Insulin Use and Clinical Outcomes in Patients Undergoing Coronary Artery Bypass Graft Surgery

Abstract

Objective: To describe insulin use and postoperative glucose control in patients undergoing coronary artery bypass graft (CABG) surgery. Methods: We examined 2,390 patients with and without diabetes enrolled in the Contemporary Analysis of Perioperative Cardiovascular Surgical Care (CAPS-Care) Study who underwent CABG surgery (01/2004 - 06/2005) to describe postoperative insulin use, variation in insulin use across different hospitals, and associated in-hospital complications and clinical outcomes. Logistic regression was used to assess the adjusted relationship between insulin use and clinical outcomes. Results: Overall, insulin was used in 82% (n=1,959) of patients, including 95% (n=1,203) with diabetes (n=1,258) and 67% (n=756) without diabetes (n=1,132). Continuous insulin was used in 35.5% of patients in the operating room and in 56% in the intensive care unit. Continuous insulin use varied significantly among centers from 8-100% in patients with diabetes. When compared with all patients not receiving insulin, insulin use in patients without diabetes was associated with a higher rate of death or major complication (adjusted odds ratio [OR]=1.54; 95% confidence interval [CI] 1.15-2.04; P=0.003). In patients with diabetes, insulin use was not associated with a higher risk of adverse outcomes (adjusted OR=1.01; 95% CI 0.52-1.98; P=0.98). Conclusion: The postoperative use of insulin is high among CABG patients in the United States of America. Insulin use in patients without diabetes was associated with worse clinical outcomes compared to patients (both with and without diabetes) who did not receive insulin. Further investigation is needed to determine the optimal use of postoperative insulin after CABG.

[ Table Omitted - see PDF ]

Abbreviations, acronyms & symbols ACSD = Adult Cardiac Surgery Database ESRD = End-stage renal disease AI = Aortic insufficiency IABP = Intra-aortic balloon pump AS = Aortic stenosis ICU = Intensive care unit AVR = Aortic valve replacement MI = Myocardial infarction BMI = Body mass index MR = Mitral regurgitation CABG = Coronary artery bypass graft MS = Mitral stenosis CAD = Coronary artery disease MVr = Mitral valve repair CAPS-Care = Contemporary Analysis of Perioperative Cardiovascular Surgical Care MVR = Mitral valve replacement CHF = Congestive heart failure NYHA = New York Heart Association CI = Confidence interval OR = Odds ratio CVA = Cerebrovascular accident STS = Society of Thoracic Surgeons EF = Ejection fraction VF = Ventricular fibrillation eGFR = Estimated glomerular filtration rate VT = Ventricular tachycardia

INTRODUCTION

Coronary artery bypass graft (CABG) surgery continues to provide a survival advantage over initial medical therapy for many groups of patients, including those with diabetes mellitus¹. As the proportion of patients with diabetes undergoing CABG continues to increase (33% in the year 2000 to 40% in 2009) and in order to maintain favorable clinical outcomes, attention to perioperative glycemic control in the intensive care unit (ICU) has become increasingly important².

In 2001, a study from Van den Berghe et al.³ at a Belgian hospital introduced the concept and importance of tight glycemic control in the ICU; results from this study influenced the recommendations of several medical societies^4-6. Nevertheless, subsequent studies have failed to reproduce these findings, thereby challenging the initial results of the Belgian hospital study³. Current data demonstrate that treatment of hyperglycemia with insulin during CABG surgery can lead to postoperative hypoglycemia^7,8 and does not always prevent hyperglycemia⁹, especially when selecting a tight blood glucose target, such as 80-110 mg/dl (4.4-6.1 mmol/l)^3,4,7,10-12. Furthermore, differences in the clinical implications of insulin use among patients with and without diabetes have not been thoroughly examined, since insulin use is typically driven by the blood glucose level without direct regard for diabetic status. To further confound these effects, there is thought to be considerable heterogeneity in insulin use among hospitals performing CABG in similar patient populations; as a result of these data inconsistencies, there is an imminent need for further study of insulin use in this patient population^5,11-13.

In our study, we explore the characteristics of insulin use by examining a large multi-institutional patient repository and we compare clinical outcomes between patients with and without diabetes as a function of insulin use. We also report hospital-level patterns of insulin use following CABG surgery and the degree of variation among these centers.

METHODS

Data Sources

The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database (ACSD) was established in 1987 as a multicenter data repository for quality improvement and clinical research. The STS ACSD presently collects data from nearly 90% of all hospitals in the United States of America with cardiothoracic surgical programs and contains detailed data including patients’ demographics, clinical profiles, and in-hospital outcomes. Data definitions are standardized, and data coordinators at individual sites receive specific training in data entry and management. Case report forms from participating sites in the United States of America and Canada are submitted to the data coordinating center (Duke Clinical Research Institute, Durham, North Carolina, United States of America) on a semiannual basis. For quality control, the STS ACSD conducts annual on-site data audits for randomly selected database participants. The accuracy of individual data elements has been validated in regional analyses with an agreement rate of more than 95%¹⁴. Overall completeness of procedure reporting and mortality event reporting in patients aged ≥ 65 years has been validated against national Medicare claims files^15,16.

Fifty STS ACSD institutional members were invited to participate in the Contemporary Analysis of Perioperative Cardiovascular Surgical Care (CAPS-Care) Study, based on a track record of high-quality data submission. Of these, 48 obtained institutional review board approval and, therefore, proceeded with data collection. These participants collected data from a total of 55 hospitals. The STS ACSD contained prospectively collected data related to baseline demographics, clinical and operative variables, and prior cardiopulmonary studies, as well as major adverse events during hospitalization and 30 days postoperatively. The CAPS-Care data collection form included variables related to preoperative clinical encounters, intraoperative care, postoperative pharmacologic care, postoperative management, and postoperative clinical events. CAPS-Care data were entered into a computerized database and linked to STS ACSD data via a unique record identification system. The present study is focused on postoperative insulin use, defined as the first 24 hours after ICU arrival.

Patient Population

A total of 2,390 patients were included in the analysis and each institution contributed an average of 50 patients (range 8 - 60), representing a randomly selected proportion of patients from each center who met inclusion criteria. Patients who underwent elective or urgent CABG from January 2004 to June 2005 were included. “High-risk” patients were defined as those with preoperative ejection fraction < 40% or age ≥ 65 years, with either diabetes mellitus or estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m^2,9,13. In 2006, Van den Berghe et al.¹¹ demonstrated that among 433 patients admitted to the ICU for less than three days, intensive insulin therapy was related to greater mortality. Furthermore, the Nice-Sugar Study reported increased mortality (27.5%) at 90 days with intensive glucose control compared to conventional control (24.9%; OR=1.14, 95% CI 1.02-1.28; P=0.02). Severe hypoglycemia was also found to occur more often with intensive insulin management (6.8% vs. 0.5%, P<0.001)⁷. In addition to the establishment of these appropriate target ranges, actual achievement of glycemic control can be clinically challenging. These studies, with varying designs, were also limited by not taking into account the variation in phlebotomy sites (i.e., arterial, venous, or capillary), enteral vs. parenteral diet, and specific insulin use patterns^13,17,18. Therefore, it is evident that the optimal method of glycemic control may vary among different subgroups of patients, and no single protocol is definitively appropriate for all patients after cardiac surgery.

In the operating room, insulin is almost always delivered intravenously (bolus or continuous) given the more immediate effect and predictable response compared to subcutaneous injections. In contrast, subcutaneous and bolus methods tend to be preferred in patients without diabetes in the postoperative setting. In the existing published literature, insulin administration methods vary widely in terms of clinical protocols and adjustment scales, and our results reiterate this institutional variability. In our study, insulin use in patients without diabetes is associated with higher morbidity and mortality rates compared to patients with diabetes. While the postoperative maximum blood glucose level has been shown to be an independent predictor of mortality in patients without diabetes, hyperglycemia is not associated with higher adjusted mortality in patients with diabetes¹⁹. These results emphasize the need to stratify guidelines for glycemic control by different subgroups of patients, particularly on the basis of baseline diabetes status.

The mechanisms of glucose variation around the time of CABG surgery are not completely understood. While acute myocardial injury or inflammation related to cardiopulmonary bypass may result in insulin resistance and subsequent hyperglycemia, often called “diabetes of injury”, alternative mechanisms have yet to be identified²⁰. Furthermore, the association between acute illness and hyperglycemia remains unclear as far as whether hyperglycemia is a marker of multisystem stress vs. a mediator of complications. Regardless, hyperglycemia has been associated with poor clinical outcomes in critically ill patients^4,21. Taking into account the role of hyperglycemia as a marker of stress during and after cardiac surgery, it is feasible that insulin administration in this setting is blunting other necessary physiologic pathways leading to worse clinical outcomes. Given the physiologic effects of insulin that extend well beyond glycemic control, perhaps the anabolic effects of this hormone are poorly tolerated in the immediate postoperative period. Further investigation is warranted to determine the pathways by which insulin is counterproductive to patient recovery and clinical outcomes.

Additional patient and procedural characteristics may also have factored into the results observed in this study. For example, preoperative lung disease and arrhythmias were more prevalent in non-diabetic patients receiving insulin. This likely has a direct influence on patient outcomes, though multivariable adjustment did not demonstrate this to be a significant contributor to our clinical endpoints. The intraoperative course also is likely to play a role, with particular attention to concomitant valve surgery, which occurred more frequently in those who did not receive insulin. The causation between concomitant procedures and outcomes are not fully understood, but additional bypass time required for these procedures may incur a greater systemic response that, in turn, requires more insulin use. Better understanding the interactions between these elements will be useful in future studies.

Limitations

Our study had several limitations. First, despite the prospective method of data collection used in the CAPS-Care database, we were limited by its post hoc design; however, we were able to perform robust adjusted analyses for several covariates among a well-powered cohort. Second, we recognize the large degree of variability among centers in relation to intraoperative and postoperative blood glucose management, as well as overall intensive care strategies. In fact, several individual patients had a combination of insulin administration routes and strategies both during and after surgery, which further adds to this limitation. This variability is likely to represent differences in practice behaviors, which may confound the indications for insulin administration at individual centers. Furthermore, the study cohort arises from patients undergoing surgery between 2004 and 2005, which may reflect practices that are less generalizable to today’s standards. However, in the current era, there still remains a lack of definitive evidence regarding the appropriate use of insulin in this setting, as well as a lack of insight into the effects of insulin use in patients without diabetes - both of which were found to be significant in our study. This further emphasizes the importance of standardizing postoperative glycemic protocols at any given institution. Finally, the choice of insulin adjustment scale and insulin formulation are among several factors that vary among participating institutions. As a limitation of the database utilized, we were not able to account for these variations, any of which may impact the adequacy of postoperative glucose management.

CONCLUSION

Insulin use and blood glucose management strategies vary greatly among centers performing CABG in both patients with and without diabetes. Overall, patients without diabetes receiving postoperative insulin appear to have higher mortality and more complications compared with patients not receiving insulin. The mechanisms behind these trends remain unclear and deserve further investigation in order to optimize postoperative glycemic control and mitigate the sequelae of postoperative hyperglycemia, particularly in patients without diabetes.

[ Table Omitted - see PDF ]

Authors' roles & responsibilities DNR Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved JBW Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved ASA Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved SL Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved RAKK Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved EDP Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved RDL Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

* This study was carried out at the Duke Clinical Research Institute, Durham, North Carolina, United States of America.

* Financial support: The Contemporary Analysis of Perioperative Cardiovascular Surgical Care (CAPS-Care) study was funded with an unrestricted research grant from Scios Inc. (Mountain View, California) to the Society of Thoracic Surgeons. The analysis and content of this manuscript were prepared independently at the Duke Clinical Research Institute.

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