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Derangement of glucose metabolism after surgery is not specific to patients with diabetes mellitus. We investigated the effect of different degrees of blood glucose control (BGC) on clinical outcomes after cardiac surgery.
We analyzed 8727 adults operated on between April 1996 and March 2004. The highest blood glucose level recorded over the first 60 hours postoperatively was used to classify patients as having good (<200 mg/dL), moderate (200 to 250 mg/dL), or poor (>250 mg/dL) BGC; 7547 patients (85%) had good, 905 (10%) had moderate, and 365 (4%) had poor BGC. Patients with inadequate BGC were more likely to present with advanced New York Heart Association class, congestive heart failure, hypertension, renal dysfunction, and ejection fraction <50% (P≤0.001). We found that 52% of patients with poor, 31% with moderate, and 8% with good BGC had diabetes mellitus. Inadequate BGC, but not diabetes mellitus (P=0.79), was associated with in-hospital mortality (good, 1.8%; moderate, 4.2%; poor, 9.6%; adjusted odds ratio: poor versus good BGC, 3.90 [95% confidence interval, 2.47 to 6.15]; moderate versus good BGC, 1.68 [95% confidence interval, 1.25 to 2.25]). Inadequate BGC also was associated with postoperative myocardial infarction (eg, odds ratio, poor versus good BGC: 2.73 [95% confidence interval, 1.74 to 4.26]) and with pulmonary and renal complications in patients without known diabetes mellitus (eg, odds ratio, poor versus good BGC: 2.27 [95% confidence interval, 1.65 to 3.12] and 2.82 [95% confidence interval, 1.54 to 5.14] respectively).
More than 50% of patients with moderate to poor BGC after cardiac surgery were not previously identified as diabetic. Inadequate postoperative BGC is a predictor of in-hospital mortality and morbidity.
Historically, diabetes mellitus (DM) has been associated with a poor clinical outcome after cardiac surgery, including a higher incidence of wound infections, ischemic events, neurological and renal complications, and mortality.1-5 Over the last decade, the incidence of DM has increased markedly in developed countries. Knowledge of the patient’s diabetic status preoperatively has led to advances in perioperative clinical management, including active and continuous blood glucose control (BGC) with improved clinical outcome.6 Nevertheless, derangement of glucose metabolism after surgery is not specific to patients with DM.7,8 It has been reported that up to 90% of those without DM had problems with their blood glucose homeostasis as a result of various surgical stresses.7,8 In such patients, the disturbances in blood glucose homeostasis have been attributed to insulin resistance and/or a failure of pancreatic β-cell function caused by the systemic inflammatory response syndrome after cardiopulmonary bypass (CPB) and its effects on systemic temperature.9-11
Over the last decade, a large body of evidence has highlighted advances in intraoperative and intensive care techniques for DM patients undergoing cardiac surgery with improved in-hospital outcome.1,2 More recently, investigators have been focusing on undiagnosed DM and non-DM patients and their likelihood of suffering postoperative derangement of glucose metabolism leading to postoperative complications.
The aim of this study was to investigate the effect of different degrees of inadequate BGC on clinical outcomes in a large consecutive series of patients undergoing cardiac surgery.
Prospectively collected data were extracted from our hospital database (Patient Analysis and Tracking Systems, Dentrite Clinical Systems, London, UK) on consecutive adult cardiac surgical patients operated on between April 1996 and March 2004. The data collection form comprises 5 sections completed consecutively by anesthetist, surgeon, intensive care unit, high-dependency unit, and ward nurses. The cohort was matched to the department of biochemistry database through the use of patient identifiers and operation date to obtain blood glucose results immediately and 12, 48, and 60 hours after surgery. All personal identifiers were then removed to make the data set anonymous. Patients with no postoperative glucose measurements were excluded. Study patients were then classified as having good, moderate, or poor glucose control if the highest recorded blood glucose level was <200 mg/dL (11.1 mmol/L), between 200 and 250 mg/dL (11.1 and 13.9 mmol/L), or >250 mg/dL (13.9 mmol/L), respectively. The cutoff points were based on reports in the literature12-14 and were defined prospectively. The complete patient selection and classification process is shown in Figure 1. Initially, data were collected on the basis of presumed consent, but since 2002, when a program of annual follow-up for all surviving patients was established, consent for the use of data has been sought.
Anesthetic and surgical techniques were as reported previously.15-17 Briefly, heparin was given to maintain the activated clotting time at >480 seconds throughout CPB. A standard CPB circuit was used with nonpulsatile flow at a rate throughout bypass of 2.4L·min−1 ·m−2 and a mean arterial pressure of 50 to 60 mm Hg.
For conventional coronary artery bypass grafting (CABG) operations, systemic temperature was maintained between 34°C and 36°C. Myocardial protection was achieved with intermittent antegrade warm-blood cardioplegia. The technique used for off-pump CABG procedures has previously been reported.18 For all other surgeries, myocardial protection was predominantly by a combination of intermittent antegrade and retrograde cold-blood cardioplegia with moderate systemic hypothermia (28°C to 32°C).
At the end of surgery, patients were transferred to the intensive care unit and ventilated with 60% oxygen using volume-controlled ventilation. The decision to extubate a patient was at the discretion of the consultant anesthetist, who followed a predefined protocol based on the presence of systemic temp of 36°C, a systolic blood pressure >100 mm Hg, pulse rate <100 bpm, and a blood loss <100 mL/h and decreasing from the chest drains.
All diabetic patients were started on a sliding-scale insulin infusion soon after surgery to maintain blood glucose levels between 5 and 8 mmol/L according to a standard protocol (Figure 2). This infusion was continued for the first 24 hours; then, patients were switched to their baseline medications, and blood sugar levels were monitored every 6 hours. For nondiabetic patients, the same sliding-scale insulin infusion was begun postoperatively if a single blood glucose measurement >8 mmol/L or 2 consecutive blood glucose measurements >7 mmol/L were observed.
Hypoglycemic medications, statins, β-blockers, diuretics, antihypertensives, angiotensin-converting enzyme inhibitors, and calcium channel blockers were routinely omitted on the day of surgery. Aspirin was omitted 3 days before surgery. On the first postoperative day, all patients were started on enoxaparin (20 mg), which was stopped at discharge, and aspirin (300 mg), which was reduced to 75 mg after 3 months. On day 1, statins, β-blockers, diuretics, antihypertensives, and angiotensin-converting enzyme inhibitors were restarted on the basis of accurate monitoring of blood pressure and renal function. After discharge, these drugs were prescribed and monitored by the family physician and through routine visits to the Cardiology Department outpatient clinic.
Diabetic patients were defined as those admitted to the hospital with a comorbid diagnosis of DM not controlled by diet alone. No patient was classified as having DM on the basis of glucose testing immediately before surgery. The highest postoperative glucose level was the single highest value from all the available postoperative recordings for each patient. Perioperative death was defined as any death occurring in hospital. In-hospital complications were recorded and defined as previously reported.15,17
Baseline and operative characteristics and postoperative outcomes were compared by use of a χ2 or Fisher’s exact test (categorical variables) or the Kruskal-Wallis test (continuous variables). Outcomes for the BGC subgroups also were compared by use of multiple logistic regression (STATA version 9.2). A backward stepwise procedure, with significance levels of 0.05 and 0.10 for the addition and exclusion of variables, respectively, was used to determine which prognostic variables were retained in the regression models. BGC and DM were included in all regression models regardless of the statistical significance. Prognostic variables considered were chosen because they showed imbalance between the groups and/or they were thought to affect outcome. Missing prognostic data were imputed with the median for continuous measures and the mode for category measures. With 1 exception (hypercholesterolemia), data were missing for <1% of cases; for hypercholesterolemia (13% missing), a separate missing data category was created. Outcome data were available for >99% of patients. The effect of BGC on outcome for DM and non-DM patients was examined by adding interaction terms to the regression models. This was done both as part of the stepwise procedure and subsequent to the stepwise modeling with consistent results. The significance of interaction terms also was assessed with bootstrapping, again with consistent results. All regression analyses used robust SEs clustered by the surgeon to allow for any nonindependence between patients operated on by the same surgeon. Results are presented as adjusted odds ratios (ORs) with 95% confidence intervals derived from 200 bootstrap samples. When a significant interaction was found (P<0.05), the effects are presented separately for the DM/non-DM and BGC subgroups. For BGC, the P values reported are for the overall effect of BGC on the outcome. To ensure that the adjusted analyses had sufficient power to identify important predictors of the outcome, only those postoperative outcomes experienced by at least 150 patients were considered. The number of outcomes of interest resulted in a large number of statistical comparisons. No correction was made for multiple comparisons, but confidence intervals and exact P values are presented throughout, and the Bonferroni-corrected probability value for overall 5% statistical significance is included as a footnote. The interpretation of the findings takes into account the consistency of the findings and their magnitude, as well as their statistical significance.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
A total of 9064 patients underwent cardiac surgery between April 1996 and March 2004 at our institution. Postoperative blood glucose measurement(s) were available for 8727 of these patients; 7457 (85.4%) had good, 905 (10.4%) had moderate, and 365 (4.2%) had poor BGC in the first 60 hours after surgery. The distribution of baseline characteristics of the 3 groups is shown in Table 1. Patients with moderate or poor BGC were more likely to have an advanced New York Heart Association class and Canadian Cardiovascular Society class, a history of congestive heart failure, hypertension, arrhythmia, renal failure, and an ejection fraction <50% (P≤0.004). We found that 48.2% of patients in the poor BGC group and 68.5% in the moderate group were nondiabetic, although moderate BGC and poor BGC were more prevalent among DM patients (P<0.001; Figure 3a). Overall, the number of patients with inadequate BGC declined over time (P<0.001; Figure 3b).
Operation details and postoperative outcomes are shown in Table 2. The majority of patients underwent CABG (≈70% in each group). Overall, 35.5% of CABG patients were operated off pump. In total, 3962 patients (45.5%) required inotropic support after surgery: 3263 (43.8%), 482 (53.3%), and 217 (59.5%) in the good, moderate, and poor BGC groups, respectively (P<0.001). In-hospital mortality was 2.3% overall; 131 (1.8%), 38 (4.2%), and 35 (9.6%) deaths occurred in the good, moderate, and poor BGC groups, respectively (P<0.001). All postoperative complications varied significantly across the BGC groups (P≤0.006). Except for transient ischemic attacks and gastrointestinal complications, all complications occurred most often in the poor BGC group. The intensive care unit and total postoperative stay also were significantly longer in the poor BGC group (P<0.001). Table 3 shows the independent predictors of in-hospital mortality. Two models were fitted: 1 with DM fitted as a single group and 1 with the DM group subdivided into non–insulin-dependent DM and insulin-dependent DM. DM per se was not identified as an independent predictor for in-hospital mortality (P=0.79), and the risk was similar for the non–insulin-dependent and insulin-dependent DM subgroups (P=0.47; data not shown). After controlling for confounding factors associated with in-hospital death and diabetic status, inadequate BGC was found to be an independent predictor of in-hospital death (P<0.001). The mortality risk associated with poor BGC was greater than with moderate control (OR, 2.32; 95% CI, 1.28 to 4.20; P=0.005) and was greater than the difference between moderate and good BGC control (OR, 1.68; 95% CI, 1.25 to 2.25; P=0.001). Other independent predictors of in-hospital death identified were age >65 years, female gender, advanced New York Heart Association class, renal failure, arrhythmias, ejection fraction <50%, presence of left main stem disease, aortic procedures, CPB time >90 minutes, operative priority, and the need for inotropes (P≤0.022 for all).
The effects of DM and inadequate BGC on mortality and morbidity after multivariate adjustment controlling for confounding factors associated with outcome are shown in Tables Tables44 and and5,5, respectively. In non-DM patients, inadequate BGC was found to be an independent predictor of pulmonary, renal, and gastrointestinal complications (overall effect of BGC, P<0.001). In this patient group, both moderate and poor BGC carried a higher risk of complications compared with good BGC, and the risk associated with moderate BGC and poor BGC were similar (P≥0.19). In contrast, for patients with diagnosed DM, the risk of pulmonary and renal complications was similar across the 3 BGC groups (P>0.07). Complication rates by BGC for non-DM and DM patients are shown in Figure 4. The risk of these complications in the moderate and poor BGC groups was lower for a patient with DM compared with a non-DM patient; the difference in risk between non-DM and DM patients was greatest among those with poor BGC (Table 4).
No significant interaction between BGC and DM was found for postoperative myocardial infarction (MI), arrhythmias, neurological or infective complications, or reoperation for bleeding/tamponade (P>0.05). DM was found to carry an increased risk for neurological and infective complications (estimated increased risk, 63% [P=0.003] and 34% [P=0.032], respectively) but not for postoperative MI, which was less common among DM patients (estimated 33% reduced risk; P=0.034). In contrast, inadequate BGC was strongly associated with postoperative MI; the risk associated with poor BGC was greater than with moderate control (68%; P=0.037) and was similar to the difference between moderate and good BGC control (62%; P=0.006). Inadequate BGC also was associated with neurological complications (overall effect of BGC, P=0.003) but not with infective complications (P=0.20). Neither DM nor BGC was independently associated with arrhythmias, and DM was not predictive of the need for reoperation for bleeding/tamponade. However, inadequate BGC was found to be associated with reoperation for bleeding/tamponade (overall effect of BGC, P=0.026). Poor BGC carried a higher risk compared with both good and moderate BGC, but the risk associated with good BGC and with moderate BGC was similar (P=0.38).
DM, ejection fraction <50%, advanced New York Heart Association class, type of operation, use of CPB, operative priority, and inotropic support were found to be associated with poor BGC (Table 6). The effect of DM differed between those patients given and those not given inotropes, as evidenced by a statistically significant interaction between DM and inotropic support (P<0.001). Poor BGC was most common among DM patients not requiring inotropes (OR, 22.7); in DM patients given inotropes, the risk of poor BGC was reduced by ≈75%, although it remained significantly higher than for a non-DM patient who required inotropes (OR, 5.71). Similarly, in non-DM patients, the risk of poor BGC increased 3-fold when inotropes were given (OR, 3.10) compared with DM patients in whom the risk reduced.
More than 50% of patients with poor and moderate BGC were not previously identified as diabetic. This is consistent with the Euro Heart Study of cardiology patients with coronary artery disease in which 50% of patients not previously identified as diabetic were found to have diabetes or impaired glucose tolerance19 but is in contrast to the study by Lauruschkat and colleagues,20 who suggested that the prevalence of undiagnosed DM in patients undergoing CABG is only 5.2%. This discrepancy can be only partly explained by our classifying patients with diet-controlled DM as nondiabetic because patients with diet-controlled DM made up only 4.5% of the moderate and 6.6% of the poor BGC groups. The stress of cardiac surgery might uncover a borderline diabetic status causing marked transient or permanent imbalance in body sugar control and leading to hyperglycemia. Because hyperglycemia has been associated with poor in-hospital and long-term outcome, including further progression of native coronary artery disease,4 our results raise the question of the need for a more accurate preoperative diagnosis of silent diabetic status. Hyperglycemia early after cardiac surgery, in the absence of excessive glucose infusion, would occur as a result of either insulin resistance or decreased insulin production caused by pancreatic β-cell failure.10 Disturbances in pancreatic β-cell secretion in the absence of autoimmune diabetes have been shown to be related to hypothermia during CPB,21 which recovers fully at the end of operation, with normal insulin secretion potential in the postoperative period.10 Insulin resistance, however, also is caused by catecholamines and cortisone secretion (surgical stress),22,23 CPB, the accompanying systemic inflammatory response syndrome, and the effects of systemic heparinization.9 Some of the findings of the present study also support this hypothesis because the use of CPB was found to be independently associated with poor BGC.
Our findings suggest that inadequate BGC, regardless of diabetic status, is an independent predictor of in-hospital mortality, postoperative MI, and neurological complications in patients undergoing cardiac surgery. Our data also suggest that in patients without diagnosed DM, inadequate BGC is a predictor of renal, pulmonary, and gastrointestinal complications.
Our results can be explained in several ways. Acute hyperglycemia occurring intraoperatively abolishes ischemic preconditioning24 and amplifies reperfusion injury25 to the heart. In addition, during ischemia, glucose is the preferred substrate for the myocardium, but marked insulin resistance leads to hyperglycemia as a result of impaired cell uptake of glucose, which in turn leads to increased concentrations of free fatty acids. Fatty acids are detrimental to the ischemic myocardium because of the increased oxygen consumption required to metabolize the new substrate.26 Hyperglycemia also leads to increased free radical release and hence increased oxidative stress, causing endothelial dysfunction, which may further affect myocardial ischemia.27-29
Several mechanisms might explain the hyperglycemia-related brain damage suggested by our study. The flow reductions during hyperglycemia could be due to the hyperosmolality of glucose. However, intraperitoneal glucose injected into rats to produce hyperglycemia was associated with 24% reduction in regional blood flow, whereas injection of D-mannitol to produce an equivalent osmolality reduced cerebral blood flow by only 10% compared with controls.30 Hyperglycemia also increases local edema and causes glucose-mediated oxidative stress and inflammation.31
DM has been shown to be a catalyst for infective complications after cardiac surgery,32-34 and our study supports this finding. Although the association between BGC and infective complications was not statistically significant (P=0.20), a trend toward a higher risk of complications with inadequate BGC was observed, which is in keeping with another report.5 Carr et al7 demonstrated that tight glucose control in both diabetic and nondiabetic patients leads to a marked reduction in the incidence of mediastinitis. Acute hyperglycemia has several effects on innate immunity: It reduces neutrophil and complement activity; it increases proinflammatory cytokines tumor necrosis factor-α and interleukin-6; and by reducing endothelial nitric oxide formation, it decreases microvascular reactivity to dilating agents such as bradykinin and impairs complement function.35
The pathophysiology of ischemic acute renal failure involves a complex interplay between renal hemodynamics, tubular, endothelial cell injury, and inflammatory process.29 Endothelial dysfunction caused by hyperglycemia contributes at the microvascular level, initiating and subsequently extending the tubular injury.36 These detrimental endothelial effects also might explain the increased incidence of pulmonary and gastrointestinal complications observed in our study. Others have reported that hyperglycemia may be associated with impairment of renal blood flow and glomerular filtration rate through a tubuloglomerular feedback mechanism.37
Our findings suggest that our insulin infusion protocol was not effective in maintaining tight blood sugar control in all patients regardless of their diabetic status. Since this analysis, we have extended our insulin infusion protocol to 48 hours after surgery to all patients regardless of their diabetic status and have adopted a stricter attitude toward initiating insulin infusion in presence of outliers (ie, patients with blood glucose level >8 mmol/L) regardless of their preoperative diabetic status. Furthermore, we now aim to keep blood glucose levels between 4.4 and 6.1 mmol/L in critically ill patients in intensive care, as suggested by Van den Berghe et al.38
The study has limitations. First, it is a retrospective analysis, although the data were collected prospectively. Those responsible for data collection were not blinded to the patient’s blood glucose levels, so the possibility of observer bias cannot be discounted. Nonetheless, when the data were collected, this analysis had not been planned. Second, it could be argued that some of our findings are due to the misclassification of DM patients. However, classifying patients according to their diabetic history, as provided by the referring cardiologist, reflects clinical practice. Using fasting glucose also has the potential for misclassification. The glucose level depends on the accuracy of the fasting duration and the choice of cutoff for DM. Furthermore, obtaining fasting glucose results is not feasible for urgent and emergency patients (>50% of study cohort). Third, operations carried out since work on this study was started were not included. The risk profile of patients treated and operative procedures have not changed since 2004, but protocol changes made in light of these findings precluded our extending the study cohort to include more recent operations. Fourth, it is possible that the differences or similarities observed between the groups were a result of unmeasured confounders or variables we did not consider for inclusion in the analysis. However, we considered all variables that showed imbalance between the groups and/or were thought to affect outcome, including the need for inotropic support after surgery. However, we were unable to comment on the specific effect of β-1 agonists, which are known to be associated with glucose homeostasis, because this information was not available; only the use of inotropes, not the type (ie, β-1 agonist, selective phosphodiesterase inhibitor, or other type), is recorded in the database. In addition, antidiabetic medications may affect the perioperative period because they are continued until the day of surgery, but BGC is monitored in all DM patients in the intensive care unit, and an insulin infusion is started when the BGC rises above the threshold. Although multivariate analysis is a theoretically sound statistical method of accounting for differences between groups in the absence of random allocation, it is recognized that no statistical model can fully account for all the differences in risk profile between the diabetic and nondiabetic patients in our study cohort. Nevertheless, this study was based on a large cohort of patients, and the analyses were limited to those outcomes that occurred in at least 150 patients, thereby ensuring the study had sufficient power to identify factors significantly associated with the outcome. A fifth limitation is the classification of patients according to their postoperative BGC. We defined the classification in advance of any analysis for the purpose of this study because no recognized guidelines are available on this topic. The 200-mg/dL (11.1-mmol/L) threshold for moderate BGC was selected because it is the cutoff point used to diagnose DM from random glucose levels,12 whereas the 250-mg/dL (13.9-mmol/L) threshold for poor BGC was based on previous reports indicating that patients with glucose values exceeding this level were at higher risk of postoperative complications, particularly deep wound infections.13,14 It would have been useful to classify patients by their hemoglobin A1c results along with the BGC data, but unfortunately, this information was not available for our study cohort. We also decided before any analysis was undertaken to exclude patients with diet-controlled diabetes (2.5% of the study cohort) from the diabetic group and include them with the patients without known diabetes. We acknowledge that this is a conservative strategy that may have diluted any effect of diabetes on outcome. Nevertheless, reclassifying these patients as diabetic in a posthoc analysis did not alter our overall conclusions; the estimated ORs followed a pattern consistent with our original analysis, and no new statistically significant effects were found. Finally, although we have identified significant associations between inadequate BGC and outcome, we cannot infer that poor BGC necessarily causes the poor outcome; increased blood sugar levels can result from postoperative complications in addition to contributing to their occurrence.
Our study shows that >50% of patients developing moderate to poor BGC after cardiac surgery were not previously identified as diabetic. Moderate to poor BGC is an independent predictor of in-hospital mortality and is strongly associated with morbidity in patients not known to be diabetic. Of the baseline variables, use of CPB, type of surgery, advanced New York Heart Association class, and poor left ventricular ejection fraction were identified as predictors of poor BGC and might be used preoperatively to risk stratify patients and to optimize their clinical management.
Our study demonstrates that inadequate blood glucose control (BGC) after cardiac surgery is not specific to patients with diabetes mellitus (DM). Inadequate BGC, regardless of DM status, was independently associated with in-hospital mortality and morbidity. Our findings have epidemiological, clinical, academic, and financial implications. We suggest that DM patients represent only a fraction of those suffering derangement of glucose metabolism after surgery. The projected future number of adults with DM is an underestimate of the number likely to be affected by deranged glucose metabolism and its related complications. Inadequate BGC after surgery seems to represent a separate clinical entity that is explained only partially by undiagnosed and diet-controlled diabetes. Our data suggest that strict protocols to maintain BGC should be used for all patients. However, the efficacy of these protocols and the pathophysiologic mechanisms of this condition need further research. In addition, further research and guidelines as to how best to manage these patients are needed. Currently, important clinical decisions such as choice of screening test, strategy for maintaining adequate BGC, and the ideal target level of BGC are often left to the individual clinician. This has resulted in inconsistencies in the definition of undiagnosed DM, stress hyperglycemia, and inadequate BGC; marked variation in estimates of prevalence; and significant variation in treatment, the impact of which remains uncertain. Our findings also may apply to patients admitted for major noncardiac surgery. The impact on life expectancy and on hospital resources is potentially enormous.
Sources of Funding: We thank the British Heart Foundation and the Garfield Weston Trust for their financial support.