondon ME, Cleveland JC Jr, Ludwig ST, et al. Off-pump coronary artery bypass is associated with improved risk adjusted outcomes. Ann Thorac Surg 2001;72: Magee MF, Jablonski KA, Stamou SC, et al. Elimination of cardiopulmonary bypass improves early survival for multivessel coronary artery bypass patients. Ann Thorac Surg 2002;73: Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003;125: Fitzgibbon GM, Kafka HP, Leach AJ, Keon WJ, Hooper GD, Burton JR. Coronary bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years. J Am Coll Cardiol 1996;28: Momin AU, Deshpande R, Potts J, et al. Incidence of sternal infection in diabetic patients undergoing bilateral internal thoracic artery grafting. Ann Thorac Surg 2005;80: Lorberboym M, Medalion B, Bder O, et al. 99m Tc-MDP bone SPECT for the evaluation of sternal ischaemia following internal mammary artery dissection. Nucl Med Commun 2002;23: Cohen AJ, Lockman J, Lorberboym M, et al. Assessment of sternal vascularity with single photon emission tomography after harvesting of the internal thoracic artery. J Thorac Cardiovasc Surg 1999;118: Kobayashi J, Tashioro T, Ochi M, et al. Early outcome of a randomized comparison of off-pump and on-pump multiple arterial coronary revascularization. Circulation 2005; 112(Suppl 1):I Gaudino M, Trani C, Glieca F, et al. Early vasoreactive profile of skeletonized versus pedicled internal thoracic artery grafts. J Thorac Cardiovasc Surg 2003;125: Ueda T, Taniguchi S, Kawata T, Mizuguchi K, Nakajima M, Yoshioka A. Does skeletonization compromise the integrity of internal thoracic artery grafts? Ann Thorac Surg 2003;125: INVITED COMMENTARY After almost 30 years of routine use, the left internal thoracic artery still remains the gold standard for coronary artery bypass grafting onto the left anterior descending coronary artery. Recently, grafting of bilateral internal thoracic arteries demonstrated long-term superiority in terms of survival and major adverse cardiac events. This benefit has also been confirmed in diabetic patients, but is counterbalanced by a significantly higher risk of deep sternal wound infection as compared with single left internal thoracic artery grafting. Skeletonization of the internal thoracic artery during harvesting has been advocated to reduce this risk. Partisans of this technique argue that skeletonization allows harvesting a longer ITA graft, improves early postoperative blood flow, and preserves the sternal blood supply and reduces the sternal infection rate. On the other hand, opponents suggest that skeletonization may alter long-term graft patency by potentially damaging endothelial function and ITA vasoreactivity by loss of the vasa vasorum. Despite several publications, the debate about the safety and efficacy of skeletonization in diabetic patients remains open. This article by Kai and colleagues [1] tries to answer this question. The question is clinically relevant in diabetics as each surgeon should be aware of the suggested short-term benefit of skeletonization on wound infection and the possible reduced patency rate. Unfortunately, Kai and colleagues [1] do not adequately answer this concern because mean follow up is only years. Nevertheless, the authors confirm an early, significant reduction in deep sternal wound infections with the use of skeletonized BITA (0.6 vs 13%). Moreover and interestingly, the short-term clinical outcome is not different between skeletonized and pedicled groups. But the reader should pay attention to the short-term survival 2007 by The Society of Thoracic Surgeons /07/$32.00 Published by Elsevier Inc doi: /j.athoracsur