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The Effect of Insulin Cardioplegia on Atrial Fibrillation After High-Risk Coronary Bypass Surgery: A Double-Blinded, Randomized, Controlled Trial

Hynninen, Marja MD*,; Borger, Michael A. MD†,; Rao, Vivek MD, PhD†,; Weisel, Richard D. MD†,; Christakis, George T. MD§,; Carroll, Jo-Ann RN*,; Cheng, Davy C. H. MD*

doi: 10.1097/00000539-200104000-00004
Cardiovascular Anesthesia: Research Report
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Atrial fibrillation after coronary bypass (CABG) surgery is an important cause of morbidity and increased resource utilization. Insulin-enhanced cardioplegia may reduce postoperative arrhythmias by improving aerobic myocardial metabolism and mitigating the deleterious effects of ischemia. We performed a double-blinded, randomized, controlled clinical trial to determine if insulin-enhanced cardioplegia decreases the risk of post-CABG atrial fibrillation in a high-risk patient population. We randomized 501 patients undergoing urgent CABG to receive insulin-enhanced (Humulin R 10 IU/L, Insulin group, n = 243) or standard (Control group, n = 258) blood cardioplegia during cardiopulmonary bypass. Patients were monitored by using continuous electrocardiography for a minimum of 3 days postoperatively. All standard cardiac medications, including β-adrenergic blockers, were continued postoperatively. Insulin-enhanced cardioplegia did not result in a significant reduction in postoperative atrial fibrillation. Furthermore, we failed to detect a difference in the incidence of conduction defects, ventricular tachycardia, or pacemaker requirements between insulin and placebo patients. Atrial fibrillation was the most common arrhythmia, occurring in 31% of all patients. Independent predictors of atrial fibrillation were elderly age, preoperative atrial fibrillation, and renal insufficiency. Right bundle branch block was the most common conduction abnormality. Predictors of right bundle branch block were elderly age, female sex, and circumflex coronary artery disease. The incidence of postoperative ventricular tachycardia, left bundle branch block, and permanent pacemaker requirement was small. We conclude that insulin-enhanced cardioplegia does not reduce the incidence of postoperative atrial fibrillation in high-risk CABG patients.

*Division of Cardiac Anesthesia and Intensive Care, and †Division of Cardiovascular Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; and §Division of Cardiovascular Surgery, Sunnybrook Health Science Centre, University of Toronto, Toronto, Ontario, Canada

Funded in part by the Medical Research Council of Canada, Grant No. MT 13513.

Presented in part at the 1999 Canadian Anesthesiologists’ Society on June 21, Calgary, Alberta.

December 14, 2000.

Address correspondence and reprint requests to Davy Cheng, MD, Division of Cardiac Anesthesia and Intensive Care, Toronto General Hospital, University Health Network, 200 Elizabeth Street, EN3-464, Toronto, Ontario, Canada M5G 2C4. Address e-mail to davy.cheng@uhn.on.ca.

IMPLICATIONS: We conducted a double-blinded, randomized, placebo-controlled trial of insulin-enhanced cardioplegia in 501 patients undergoing urgent coronary bypass surgery. Insulin did not decrease the incidence of postoperative atrial fibrillation when compared with placebo. We also failed to demonstrate a difference in the incidence of other postoperative arrhythmias between the two groups of patients.

Arrhythmias and conduction abnormalities after coronary artery bypass graft (CABG) surgery are a common clinical problem. Atrial fibrillation is the most common arrhythmia with a reported incidence ranging from 10% to 50%(1–3). Postoperative atrial fibrillation is an important cause of morbidity and increased hospital length of stay (4–6), which in turn, results in increased costs of medical care and resource utilization.

The pathophysiology of postoperative atrial fibrillation is multifactorial. Previous studies of preoperative risk factors have yielded conflicting results, with advanced age being the only risk factor consistently identified (7). Intraoperative ischemic insult to the atria is thought to be an important predisposing factor for postoperative atrial arrhythmias. The atria are frequently electromechanically active during aortic cross-clamping and cardioplegic delivery, implying that atrial preservation is suboptimal (8,9). Such atrial activity during ischemic periods leads to anaerobic glycolysis, with subsequent lactate and acid accumulation. Perioperative ischemia and lactic acidosis can cause electrical instability, leading to postoperative arrhythmias (8,9). Other possible etiologic factors for post-CABG atrial fibrillation include pericarditis, excessive production of catecholamines, and intravascular volume changes (7).

Despite progressive improvements in CABG surgery results, patients with unstable angina and recent infarction continue to have increased morbidity and mortality (10). The increased risk may be a result of increased myocardial injury, which contributes to decreased ventricular function and an increased incidence of postoperative arrhythmias and low cardiac output syndrome (11,12). High-risk patients may undergo periods of ischemic metabolism while waiting for surgery and may therefore benefit from a metabolic intervention.

Several experimental studies have demonstrated the beneficial effect of glucose and insulin infusion on myocardial performance during CABG surgery (13–15), presumably via restoration of myocardial energy supplies. However, these studies have not focused on the effect of insulin on perioperative arrhythmias. In addition, the glucose-insulin infusion used in these studies has not been given as a part of the cardioplegic solution during the ischemic period.

We have previously demonstrated that insulin improves myocardial aerobic metabolism and increases post-CABG ventricular function (16,17). We hypothesized that improved aerobic metabolism will mitigate the deleterious effects of intraoperative atrial ischemia and thus decrease the risk of postoperative atrial arrhythmias. We therefore performed a randomized, double-blinded, placebo-controlled study to determine whether insulin-enhanced cardioplegia would decrease the rate of postoperative atrial fibrillation in a high-risk patient population.

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Methods

Population

Patients were part of a continuing trial assessing the effect of insulin cardioplegia on postoperative myocardial infarction and low cardiac output syndrome, and therefore, these endpoints are not presented in this article. A sample size of 500 patients was chosen in order to obtain a high power (> 99%) of detecting a 30% relative risk reduction in atrial fibrillation, based on an expected incidence of 30% and an α-level of 0.05.

All patients who were admitted to a coronary care unit after an ischemic episode (angina or infarction) and required urgent CABG during the same hospitalization were eligible to participate in this study. Eligible patients included those with postinfarct angina, Canadian Cardiovascular Society class IV angina, angina with rapidly increasing intensity, and severe left main disease. A total of 501 patients operated on in one university-affiliated center between December 1995 and October 1997 were included in the current study. Patients who required simultaneous valvular or extracardiac procedures, left ventricle (LV) aneurysm resection, or redo sternotomy were excluded. The study protocol was approved by our IRB, and all patients gave written, informed consent to participate.

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Anesthetic Management

All cardiac medications including β-adrenergic blockers were continued until the morning of surgery. Patients were premedicated with either sublingual lorazepam (1–3 mg) or IM morphine (5–10 mg) and perphenazine (2.5–5 mg) according to the anesthesiologist’s preference. Pulmonary artery catheters and arterial cannulas were used for perioperative monitoring. Patients were anesthetized by using a small-dose fentanyl regimen (10–15 μg/kg), aiming to early tracheal extubation. Isoflurane (0.4%–1.5%) and midazolam (up to 0.1 mg/kg) were used for maintenance of anesthesia. Pancuronium was used to facilitate tracheal intubation. Propofol infusion (2–4 mg · kg−1 · h−1) was started at the beginning of the cardiopulmonary bypass (CPB) and was continued 2–4 h postoperatively to keep patients sedated until they were warm and hemodynamically stable.

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Surgery and Myocardial Protection

All patients underwent median sternotomy and were placed on CPB. A single, two-staged right atrial cannula was used for venous drainage. Left atrial venting was not performed. Hematocrit was maintained between 20% and 25% during CPB, pump flow rates between 2.0 and 2.5 L · min−1 · m−2, and mean arterial pressure between 60 and 80 mm Hg. Systemic body temperature was allowed to drift to 34°C, with active rewarming at the end of CPB. All anastomoses were completed during a single aortic cross-clamp period. Cold (10°C) or tepid (29°C) antegrade or retrograde blood cardioplegia was used for myocardial protection according to the surgeon’s preference. Our cardioplegic solution has been previously described (18), consisting of oxygenated blood mixed with crystalloid in an 8:1 ratio to achieve a final concentration of 6 mEq/L of magnesium sulfate, 50 mmol/L of glucose, and either a small (8 mEq/L) or large (27 mEq/L) concentration of potassium chloride. All patients received an initial infusion of the large potassium solution followed by maintenance with the small potassium formulation.

Patients were randomized to receive either standard blood cardioplegia (Control group) or standard blood cardioplegia enhanced with insulin (Insulin group). Patients who were randomized to the Placebo (Control) group had an equivalent volume of inactive diluent added to each bag of crystalloid cardioplegia. Patients randomized to the Insulin group had human insulin (Humulin R; Eli Lilly, Mississauga, Canada) added to the crystalloid solution to achieve a final concentration of 10 IU/L in the blood cardioplegic mixture.

Randomization was via an opaque sealed envelope opened at the time of anesthetic induction and was stratified by surgeon to account for differences in myoprotective strategies. The surgeon, anesthesiologist, and perfusionist were blinded to patient group assignment.

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Postoperative Management

All patients were transferred postoperatively to the intensive care unit (ICU). Propofol infusions were discontinued in the ICU when patients were hemodynamically stable, were not bleeding excessively (>100 mL/h), and had reached a body temperature of 36.5°C. Patients’ tracheas were routinely extubated when they were awake, were following commands, were able to create a negative inspiratory force of -20 cm H2O, and had a vital capacity of >10 mL/kg (19). In hemodynamically unstable patients, sedation was continued as a morphine infusion supplemented with midazolam when needed.

Dopamine was used as a first line inotrope if the cardiac index was <2.0 L · min−1 · m−2 or if the systolic blood pressure was <90 mm Hg after optimization of filling pressures. More severe hemodynamic compromise led to the initiation of epinephrine, norepinephrine, dobutamine, or milrinone as indicated. Patients requiring sustained inotropic support were considered candidates for intraaortic balloon pump insertion (11). Stable patients were transferred to the surgical floor on the first postoperative day. Patients were started on β-adrenergic blockers 1 day postoperatively only if they were receiving these medications preoperatively.

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Arrhythmia Data

Patients were continuously monitored by telemetry to a central nursing station monitor (Hewlett Packard M2350A; Andover, ME) while in the ICU and nursing ward. Monitors were continuously observed by a trained nurse and were set to alarm for all common arrhythmias. Telemetry was discontinued in patients who remained in sinus rhythm 48 h after transfer to the surgical ward, and only symptomatic arrhythmias were recorded thereafter. A 12-lead electrocardiogram was collected immediately after surgery and on the first, third, and fifth postoperative days. A single physician (MH) who was blinded to patient group assignment reviewed all electrocardiographic data.

Atrial fibrillation was defined as an irregular rhythm with no organized atrial activity persisting >30 s. Atrial flutter always occurred in association with atrial fibrillation and, therefore, was recorded as atrial fibrillation. Ventricular tachycardia was defined as six or more consecutive, regular, wide-complex beats at a rate of >120/min. Intracardiac conduction defects were defined as wide-complex beats with appropriate corresponding morphology. Patients were considered to have an arrhythmia if it occurred any time in the postoperative period, regardless of whether treatment was instituted.

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Statistical Analysis

Data were expressed as mean ± sd for continuous variables and as percentages for categorical variables. Univariate analyses were performed by using the χ2 test (or Fisher’s exact test where appropriate) for categorical variables and Student’s t-test (or Wilcoxon ranked sum test where appropriate) for continuous variables. Stepwise logistic regression models included all variables suggested by the univariate analyses (P < 0.25) or those judged to be clinically important. The model with the best Hosmer-Lemeshow goodness-of-fit statistic and receiver operator characteristic curve was chosen, as previously described (11). All analyses were performed by using the SAS program (SAS Institute, Cary, NC).

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Results

Of the 501 patients, 243 were randomized to the Insulin Treatment group and 258 patients to the Control group. Preoperative clinical characteristics of these patients are shown in Table 1. The two groups of patients were similar for all preoperative variables, with the exception of an increased prevalence of LV dysfunction in the Insulin group (Table 1).

Table 1

Table 1

Intraoperative variables for the two groups are displayed in Table 2. There were no statistically significant differences between the two groups of patients for any of the intraoperative characteristics listed, with the exception of peak serum glucose and potassium levels.

Table 2

Table 2

Postoperative variables were also similar for the two groups of patients including time to tracheal extubation (8.8 ± 6.7 vs 9.4 ± 7.1 h for Insulin versus Control, respectively), ICU length of stay (1.8 ± 3.2 vs 1.9 ± 3.7 days), and length of postoperative hospital stay (8.7 ± 14.6 vs 7.8 ± 10 days, all P values nonsignificant).

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Postoperative Arrhythmias

Atrial fibrillation was the most common postoperative arrhythmia, with a peak incidence on the second day after CABG (Table 3). The cumulative incidence of atrial fibrillation was 31.1% in the Insulin group and 30.1% in the Control group (P = 0.80). Stepwise logistic regression revealed the following predictors for postoperative atrial fibrillation (with odds ratios [OR] and 95% confidence intervals [CI] in parentheses): 1) age > 70 yr (OR 1.07, CI 1.05–1.09), 2) preoperative atrial fibrillation (OR 9.87, CI 2.69–36.31), and 3) preoperative creatinine level > 150 μmol/l (OR 10.23, CI 1.10–94.82).

Table 3

Table 3

The incidence of ventricular tachycardia was infrequent at all time points (Table 4). The cumulative incidence of ventricular tachycardia was 9.4% in the Insulin group versus 8.5% in the Control group (P = 0.71). Most episodes of ventricular tachycardia were nonsustained and did not require treatment.

Table 4

Table 4

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Postoperative Conduction Defects

Right bundle branch block (RBBB) was the most common conduction abnormality postoperatively, with a peak incidence immediately after arrival in the ICU (Table 5). There was no difference in the incidence of RBBB between the two groups of patients. Stepwise logistic regression analysis revealed the following predictors for RBBB: 1) age >70 yr (OR 1.03, CI 1.00– 1.06), 2) female sex (OR 1.84, CI 1.06–3.20), and 3) diseased circumflex vessel (OR 2.68, CI 1.34–5.34). Left bundle branch block (LBBB) was uncommon, occurring in only 8.9% of all patients. There was no difference in the incidence of LBBB between the two treatment groups. The cumulative incidence of any intracardiac conduction abnormality (RBBB or LBBB) was 17.7% in the Insulin group versus 14.7% in the Control group (P = 0.37).

Table 5

Table 5

Temporary postoperative atrial or ventricular pacing was required in 39.3% of patients in the Insulin group and 42.9% in the Control group (P = 0.42). Pacing was used in the majority of patients for bradycardia, not for atrioventricular conduction abnormalities. However, on the fifth postoperative day, there were two patients in the Control group who still required pacing with epicardial wires versus none in the Insulin group.

On arrival to the ICU, 48.1% of patients in the Insulin group and 52.3% of patients in the Control group (P = 0.38) were free of any arrhythmia or conduction defect and were not paced. On the fifth postoperative day, the respective values were 70.8% and 75.2% (P = 0.32).

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Discussion

Postcardiac surgery arrhythmias are associated with significant morbidity and are an important cause of increased resource utilization (1–6,20). Many investigators have studied predictors of postoperative arrhythmias, particularly atrial fibrillation, and have examined various methods of prevention and treatment. In the current study, we studied the occurrence of arrhythmias and conduction defects in a high-risk patient group undergoing urgent CABG surgery using cardioplegic arrest and CPB. We focused on patients undergoing urgent CABG surgery (i.e., those requiring CABG during the same hospitalization as their admission for an acute ischemic event). We chose this patient population because of their increased incidence of cardiac morbidity (11,12), thereby improving the chance of detecting a statistically significant difference between treatment groups.

We were unable to detect a beneficial effect of glucose-insulin cardioplegia on the incidence of postoperative atrial fibrillation in the current double-blinded, randomized, controlled clinical trial. Independent predictors of atrial fibrillation were elderly age, previous atrial fibrillation, and renal insufficiency. Although several different risk factors have been previously identified (1–3), advanced age is the only consistent predictor of postoperative atrial fibrillation (7). It should be noted that all patients who were taking preoperative β-adrenergic blockers in the current trial continued to receive β-adrenergic blocker after CABG. Continuation of β-adrenergic blocker therapy after cardiac surgery results in a significant reduction in the incidence of atrial fibrillation (21,22).

Our randomized trial also failed to detect a beneficial effect of insulin-enhanced cardioplegia on postoperative conduction abnormalities. Previous studies using crystalloid cardioplegia have demonstrated conduction abnormalities in 20%–58% of patients after CABG, persisting in 3%–22% of patients at discharge (23,24). Studies using cold-blood cardioplegia have produced similar values (25,26). Flack et al. (27) compared warm- and cold-blood cardioplegia and found that the incidence of conduction abnormalities was significantly reduced in the normothermic cardioplegia group. The incidence of RBBB among the 501 patients in this study was small (12%–14% on arrival to the ICU and 4%–6% on the fifth postoperative day), which may indicate good myocardial protection in our patient population, even though normothermic cardioplegia was not used.

Exogenous glucose may be a superior substrate for the myocardium during periods of ischemia (17). Insulin stimulates the pyruvate dehydrogenase enzyme and improves Krebs cycle metabolism after ischemia (17,28). Additional possible beneficial effects of glucose-insulin include a reduction in circulating free fatty acids, which have deleterious effects on ischemic myocardium (29). In experimental studies with regional myocardial ischemia, glucose-insulin infusion decreased infarct size, increased ATP and creatinine phosphate levels, and improved ventricular function (30–32). Several clinical studies have shown beneficial effects of glucose and insulin infusions during cardiac operations (13,33,34), while others have not proven efficient (35).

The current large, randomized, controlled study of urgent CABG surgery patients reveals that cardioplegia, enhanced with glucose and insulin, has no effect on the incidence of postoperative arrhythmias or conduction abnormalities. Any possible beneficial effect of insulin infusion on myocardial metabolism was not reflected in postoperative electrical disturbances. Additionally, patient length of ICU and hospital stay was not affected by insulin-enhanced cardioplegia.

Our findings are in contrast to previously published studies. In a small, nonblinded, prospective randomized study, Lazar et al. (36) demonstrated a significant effect of perioperative glucose-insulin solutions on postoperative clinical outcomes in patients undergoing urgent CABG for unstable angina. These investigators used an insulin infusion delivered via a central vein at 0.05 IU · kg−1 · h−1. In the group receiving insulin, the authors found a significant reduction in inotrope scores, overall weight gain, ventilation times, and ICU and hospital lengths of stay. Insulin treatment also resulted in a decreased incidence of postoperative atrial fibrillation (13% vs 53% in the control group, P = 0.02).

There are several possible explanations for the discrepancies. Our study delivered insulin directly to the heart as part of the cardioplegic formulation. A previous clinical study from our institution demonstrated that this technique resulted in a significant improvement in load-independent indices of LV function (16). However, our treatment strategy did not include any insulin therapy after aortic cross-clamp removal. In contrast, Lazar et al. (36) continued insulin therapy for 12 hours after myocardial reperfusion. In addition, the smaller postoperative weight gain observed by Lazar et al. (36) in the insulin group may have contributed to the decreased incidence of atrial arrhythmias. A combination approach, involving both cardioplegic insulin delivery and postoperative IV therapy, may be optimal in preventing arrhythmias and improving LV functional recovery.

A limitation of this study is that telemetry was discontinued 48 hours after transfer to the surgical ward (3 to 4 days postoperatively for the majority of patients), in patients who remained in sinus rhythm. It is therefore possible that short episodes of asymptomatic atrial fibrillation may have been undetected. However, previous studies have demonstrated that most arrhythmias occur in the first three days postcardiac surgery (7). In addition, it is unlikely that more of these episodes would have occurred in one treatment group than the other. Given the randomized design of our trial and our sufficient sample size, we feel that our conclusions are justified.

In conclusion, we were unable to detect a beneficial effect of insulin-enhanced cardioplegia on atrial fibrillation after high-risk CABG surgery. Further studies are required to determine the optimal use of insulin during cardiac surgery.

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