More than 1.5 million open-heart operations are performed each year worldwide.1 Progress in surgical and anesthetic management as well as cardioprotective techniques has contributed to lower the operative mortality despite the increasing burden of associated illnesses and more complex surgical procedures.2,3
Since 1962, the cardioprotective effect of glucose–insulin–potassium (GIK) infusion has generated interest in the treatment of patients with acute coronary syndrome and those undergoing cardiac surgery.4,5 Mounting experimental evidence has implicated insulin as improving cardiomyocyte survival through activation of the phosphoinositide 3-kinase/protein kinase B/Akt pathway and increasing myocardial energy efficiency to generate high-energy phosphate compounds.6
Impairment in ventricular performances occurs within the first 12–24 hours after cardiopulmonary bypass (CPB) and ranges from silent self-limited functional deterioration to low cardiac output syndrome (LCOS) requiring pharmacological support and/or mechanical circulatory assistance.7,8 The underlying mechanisms involve depletion of myocardial energetic substrates, generation of oxygen-derived free radicals, coronary embolization, and the release of inflammatory mediators triggered by ischemia–reperfusion, CPB, and surgical tissue trauma.9 A wide spectrum of pathological conditions is associated with postcardiotomy ventricular dysfunction (PCVD), namely ischemic and necrotic changes, as well as apoptosis of cardiomyocytes along with coronary endothelial dysfunction and down-regulation of β-adrenergic receptors.10
Although better ventricular function and lesser myocardial injuries have been reported in cardiac patients pretreated with GIK, there are uncertainties regarding hard clinical end points.11,12 Knowing that LCOS is a frequent cause of operative mortality,13,14 there is a need to optimize myocardial protection, particularly in the high-risk group of cardiac surgical patients.
In this randomized controlled trial (RCT), we aimed to investigate the clinical impact of GIK in moderate- to high-risk patients undergoing open-heart surgery. The primary end point was the incidence of PCVD, a surrogate of LCOS, and secondary end points were the intraoperative changes in left ventricular (LV) systolic function, the postoperative release of cardiac troponin, the occurrence of major complications, and the length of stay in hospital and in intensive care unit (ICU).
Study Design and Patient Selection
This single-center, randomized, placebo-controlled, double-blinded trial was approved by the institutional review board at the University Hospital of Geneva (CER: 08-095) and was registered before patient enrollment at ClinicalTrials.gov (NCT00788242; principal investigator: Christoph Ellenberger; date of registration: November 10, 2008). Written consent was obtained from each eligible participant. From January 1, 2009, to December 31, 2013, patients with severe aortic valve stenosis and/or coronary artery disease scheduled for elective aortic valve replacement (AVR) and/or coronary artery bypass surgery (CABG) were all screened and included if they had a Bernstein–Parsonnet score >7. Exclusion criteria consisted of emergent or off-pump surgery, preoperative critical conditions, poorly controlled diabetes mellitus (glucose >12 or <3 mmol·L−1 ≥3 episodes/wk), severe liver disease (Child–Pugh C stage), and dementia or significant cerebrovascular disease (Supplemental Digital Content, Annex A, http://links.lww.com/AA/C190).
Randomization and Blinding
Consenting patients were randomized on a 1:1 basis into GIK or placebo arms, using permuted blocks of 4 patients and stratified by Bernstein–Parsonnet at score ≤15 or >15. The allocation sequence was generated with the computer program STATA 10 (Stata Corp, College Station, TX), and the codes were stored in sealed envelopes. The unlabeled study solution and codes (saline or GIK) were prepared by an anesthesia nurse who was not involved in data recordings nor in perioperative patient management. The anesthesiologists, surgeons, and intensivists were all blinded to group allocation as well as the 2 research assistants (RAs: RA1 and RA2) who recorded, separately, preoperative and intraoperative data (RA1) and postoperative clinical outcome data (RA2).
Standard monitoring included a radial arterial line, a central jugular venous catheter, transesophageal echocardiography (TEE), and bispectral analysis of the electroencephalographic signals. A single intrathecal injection of morphine (10 µg·kg−1) was administered to all patients without hemostatic disorders and dual antiplatelet therapy to optimize analgesia and facilitate weaning from the ventilator. Anesthesia was induced intravenously with sufentanil (10–15 µg), ketamine (0.5–0.8 mg·kg−1), and propofol (1–1.5 mg·kg−1). Neuromuscular blockade was achieved with rocuronium, the trachea was intubated, and the lungs were mechanically ventilated with low tidal volume (6–8 mL·kg−1 of predicted body weight), a positive end-expiratory pressure of 5–10 cm of water, and hourly alveolar recruitment maneuvers (except during the CBP period). Anesthesia was maintained with intravenous propofol to target bispectral analysis of the electroencephalographic signals values between 40 and 60 throughout the whole surgical procedure. Inhaled sevoflurane (1–1.5 minimal alveolar concentration) was administered over at least 30 minutes before the start of CPB as a mean to enhance myocardial protection by anesthetic preconditioning.15
All surgical procedures were performed via a full sternotomy and under normothermic nonpulsatile CPB by board-certified cardiac surgeons. The circuit and the membrane oxygenator were primed with 2 L of fluids (1 L Ringer’s acetate and 1 L of hydroxyethyl starch 6% 130/0.4). Antifibrinolytic therapy consisted of tranexamic acid 15 mg·kg−1 administered as an intravenous bolus with an additional dose of 10 mg·kg−1 in the CPB priming fluid. During aortic cross-clamping, myocardial protection was achieved by intermittent antegrade infusion of cold blood (supplemented with 10 mEq of potassium chloride in the first cardioplegia). Insulin, glucose, or other components were not added in the blood cardioplegia solution. At the end of the procedure and after aortic unclamping, weaning from the CPB was guided by TEE assessment and hemodynamic measurements based on invasive pressure monitoring (Supplemental Digital Content, Annex B, http://links.lww.com/AA/C190).16 Briefly, after resumption of a satisfactory heart rate and rhythm, venous return and arterial inflow of the heart–lung machine were both reduced and the preload of the heart was progressively increased with blood drawn from the reservoir. Besides titration of fluids, cardiovascular medications were given to target-specific hemodynamic end points: LV end-diastolic diameter (up to preoperative values or 2.2–2.8 cm/m2), mean arterial pressure between 65 and 100 mm Hg, and heart rate between 70 and 100 beats/min.
Before GIK/saline administration and at the end of surgery (closed chest), a comprehensive TEE examination was performed by 2 anesthesiologists certified in perioperative TEE and LV systolic function was assessed by calculating the fractional area change (FAC). The FAC was determined offline by measuring the LV end-systolic and end-diastolic areas (EDAs) from the transgastric midpapillary short-axis view (FAC = [EDA − end-systolic area]/EDA).
Patients randomized in the placebo group received a saline solution (NaCl, 0.9%), and those randomized to the GIK group were given GIK solution (human Actrapid [Novo Nordisk, Bagsvaerd, Denmark] 20 IU and potassium chloride 10 mEq in 50 mL of 40% glucose). These solutions were given via the central venous catheter over 60 minutes on anesthetic induction. After preliminary testing different dosages and based on previous studies, we selected a GIK regimen with 1 IU insulin per gram of glucose.17 In both groups, blood glucose concentrations (BGCs) were measured with a blood gas analyzer (ABL 800; Radiometer Medical ApS, Brønshøj, Denmark), every 30 minutes before and during CPB and hourly thereafter. Supplemental insulin or glucose was administered intravenously to maintain BGC between 4.5 and 10 mmol·L−1 throughout surgery. Patients with BGC between 10 and 12 mmol·L−1 received 2-IU intravenous bolus of insulin with a continuous infusion of 2 IU·hour−1 until the next test schedule, patients with a BGC value between 13 and 15 mmol·L−1 received a 3-IU intravenous bolus followed by a continuous infusion of 3 IU·hour−1, and those with a BGC value exceeding 15 mmol·L−1 received a 4-IU intravenous bolus followed by a continuous infusion of 4 IU·hour−1 until the next measurement of BGC.
Study End Points and Measurements
The primary outcome was the occurrence of PCVD within the first 48 hours after weaning from CPB. The diagnostic criterion of PCVD was the need of inotropic support for at least 120 minutes (dobutamine ≥5 µg kg−1 minute−1, epinephrine ≥0.05 µg kg−1 minute−1, milrinone >0.3 µg kg−1 minute−1) and/or the need for an intraaortic balloon pump. The indication to initiate treatment with inotropes was the development of new/worsening ventricular dysfunction as assessed by TEE in the presence of low mean arterial pressure (<70 mm Hg) not responsive to fluid loading and/or vasopressor therapy. Conversely, the decision to withdraw inotropic treatment was guided by TEE assessment along with changes in hemodynamic condition over the early hours after CPB.
The secondary clinical end points were intraoperative changes in FAC, in-hospital mortality and the occurrence of cardiovascular adverse events (new or worsening LV failure, myocardial infarct, atrial fibrillation, stroke), respiratory complications (atelectasis, pneumonia, mechanical ventilation >24 hours), and the length of stay in ICU and in hospital. A modified version of the Dindo–Clavien systemic classification was used to report major adverse events (grade 2 and higher) (Supplemental Digital Content, Annex C, http://links.lww.com/AA/C190).18 On the morning of the first and second day after surgery, arterial blood was sampled for measurement of plasma troponin-I concentrations (Beckman cTnI assay; Beckman Coulter, Brea, CA; cutoff, 0.09 ng·mL−1).
All data related to patient demographic information, comorbidities, current medications, anesthetics and surgical management (intravenous fluids, duration of aortic cross-clamping and CPB, type of surgery, glycemia control), and postoperative clinical outcome (duration of mechanical ventilation, serum creatinine, and troponin-I concentrations) were prospectively collected and recorded on a dedicated case report form separated into 2 parts (the first including preoperative and intraoperative items and the second including postoperative clinical outcome data).
All collected data were checked for completeness and were tested with the Kolmogorov–Smirnov test for normality. Summary descriptive statistics were computed for pre-, intra-, and postoperative variables, including frequencies (percentages [%]), medians (interquartile range [IQR], 25%–75%), means (standard deviations), and risk ratios (RRs) (95% confidence interval [CI]). To analyze differences between the 2 groups, 2-sided unpaired t tests, Wilcoxon rank sum tests, or χ2 tests were used where appropriate. One-way and repeated-measures analysis of variance were used to assess the changes in FAC intraoperatively. Exploratory subgroup analysis was conducted using a multivariable logistic regression model to assess whether the effect of GIK on PCVD was dependent on patient age, gender, LV ejection fraction (LVEF), Bernstein–Parsonnet score, the presence of diabetes mellitus, the type of surgery (CABG, AVR, or combined), and the duration of CPB. Interaction was assessed separately for each factor using a significance criterion of 0.15 to adjust for the low power of detecting interaction.
Standardized differences (STDs) were used to assess imbalances between baseline characteristics between the 2 groups and to compute adjusted treatment effects using multivariable logistic regression (inclusion criterion STD >10). To reduce the number of statistical tests, secondary study end points were combined into composite outcomes of cardiovascular complications (atrial fibrillation, new or worsening LV failure, myocardial infarct, and stroke) and respiratory complications (atelectasis, pneumonia, and ventilation ≥24 hours). Statistical tests were conducted using STATA 14 software (Stata Corp, College Station, TX).
Based on a previous cohort study, we assumed a baseline incidence of 38% PCVD and we expected a 50% risk reduction in the GIK group compared with placebo treatment.19 A sample of 88 patients per group was required (80% power; 2-sided test; type I error of 0.05), and to compensate for possible dropouts, we planned to enroll 226 patients.
A total of 295 patients were screened; 243 provided consents, and 112 were randomized in the placebo group and 112 in the GIK group (Figure 1). Two patients who underwent off-pump CABG surgery were excluded and 222 patients were analyzed: 112 in the placebo group and 110 in the GIK group.
Preoperative patient demographics, clinical characteristics, and laboratory results are shown in Table 1. The overall operative risk profile according to the Bernstein–Parsonnet score was similar in the 2 groups. However, patients in the GIK group presented lower LVEF and higher prevalences of coronary heart disease, hypertension, diabetes, hypercholesterolemia, and β-blocker treatment compared with the placebo group. As shown in Table 2, the GIK group also included a higher proportion of CABG and a lower proportion of AVR surgery. The duration of CPB and aortic cross-clamping as well as the administration of crystalloids, colloids, and blood products were similar in the 2 groups. Intraoperatively, the BGC did not differ between the 2 groups; however, a higher proportion of GIK-treated patients required additional insulin (41 [37.3%] vs 20 [17.9%] in the placebo group; P = .001) and additional glucose (14 [8.1%] vs 4 [3.6%] in the placebo group; P = .012). The median additional dose of insulin was 5.1 IU (IQR 25–75, 3.6–9.0) in the GIK group and 4.0 IU (IQR 25–75, 4.0–9.4) in the placebo group.
As reported in Table 3, PCVD occurred in 63 patients (Table 3) and the GIK treatment was associated with a reduced occurrence of PCVD (RR 0.41 with 95% CI, 0.25–0.66). Across all prespecified subgroups—gender (men or women), age (<75 or ≥75 years), presence/absence of diabetes mellitus, LVEF (<40% or ≥40%), Bernstein–Parsonnet score (≤22 or >22), type of surgery (AVR or CABG), and duration of CPB (<100 or ≥100 minutes)—the GIK intervention was associated with a lower incidence of PCVD compared with placebo (Figure 2). Noteworthy, the effect of GIK on PCVD varied according to baseline LV function (LVEF ≥40%: RR, 0.19; 95% CI, 0.08–0.46 and LVEF <40%: RR, 0.53; 95% CI, 0.32–0.87) and to the duration of CBP (CPB ≤100 minutes: RR, 0.18; 95% CI, 0.06–0.58 and CPB >100 minutes: RR, 0.50; 95% CI, 0.30–0.85). After adjusting for imbalances in baseline characteristics, the multivariable logistic regression confirmed the favorable effect of GIK on PCVD (RR, 0.28 with 95% CI, 0.14–0.53). The following variables had been included in the logistic regression model (STD >10): gender, hypertension, coronary heart disease, aortic stenosis, pulmonary hypertension, hypercholesterolemia, diabetes mellitus, Karnofsky performance status ≤50%, low LVEF, New York Heart Association class, β-blocker use, calcium antagonist use, diuretics, antiplatelets, and creatinine clearance.
Secondary Study End Points
Intraoperative hemodynamic changes are illustrated in Figure 3. In the GIK group, the LV FAC was higher at the end of surgery compared with the start of surgery (mean difference, +2.3%; 95% CI, 0.8–3.8; P = .002), whereas in the placebo group, there was a decline in FAC (mean difference, −6.1%; 95% CI, −7.6 to −4.6; P < .001). After weaning from CPB, the EDA did not differ between the 2 groups (12.7 [2.9] in the placebo group and 12.9 [3.7] in the GIK group; P < .658), indicating similar LV preload conditions.
The use of GIK was also associated with lower plasma troponin levels on the first postoperative day (2.9 ng·mL−1 [IQR, 1.5–6.6] vs 4.3 ng·mL−1 [IQR, 2.4–8.2] compared with placebo; P = .009) and fewer patients had plasma troponin levels >10 ng·mL−1 (13 [12%] vs 26 [23%]; P = .034). Postoperative creatinine phosphokinase and creatinine kinase-MB plasma levels did not differ between the 2 groups.
In-hospital mortality did not differ between the 2 groups. Compared with the placebo group, GIK-pretreated patients presented fewer postoperative cardiovascular complications (RR, 0.69 [95% CI, 0.55–0.87]; P = .001) and fewer respiratory complications (RR, 0.55 [95% CI, 0.42–0.71]; P < .001) as well as shorter ICU and hospital length of stay (Table 3). After adjusting for imbalances in baseline characteristics, multivariable logistic regression confirmed the favorable effect of GIK on postoperative cardiovascular and respiratory complications.
In this trial, the administration of GIK before aortic cross-clamping resulted in a 59% reduction in PCVD. Besides lesser requirement for inotropes, GIK pretreatment was associated with better preservation of systolic function of the LV after weaning from bypass, lesser release of cardiac troponin, and fewer postoperative cardiovascular and respiratory complications along with shorter ICU and hospital length of stay compared with placebo-treated patients.
The need for inotropic support has been reported to vary from 20% to 100% of patients undergoing valvular aortic or CABG.20,21 This variability has been attributed to the heterogeneity of the surgical population, the lack of local guidelines or algorithm, and the wide range in clinical experience and skills of the surgical/anesthetic teams.
In this RCT, we included moderate- to high-risk cardiac patients based on the Bernstein–Parsonnet score, a validated tool to predict the need for inotropes and early mortality after open cardiac surgery.22,23 As expected, 40% of patients in the placebo group presented PCVD and 85% were treated with inotropes during and after weaning from CPB. Processes of care for anesthetic management, myocardial protection, and surgical techniques were all standardized, and goal-directed strategies were applied by well-trained health care professionals. The use of a pulmonary artery catheter was not deemed justified in these cardiac surgical patients.24 In agreement with expert-based guidelines,25 intravascular fluid loading and the administration of cardiovascular drugs were aimed to optimize circulatory preload, ventricular contractility, and vascular resistance based on TEE and invasive pressure monitoring. De Hert et al26 demonstrated the crucial role of preload optimization in restoring both systolic and diastolic LV function at the time of CPB separation. Using such protocol-driven hemodynamic approach during CPB weaning, cardiac preload as expressed by the EDA did not differ between the 2 groups and inotropic drugs (mainly adrenergic receptor agonists) were selectively administered to patients with impaired ventricular contractility as assessed by TEE. Patients with adequate cardiac function were not given inotropes and therefore could not experience deleterious effects related to sustained activation of the cyclic adenosine monophosphate pathway owing to β-adrenergic receptor stimulation or cyclic nucleotide phosphodiesterase inhibition. Several cohort studies using propensity score matching have identified perioperative inotrope treatment as a predictive factor of early mortality, cardiac morbidity, and renal failure after cardiac surgery.22,27,28
In the current trial, better preservation of the FAC of the LV after weaning from CPB and lesser release of troponin-I on the first postoperative day in the GIK-treated patients were surrogate markers of enhanced myocardial protection. After cardiac and noncardiac surgery, the release of cardiac troponin has been shown to convey prognostic implications since elevated postoperative plasma levels of troponin are associated with greater need for inotropes and increased risks of early mortality and heart failure.29
Our positive results confirmed those reported earlier in 2 RCTs conducted at the University Hospital in Birmingham.29,30 In these studies including low-risk patients, the infusion of GIK—from the start of surgery until 6 hours after CPB—was associated with a lower incidence of LCOS and a higher cardiac index regardless of the type of surgery, whereas myocardial injuries were attenuated after CABG surgery30 but not after AVR31 surgery. In a meta-analysis of 33 RCTs including 2133 patients undergoing on-pump cardiac surgery, Fan et al32 reported lesser need for inotropes and fewer myocardial infarct with shorter ICU length of stay in GIK-treated patients compared with those receiving usual care. In contrast, another meta-analysis of 14 RCTs including CABG surgery only reported a minor reduction in ICU length of stay with no impact on the incidence of postoperative arrhythmias, myocardial infarct, and infection.33 Recently, Duncan et al34 also failed to demonstrate any meaningful improvement in systolic ventricular function in low-risk patients treated with the hyperinsulinemic normoglycemic clamp technique during the whole surgical period.
In the majority of these RCTs, the critical CPB weaning period was poorly described and goal-directed hemodynamic approaches for fluid infusion and cardiovascular medications were often not implemented. Deficiencies in blinding and concealment of allocation could challenge the validity of some these studies. The negative results could be explained by the efficacy of the usual myocardial protective modalities (eg, hypothermic blood or crystalloid solution) and the inclusion of low-risk patients (eg, preserved LV function, no ventricular remodeling).
The rationale for using GIK to enhance myocardial protection in cardiac surgery is based onpromoting glucose as the primary myocardial energy substrate, decreasing circulating free fatty acid levels, stabilizing myocardial membrane electrical gradient, and promoting cell survival while avoiding hyper/hypoglycemic events.6 To achieve these goals and in contrast to previous studies, we limited the GIK infusion before aortic cross-clamping over a shorter period (60 minutes). Animal studies have demonstrated that the administration of GIK before the onset of myocardial ischemia resulted in greater availability of glycogen within the myocardium providing therefore the possibility to generate adenosine triphosphate (ATP) through glycogenolysis and anaerobic glycolysis.35,36 Higher glycogen content and better preservation of myocardial ATP stores coupled with enhanced recovery of ventricular contractility have been demonstrated during the reperfusion period when insulin was given before the onset of myocardial ischemia.37 Poorly controlled glucose concentrations, particularly during the reperfusion period, have been shown to generate/amplify myocardial injury and brain damage that would abolish or mitigate any potential organ protective effects afforded by GIK.38 In our study, no patient experienced severe hyperglycemia or hypoglycemia, BGCs being tightly controlled and any deviation from normal being rapidly corrected in both groups. In addition, insulin was administered at a higher dosage (~4.5 mIU/kg/min) in combination with glucose (1:1 ratio, insulin IU/glucose gram). At an infusion rate higher than 2 mIU/kg/min, insulin has been shown effective in suppressing free fatty acid production and gluconeogenesis in the context of fasting and surgical stress-induced release of catabolic hormones.39 Therefore, the administration of such GIK regimen closely mimics the “fed state” and by switching the energetic pathway from fatty acids to glucose oxidation. Both in experimental conditions of ischemia–reperfusion and of cardiac failure, greater efficiency in myocardial ATP production has been demonstrated along with improved mechanical function of the left ventricle.40,41
Our results should be interpreted within the confines of some limitations. First, as the main study entry criteria was an elevated operative risk based on the Bernstein–Parsonnet score, patient’s characteristics and the type of surgery differed between the 2 groups with obvious correlation regarding some characteristics (eg, hypertension, coronary artery diseases, diabetes mellitus, low LVEF, cardiovascular medications). After adjustment for these unbalanced characteristics, the cardioprotective effect of GIK was confirmed. All estimates of the subgroup analysis supported GIK cardio protection. However, effect modification related to LVEF and CPB duration could not be excluded due to the low power of the tests for interaction.
Second, we acknowledge that the diagnosis of PCVD, the primary study outcome, was based on subjective operator-dependent criteria. Yet, the lower incidence of PCVDs in the GIK-treated patients was also supported by TEE documentation of better preservation of LV systolic function after CPB weaning, as well as by an attenuated release of cardiac troponin and a reduced occurrence of cardiovascular and respiratory complications. As heart and lungs are anatomically and functionally closely related, postoperative impairment in cardiac function has been identified as a risk factor for prolonged ventilation time and longer stay in ICU.42,43 Accordingly, better recovery in cardiac function in GIK-treated patients likely contributed to the reduced occurrence in major postoperative pulmonary complications along with faster weaning from the ventilator.
Finally, the GIK solution was given at a fixed dose and limited to the prebypass period, mainly for safety reasons and simplicity to implement. It remains questionable if the continuation of GIK infusion throughout the aortic cross-clamping time and after weaning from bypass could further enhance cardio protection or increase the risks of hypo/hyperglycemia. Conversely, some patients may be unresponsive to the metabolic and nonmetabolic effects of insulin.
In conclusion, we demonstrated that prebypass GIK infusion coupled with tight glycemic control improves postbypass ventricular function, attenuates myocardial injuries, and reduces the incidence of cardiac and respiratory complications after CABG and AVR surgery. Given its safety profile and effectiveness, this simple and low-cost metabolic cocktail might be considered a valuable adjuvant to the current myocardial protective strategy, particularly in moderate- and high-risk patients undergoing open-heart surgery. Further studies are needed to determine the optimal dosage of GIK and also its effectiveness in emergency cardiac surgery where the elevated levels of circulatory catecholamines and inflammatory mediators could counteract the GIK-induced cardioprotective mechanisms.
Name: Christoph Ellenberger, MD, MSc.
Contribution: This author helped conceive and design the study, analyze and interpret the data, and draft and critically revise the manuscript.
Name: Tornike Sologashvili, MD.
Contribution: This author helped collect the data and prepare the manuscript.
Name: Lukas Kreienbühl, MD.
Contribution: This author helped conduct the study, and acquire and interpret the data.
Name: Mustafa Cikirikcioglu, MD.
Contribution: This author helped collect the data and prepare the manuscript.
Name: John Diaper, RA.
Contribution: This author helped conduct the study, acquire, analyze, and interpret the data, and critically revise the manuscript.
Name: Marc Licker, MD.
Contribution: This author helped conceive and design the study, supervise conduct of the study and data acquisition, and draft and critically revise the manuscript.
This manuscript was handled by: W. Scott Beattie, PhD, MD, FRCPC.
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