Gregory A. Nuttall

Intensive Intraoperative Insulin Therapy versus Conventional Glucose Management during Cardiac Surgery: A Randomized Trial

Context Intensive insulin therapy used to maintain normoglycemia during intensive care after cardiac surgery improves perioperative outcomes. Its effect during cardiac surgery is unknown. Contributions The authors randomly assigned 400 cardiac surgical patients to tight glycemic control (blood glucose level, 4.4 to 5.6 mmol/L [80 to 100 mg/dL]) during surgery or usual intraoperative care. All patients received tight glycemic control in the cardiac intensive care unit. The groups had the same risk for perioperative adverse events (risk ratio, 1.0 [95% CI, 0.8 to 1.2]). The intensive treatment group had more strokes (8 vs. 1) and more deaths (4 vs. 0) than the conventional treatment group. Caution The authors performed the study at a single center. Implications Maintaining normoglycemia during cardiac surgery does not improve outcomes and might worsen them. The Editors Hyperglycemia occurs frequently in patients with and without diabetes during cardiac surgery, especially during cardiopulmonary bypass surgery (1, 2). In a study by Van den Berghe and colleagues (3), intensive insulin therapy after surgery reduced morbidity and death in critically ill patients, most of whom underwent cardiac surgery. As a result, professional organizations have recommended rigorous glycemic control in hospitalized patients (4) and strict glycemic control is now routine practice during the postoperative period in cardiac surgical patients. However, no consensus exists on the optimal management of intraoperative hyperglycemia in cardiac surgical patients because of the lack of evidence from randomized trials. Researchers are increasingly extrapolating evidence from studies that assess the role of strict postoperative glycemic control in critically ill patients to advocate for intravenous insulin therapy for patients in the operating room (3, 57). Evidence, strictly from observational studies, suggests that tight intraoperative glycemic control may reduce postoperative complications (810). We recently reported, in a retrospective, observational study of 409 cardiac surgical patients, that intraoperative hyperglycemia was an independent risk factor for perioperative complications, including death, after adjustment for postoperative glucose concentrations. Each 1.1-mmol/L (20 mg/dL) increase in glucose concentration greater than 5.6 mmol/L (>100 mg/dL) during surgery was associated with a 34% increase in the likelihood of postoperative complications (8). An association between intraoperative hyperglycemia and adverse outcomes based on observational studies does not prove causality. Because hyperglycemia can adversely affect immunity, wound healing, and vascular function, the concept that normoglycemia be maintained during the relatively brief duration of cardiac surgery seems plausible (1116). On the other hand, the degree of intraoperative hyperglycemia may merely reflect the severity of underlying stress. If so, prevention of hyperglycemia might not reduce perioperative complications, and the risks and costs of intensive intraoperative glycemic management may outweigh the benefits. Simple, safe, and effective insulin infusion algorithms that achieve rigorous intraoperative glycemic control are lacking. To address these questions, we conducted a randomized, controlled trial at 1 center to determine whether maintenance of near normoglycemia during cardiac surgery by using intraoperative intravenous insulin infusion reduced perioperative death and morbidity when added to rigorous postoperative glycemic control. Methods Design Overview This was a randomized, open-label, controlled trial with blinded assessment. We randomly assigned patients to receive intensive insulin therapy to maintain intraoperative glucose levels between 4.4 (80 mg/dL) and 5.6 mmol/L (100 mg/dL) or conventional treatment. By design, both groups were postoperatively treated with strict glycemic control to ensure that the observed difference in outcome could be attributed to the effects of intraoperative glycemic control. Setting We performed the study at St. Marys Hospital, Rochester, Minnesota, which is a tertiary care teaching hospital with 1157 beds and an average of more than 41000 admissions per year. Participants Adults undergoing elective cardiac surgery between July 2004 and April 2005 were eligible for enrollment in our study. We excluded patients who had off-pump cardiopulmonary bypass procedures. The Mayo Foundation Institutional Review Board, Rochester, Minnesota, approved the protocol. Randomization and Interventions Before we enrolled patients in our randomized trial, we enrolled 20 patients in a 2-week pilot trial to ensure that the anesthesiologists in the operating room and the nursing staff in the intensive care units (ICUs) had adequate experience with the study insulin infusion algorithm. The 20 patients received intensive insulin therapy during surgery and for 24 hours after surgery. The pilot period data allowed us to modify the graded insulin infusion to achieve desired glucose concentration goals. We built safety features into our infusion protocol to minimize hypoglycemia. We discontinued the infusion when glucose levels were less than 4.4 mmol/L (<80 mg/dL) and initiated dextrose infusion. When glucose levels decreased to less than 3.3 mmol/L (<60 mg/dL), we treated hypoglycemia according to a standardized hypoglycemia protocol. Per protocol, patients treated in the pilot phase were not included in the analyzed cohort. Study coordinators obtained written informed consent from all patients who met eligibility criteria. We randomly assigned patients to receive intensive or conventional intraoperative insulin therapy. Randomization was computer-generated with permuted blocks of 4, with stratification according to surgeon, surgical procedure (coronary artery bypass grafting [CABG] with or without other procedures and no CABG), and diabetes. The randomization assignments were concealed in opaque, sealed, tamper-proof envelopes that were opened sequentially by study personnel after participants signed the patient consent form. We could not possibly know, before obtaining consent, the few patients who would not have intraoperative hyperglycemia (glucose concentration of 5.6 mmol/L or more [100 mg/dL]). Therefore, per protocol, patients who gave consent were randomly assigned, and those whose glucose levels were less than 5.6 mmol/L (<100 mg/dL) during surgery were not included in the final analyses. Intraoperative Period Intensive Treatment Patients in the intensive treatment group received a continuous intravenous insulin infusion, 250 units of NovoLin R (Novo Nordisk, Princeton, New Jersey) in 250 mL of 0.45% sodium chloride, when their blood glucose levels exceeded 5.6 mmol/L (>100 mg/dL). We adjusted the infusions to maintain blood glucose levels between 4.4 (80 mg/dL) and 5.6 mmol/L (100 mg/dL). We adjusted the dose according to a standardized algorithm used by anesthesiologists (Appendix Table 1). Appendix Table 1. Insulin Infusion Protocol* Conventional Treatment Patients in the conventional treatment group did not receive insulin during surgery unless their glucose levels exceeded 11.1 mmol/L (200 mg/dL). If glucose concentration was between 11.1 (200 mg/dL) and 13.9 mmol/L (250 mg/dL), patients received an intravenous bolus of 4 units insulin every hour until the glucose concentration was less than 11.1 mmol/L (<200 mg/dL). If the intraoperative glucose concentration was greater than 13.9 mmol/L (>250 mg/dL), patients received an intravenous infusion of insulin that was continued until the glucose level was less than 8.3 mmol/L (<150 mg/dL). In both study groups, we measured arterial plasma glucose concentration every 30 minutes, starting just before anesthetic induction by using hexokinase method on a Double P Modular System (Roche Diagnostics, Indianapolis, Indiana). Intraoperative procedures, including cardiopulmonary bypass, monitoring, laboratory testing, and treatment, were left to the discretion of anesthesiologists and cardiac surgeons. There was no standard protocol for monitoring and managing intraoperative potassium levels. Postoperative Period Intravenous insulin infusion was started in patients in the conventional treatment group on their arrival in the ICU. Thereafter, both study groups were treated identically, with the intravenous insulin infusion rates adjusted by a nursing staff that was not involved with the study according to a standard protocol. The target blood glucose range was 4.4 (80 mg/dL) to 5.6 mmol/L (100 mg/dL) (Appendix Table 1). Arterial blood glucose levels were measured every 1 to 2 hours by using the Accu-Check Inform blood glucose monitoring system (glucometer) (Roche Diagnostics). During the first 24 hours after surgery, patients were given only clear liquids by mouth; we did not administer subcutaneous insulin or oral diabetic medications during this time. Thereafter, the hospital diabetes consulting service saw all patients and provided individualized recommendations for ongoing care. Outcomes and Measurements The primary outcome variable was a composite of death, sternal wound infections, prolonged pulmonary ventilation, cardiac arrhythmias (new-onset atrial fibrillation, heart block requiring permanent pacemaker, or cardiac arrest), stroke, and acute renal failure within 30 days after surgery. Secondary outcome measures were length of stay in the ICU and hospital. Trained study personnel identified the occurrence of a complication through chart abstraction by using confirmable, objective criteria in accordance with standardized definitions from the Society of Thoracic Surgeons (STS) database committee (17). Personnel who assessed outcomes were not aware of patient treatment assignment or of the study hypothesis. Follow-up Procedures We contacted patients by telephone and used a standardized telephone survey at 30 days after surgery to assess outcomes that occurred after discharge. We considered pat

Intraoperative Hyperglycemia and Perioperative Outcomes in Cardiac Surgery Patients

OBJECTIVE To estimate the magnitude of association between intraoperative hyperglycemia and perioperative outcomes in patients who underwent cardiac surgery. PATIENTS AND METHODS We conducted a retrospective observational study of consecutive adult patients who underwent cardiac surgery between June 10, 2002, and August 30, 2002, at the Mayo Clinic, a tertiary care center in Rochester, Minn. The primary independent variable was the mean intraoperative glucose concentration. The primary end point was a composite of death and infectious (sternal wound, urinary tract, sepsis), neurologic (stroke, coma, delirium), renal (acute renal failure), cardiac (new-onset atrial fibrillation, heart block, cardiac arrest), and pulmonary (prolonged pulmonary ventilation, pneumonia) complications developing within 30 days after cardiac surgery. RESULTS Among 409 patients who underwent cardiac surgery, those experiencing a primary end point were more likely to be male and older, have diabetes mellitus, undergo coronary artery bypass grafting, and receive insulin during surgery (P< or =.05 for all comparisons). Atrial fibrillation (n=105), prolonged pulmonary ventilation (n=53), delirium (n=22), and urinary tract infection (n=16) were the most common complications. The initial, mean, and maximal intraoperative glucose concentrations were significantly higher in patients experiencing the primary end point (P<.01 for all comparisons). In multivariable analyses, mean and maximal glucose levels remained significantly associated with outcomes after adjusting for potentially confounding variables, including postoperative glucose concentration. Logistic regression analyses indicated that a 20-mg/dL increase in the mean intraoperative glucose level was associated with an increase of more than 30% in outcomes (adjusted odds ratio, 1.34; 95% confidence Interval, 1.10-1.62). CONCLUSION Intraoperative hyperglycemia is an independent risk factor for complications, including death, after cardiac surgery.

Efficacy of a simple intraoperative transfusion algorithm for nonerythrocyte component utilization after cardiopulmonary bypass.

Background Abnormal bleeding after cardiopulmonary bypass (CPB) is a common complication of cardiac surgery, with important health and economic consequences. Coagulation test–based algorithms may reduce transfusion of non-erythrocyte allogeneic blood in patients with abnormal bleeding. Methods The authors performed a randomized prospective trial comparing allogeneic transfusion practices in 92 adult patients with abnormal bleeding after CPB. Patients with abnormal bleeding were randomized to one of two groups: a control group following individual anesthesiologist’s transfusion practices and a protocol group using a transfusion algorithm guided by coagulation tests. Results Among 836 eligible patients having all types of elective cardiac surgery requiring CPB, 92 patients developed abnormal bleeding after CPB (incidence, 11%). The transfusion algorithm group received less allogeneic fresh frozen plasma in the operating room after CPB (median, 0 units; range, 0–7 units) than the control group (median, 3 units; range, 0–10 units) (P = 0.0002). The median number of platelet units transfused in the operating room after CPB was 4 (range, 0–12) in the algorithm group compared with 6 (range, 0–18) in the control group (P = 0.0001). Intensive care unit (ICU) mediastinal blood loss was significantly less in the algorithm group. Multivariate analysis demonstrated that transfusion algorithm use resulted in reduced ICU blood loss. The control group also had a significantly greater incidence of surgical reoperation of the mediastinum for bleeding (11.8%vs. 0%;P = 0.032). Conclusions Use of a coagulation test–based transfusion algorithm in cardiac surgery patients with abnormal bleeding after CPB reduced non-erythrocyte allogeneic transfusions in the operating room and ICU blood loss.

Effects of Red-Cell Storage Duration on Patients Undergoing Cardiac Surgery

BACKGROUND Some observational studies have reported that transfusion of red-cell units that have been stored for more than 2 to 3 weeks is associated with serious, even fatal, adverse events. Patients undergoing cardiac surgery may be especially vulnerable to the adverse effects of transfusion. METHODS We conducted a randomized trial at multiple sites from 2010 to 2014. Participants 12 years of age or older who were undergoing complex cardiac surgery and were likely to undergo transfusion of red cells were randomly assigned to receive leukocyte-reduced red cells stored for 10 days or less (shorter-term storage group) or for 21 days or more (longer-term storage group) for all intraoperative and postoperative transfusions. The primary outcome was the change in Multiple Organ Dysfunction Score (MODS; range, 0 to 24, with higher scores indicating more severe organ dysfunction) from the preoperative score to the highest composite score through day 7 or the time of death or discharge. RESULTS The median storage time of red-cell units provided to the 1098 participants who received red-cell transfusion was 7 days in the shorter-term storage group and 28 days in the longer-term storage group. The mean change in MODS was an increase of 8.5 and 8.7 points, respectively (95% confidence interval for the difference, -0.6 to 0.3; P=0.44). The 7-day mortality was 2.8% in the shorter-term storage group and 2.0% in the longer-term storage group (P=0.43); 28-day mortality was 4.4% and 5.3%, respectively (P=0.57). Adverse events did not differ significantly between groups except that hyperbilirubinemia was more common in the longer-term storage group. CONCLUSIONS The duration of red-cell storage was not associated with significant differences in the change in MODS. We did not find that the transfusion of red cells stored for 10 days or less was superior to the transfusion of red cells stored for 21 days or more among patients 12 years of age or older who were undergoing complex cardiac surgery. (Funded by the National Heart, Lung, and Blood Institute; RECESS ClinicalTrials.gov number, NCT00991341.).

Cardiac Risk of Noncardiac Surgery after Percutaneous Coronary Intervention with Drug-eluting Stents

Background:The American College of Cardiology released a scientific advisory that included a recommendation to delay elective of noncardiac surgery (NCS) for 1 yr after percutaneous coronary intervention (PCI) with a drug-eluting stent (DES). Methods:This single-center, retrospective study examined the risk for complications of NCS performed within 2 yr after DES placement and examined whether this risk changed based on the time between procedures. The primary endpoint was major adverse cardiac events (MACEs) during the hospitalization for NCS. Bleeding events were analyzed as a secondary endpoint. Results:From April 22, 2003, to December 31, 2006, a total of 520 patients underwent NCS within 2 yr after PCI with a DES at Mayo Clinic. The majority, 84%, of the DES placed were Cypher stents. The frequency of MACE was not found to be significantly associated with the time between PCI and NCS (rate of MACEs 6.4, 5.7, 5.9, and 3.3% at 0–90, 91–180, 181–365, and 366–730 days after PCI with DES, respectively; P = 0.727 for comparison across groups). Characteristics found to be associated with MACEs in univariate analysis were advanced age (P = 0.031), emergent NCS (P = 0.006), shock at time of PCI (P = 0.035), previous history of myocardial infarction (P = 0.046), and continuation of a thienopyridine (ticlopidine or clopidogrel) into the preoperative period (P = 0.040). The rate of transfusion did not seem to be associated with antiplatelet therapy use. Conclusions:The risk of MACEs with NCS after DES placement was not significantly associated with time from stenting to surgery, but observed rates of MACEs were lowest after 1 yr.

Time and cardiac risk of surgery after bare-metal stent percutaneous coronary intervention

Background:The duration of time that elective noncardiac surgery (NCS) should be delayed after percutaneous coronary intervention (PCI) with bare metal stents (BMSs) is unknown. Methods:This large, single-center, retrospective study examined the relation between complication rate in patients with BMSs undergoing NCS and the duration of time between PCI and NCS. Primary endpoints included in-hospital major adverse cardiac events (death, myocardial infarction, stent thrombosis, or repeat revascularization with either coronary artery bypass grafting or PCI of the target vessel) and bleeding events. The relation between the events and the timing of noncardiac surgery after PCI with BMS was assessed using univariate analysis and multiple logistic regression. Results:From January 1, 1990, to January 1, 2005, a total of 899 patients were identified. The frequency of major adverse cardiac events was 10.5% when NCS was performed less than 30 days after PCI with BMS, 3.8% when NCS was performed between 31 and 90 days after PCI with BMS, and 2.8% when NCS was performed more than 90 days after PCI with BMS. In univariate and multivariate analyses, a shorter time interval between PCI with BMS and noncardiac surgery was significantly associated with increased incidence of major adverse cardiac events (univariate: P < 0.001; odds ratio = 4.0; 95% confidence interval, 2.0–8.3; multivariate: P = 0.006; odds ratio = 3.2; 95% confidence interval, 1.5–6.9). Bleeding events were not associated with time between PCI with BMS and NCS or with the use of antiplatelet therapy in the week before NCS. Conclusions:The incidence of major adverse cardiac events is lowest when NCS is performed at least 90 days after PCI with BMS.

Predictors of blood transfusions in spinal instrumentation and fusion surgery

STUDY DESIGN A retrospective review of 244 adult spine instrumentation and fusion surgery cases (1994-1995) from one institution. OBJECTIVES To ascertain the predictors of blood transfusions for adult patients undergoing different types of multilevel spine surgery. SUMMARY OF BACKGROUND DATA Blood loss and transfusion requirements during and after multilevel spine surgeries have always been perceived as great. Identifying the predictors of blood transfusion with this type of surgery may aid in reducing the amount of blood loss and the transfusion requirements. METHODS The charts of 244 adult patients who underwent multilevel spine surgery from January 1994 to July 1995 were retrospectively reviewed. RESULTS A large percentage of patients required blood transfusion. The significant determinants for increased amounts of allogeneic red blood cell units transfused on the day of surgery using linear multiple regression modeling were low preoperative hemoglobin concentration, tumor surgery, increased number of posterior levels surgically fused, history of pulmonary disease, decreased amount of autologous blood available, and no use of the Jackson table (R2 = 0. 63). The significant determinants for an increased amount of autologous red blood cell units transfused on the day of surgery using linear multiple regression modeling were increased autologous red blood cells available, low preoperative hemoglobin concentration, and increased number of posterior levels surgically fused (R2 = 0. 60). CONCLUSION The need for transfusion is associated with multiple factors, suggesting that a multifaceted, integrated approach may be necessary to reduce this risk.

Plasma Tranexamic Acid Concentrations During Cardiopulmonary Bypass

Although tranexamic acid is used to reduce bleeding after cardiac surgery, there is large variation in the recommended dose, and few studies of plasma concentrations of the drug during cardiopulmonary bypass (CPB) have been performed. The plasma tranexamic acid concentration reported to inhibit fibrinolysis in vitro is 10 &mgr;g/mL. Twenty-one patients received an initial dose of 10 mg/kg given over 20 min followed by an infusion of 1 mg · kg−1 · h−1 via a central venous catheter. Two patients were removed from the study secondary to protocol violation. Perioperative plasma tranexamic acid concentrations were measured with high-performance liquid chromatography. Plasma tranexamic acid concentrations (&mgr;g/mL; mean ± sd [95% confidence interval]) were 37.4 ± 16.9 (45.5, 29.3) after bolus, 27.6 ± 7.9 (31.4, 23.8) after 5 min on CPB, 31.4 ± 12.1 (37.2, 25.6) after 30 min on CPB, 29.2 ± 9.0 (34.6, 23.8) after 60 min on CPB, 25.6 ± 18.6 (35.1, 16.1) at discontinuation of tranexamic acid infusion, and 17.7 ± 13.1 (24.1, 11.1) 1 h after discontinuation of tranexamic acid infusion. Four patients with renal insufficiency had increased concentrations of tranexamic acid at discontinuation of the drug. Repeated-measures analysis revealed a significant main effect of abnormal creatinine concentration (P = 0.02) and time (P < 0.001) on plasma tranexamic acid concentration and a significant time × creatinine concentration interaction (P < 0.001).

Risk factors for ischemic optic neuropathy after cardiopulmonary bypass: A matched case/control study

Visual loss (acuity or field) secondary to ischemic optic neuropathy (ION) is a rare but devastating complication of cardiac surgery involving cardiopulmonary bypass (CPB). We determined clinical features and risk factors for ION by a retrospective time-matched, case-control study. ION was identified in 17 (0.06%) patients out of 27,915 patients who underwent CPB between January 1, 1976, and December 31, 1994. For each ION patient, two patients who underwent CPB exactly 2 wk before the ION patient were selected as controls. Data were analyzed by using conditional logistic regression with the 1:2 matched-set feature of 17 cases and 34 controls. Two-tailed P values ≤0.05 were considered significant. From bivariate analysis, smaller minimum postoperative hemoglobin concentration (odds ratio [OR] = 1.9, P = 0.047) and the presence of atherosclerotic vascular disease (OR = 7.0, P = 0.026) were found to be independently associated with ION after CPB, as were smaller minimum postoperative hemoglobin concentration (OR = 2.2, P = 0.027) and preoperative angiogram within 48 h of surgery (OR = 7.2, P = 0.042). In ION patients, 13 (76.5%) of 17 experienced a minimum postoperative hemoglobin value of <8.5 g/dL, whereas only 14 (41.2%) of 34 control patients experienced values <8.5 g/dL.

Does intraoperative hetastarch administration increase blood loss and transfusion requirements after cardiac surgery

Hetastarch is used for intravascular volume expansion in cardiac surgery. Studies show conflicting effects of intraoperative hetastarch administration on postoperative bleeding. Hetastarch was routinely used for volume expansion during cardiovascular surgeries at our institution until its use was discontinued intraoperatively. We performed a retrospective chart review on patients undergoing primary coronary artery bypass grafting, valve repair or replacement requiring cardiopulmonary bypass (n = 444), 234 of which received intraoperative hetastarch and 210 did not. There was no difference in demographics, cardiac surgery, or cardiopulmonary bypass duration between the two groups. Blood loss for 0–4 h postoperatively was 377 ± 244 mL in the group not receiving hetastarch compared with 515 ± 336 mL in the group that received hetastarch (P < 0.001). For 0–24 h postoperatively, blood loss was 923 ± 473 mL versus 1,283 ± 686 mL in the absence and presence of hetastarch, respectively (P < 0.001). Allogeneic transfusion requirements (cryoprecipitate, fresh frozen plasma, and platelets) were larger in the hetastarch group (all P < 0.001). Nearly all (99%) patients in the hetastarch group received less than the manufacturer’s recommended dose (20 mL/kg) of hetastarch. Implications: Our large retrospective study suggests that intraoperative use of hetastarch in primary cardiac surgery with cardiopulmonary bypass may increase bleeding and transfusion requirements. A large prospective study is needed to determine if intraoperative administration of hetastarch should be avoided during cardiovascular surgery.