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Ann Thorac Surg 2010;90:22-29. doi:10.1016/j.athoracsur.2010.03.093
© 2010 The Society of Thoracic Surgeons
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Original Articles: Pediatric Cardiac

Tight Glycemic Control Protects the Myocardium and Reduces Inflammation in Neonatal Heart Surgery

Dirk Vlasselaers, MD, PhDa,*, Dieter Mesotten, MD, PhDa, Lies Langouche, PhDa, Ilse Vanhorebeek, PhDa, Ingeborg van den Heuvel, MDa, Ilse Milants, RNa, Pieter Wouters, MSa, Patrick Wouters, MD, PhDc, Bart Meyns, MD, PhDb, Mette Bjerre, PhDd, Troels Krarup Hansen, MD, PhDd, Greet Van den Berghe, MD, PhDa

a Department of Intensive Care Medicine, Katholieke Universiteit Leuven, Belgium
b Department of Cardiac Surgery, Katholieke Universiteit Leuven, Belgium
c Department of Anesthesiology, Universiteit Gent, Belgium
d Immunoendocrine Research Unit, Aarhus University Hospital, Denmark

Accepted for publication March 30, 2010.

Abbreviations and Acronyms BG = blood glucose; BNP = brain-natriuretic peptide; CHS = congenital heart surgery; CIT = conventional insulin therapy; CO = cardiac output; CPB = cardiopulmonary bypass; CRP = C-reactive protein; cTnI = cardiac troponin-I; DSC = delayed sternal closure; d-TGA = transposition great arteries; eNOS = endothelial nitric oxide synthase; GIK = glucose-insulin-potassium; HFABP = heart fatty acid binding-protein; IL = interleukin; I-R = ischemia and reperfusion; NO = nitric oxide; PI3K = phosphatidylinositol-3-kinase; (P)ICU = (pediatric) intensive care unit; PM = temporary pacemaker; TA = truncus arteriosus; TGC = tight glycemic control

* Address correspondence to Dr Vlasselaers, University Hospitals Leuven, Department of Intensive Care Medicine, Herestraat 49, B-3000 Leuven, Belgium (Email: dirk.vlasselaers{at}uzleuven.be).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Neonatal cardiac surgery evokes hyperglycemia and a systemic inflammatory response. Hyperglycemia is associated with intensified inflammation and adverse outcome in critically ill children and in pediatric cardiac surgery. Recently we demonstrated that tight glycemic control (TGC) reduced morbidity and mortality of critically ill children. Experimental data suggest that insulin protects the myocardium in the setting of ischemia-reperfusion injury, but this benefit could be blunted by coinciding hyperglycemia. We hypothesized that insulin-titrated TGC, initiated prior to myocardial ischemia and reperfusion, protects the myocardium and attenuates the inflammatory response after neonatal cardiac surgery.

Methods: This is a prospective randomized study at a university hospital. Fourteen neonates were randomized to intraoperative and postoperative conventional insulin therapy or TGC. Study endpoints were effects on myocardial damage and function; inflammation, endothelial activation, and clinical outcome parameters.

Results: Tight glycemic control significantly reduced circulating levels of cardiac troponin-I (p = 0.009), heart fatty acid-binding protein (p = 0.01), B-type natriuretic peptide (p = 0.002), and the need for vasoactive support (p = 0.008). The TGC suppressed the rise of the proinflammatory cytokines interleukin-6 (p = 0.02) and interleukin-8 (p = 0.05), and reduced the postoperative increase in C-reactive protein (p = 0.04). Myocardial concentrations of Akt, endothelial nitric-oxide synthase, and their phosphorylated forms were not different between groups.

Conclusions: In neonates undergoing cardiac surgery, intraoperative and postoperative TGC protects the myocardium and reduces the inflammatory response. This appears not to be mediated by an early, direct insulin signaling effect, but may rather be due to independent effects of preventing hyperglycemia during reperfusion.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
The perioperative period of congenital heart surgery (CHS) can be challenging as these procedures generate a systemic inflammatory reaction and endocrine-metabolic stress responses. Consequently, hyperglycemia is common during and after CHS [1, 2], which is associated with increased morbidity and mortality [3–5]. A recent study showed that tight glycemic control (TGC) significantly reduced morbidity and mortality in critically ill children [6].

Impaired myocardial function is often present after neonatal CHS [7] complicating the postoperative course. It is triggered by multiple mechanisms like surgical trauma, ischemia and reperfusion (I-R) injury, local and systemic inflammation, and oxidative stress [8].

Hyperglycemia is associated with poor outcome in patients with myocardial ischemia, yet a direct causative role in aggravating I-R injury is speculative [9]. Experimental data suggest that hyperglycemia may induce oxidative stress, generate proinflammatory cytokines, and increase myocardial apoptosis. Insulin, given at the time of reperfusion, reduces myocardial I-R injury in animal models, partially by attenuation of apoptosis [10]. This is mediated by phosphatidylinositol-3-kinase (PI3K) and endothelial nitric oxide synthase (eNOS), and the concurrent local increase of nitric oxide (NO) production [11]. However, myocardial protection by insulin may be abolished by hyperglycemia during reperfusion [12].

A cocktail of glucose, insulin, and potassium (GIK) can protect the ischemic myocardium in patients with myocardial ischemia and during cardiac surgery [13, 14]. Other trials reported no favorable effect of GIK, possibly explained by concomitant hyperglycemia [15].

Congenital heart surgery with cardiopulmonary bypass (CPB) may impair endothelium-dependent vasodilatation [16]. We previously showed that TGC protects the endothelium of adult intensive care unit (ICU) patients [17]. In an animal model we demonstrated that hyperglycemia inhibits normal endothelium-dependent vasorelaxation, which can be prevented by maintaining normoglycemia [18].

We hypothesized that in neonatal CHS, TGC to age-adjusted normal fasting levels using insulin infusion, initiated prior to surgery and continued postoperatively, protects the myocardium and attenuates the inflammatory and endothelial responses. We investigated a potential direct insulin-mediated mechanism through the PI3K/Akt pathway and eNOS activation.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Patients
This study comprised a predefined subgroup analysis as part of a prospective randomized controlled trial [6]. A subgroup of neonates with transposition of the great arteries (d-TGA) or truncus arteriosus, scheduled for surgical repair, was prospectively and randomly assigned to conventional insulin therapy (CIT) or TGC, initiated at induction of anesthesia and continued throughout surgery and stay in the pediatric (P) ICU. Allocation to treatment groups was done by sealed envelopes. The protocol was approved by the hospital ethical committee and informed consent was obtained from the parents. The study was registered at ClinicalTrials.gov by the identifier number NCT00214916.

Perioperative Management
Anesthesia was induced and maintained with sevoflurane, sufentanil, pancuronium, and midazolam. Sedation in PICU comprised piritramide in continuous infusion and intermittent bolus injections of midazolam. Priming volume of the CPB circuit was 220 mL, consisting of a mixture of packed red blood cells (hematocrit 30%), albumin 20% (10 mL/kg), crystalloids, and 30 mg/kg methylprednisolone. Cardioprotection was delivered by anterograde crystalloid cardioplegia (Plegivex 40 mL/kg; Larne, Northern Ireland) and topical cooling. Patients were cooled to 32°C and received ultrafiltration during CPB. For weaning of CPB, all neonates received dobutamine and milrinone. Hemodynamic support was individually adapted by the attending physician based on clinical evolution.

Experimental Protocol
During surgery all neonates received a baseline infusion of glucose 20% with 20 units of insulin (Actrapid; Novo Nordisk A/S, Bagsvaerd, Denmark) and 20 milliequivalent potassium chloride (500 mL, running at 3 mL/kg/hour). In the TGC group, the principle of a hyperinsulinemic-normoglycemic clamp was applied. We used a modified version of a previously described protocol [19]. In brief, the target blood glucose (BG) range during and after surgery was set at 50 to 80 mg/dL. This target level was chosen, incorporating a safety margin, based on normal fasting BG levels in healthy neonates (31to 60 mg/dL) [20, 21]. A continuous insulin infusion (Actrapid) was started and continued throughout the surgical procedure at 0.3 international units kg–1 · hour–1. If necessary, the speed of the glucose infusion was adjusted to keep the BG in target. The BG was analyzed every 15 minutes in arterial blood. Postoperatively, BG policy was continued by insulin-titration to the BG target range in the presence of a standard intravenous and enteral feeding protocol. Arterial BG was checked at least hourly until the BG was in the target range and stable. The BG control was left to the discretion of the bedside nurse and checked at least every four hours. Insulin infusions were continued until discharge from PICU or stopped earlier when more than two-thirds of caloric intake was administered as intermittent bolus feeding.

In the CIT group hyperglycemia was only treated with insulin infusion when BG exceeded 215 mg/dL twice, and insulin was stopped when BG was below 180 mg/dL.

Neonatal hypoglycemia was defined as BG less than 30 mg/dL [22]. Insulin infusions were stopped when BG was less than 50 mg/dL and 1mL/kg of a 50% dextrose solution was given when BG was less than 30 mg/dL.

Myocardial biopsies of the right atrium were taken at time of cannulation and decannulation to study the effects of I-R injury on the PI3K/Akt signaling pathway and eNOS. Small skeletal muscle biopsies from the musculus abdominis rectus were taken at the start and end of surgery. All biopsies were snap frozen in liquid nitrogen and stored at minus 80°C.

Biochemical Analyses
Blood glucose was exclusively determined with the ABL 715 blood gas analyzer (Radiometer, Bronshoj, Denmark) [23]. Serum insulin, C-peptide, N-terminal pro brain natriuretic peptide (NT-proBNP), cardiac troponin-I (cTnI), heart fatty acid binding-protein (HFABP), C-reactive protein, intercellular adhesion molecule-1, E-selectin, and serum concentrations of cytokines (interleukin [IL]-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, tumor necrosis factor-alpha) were all analyzed according the manufacturers' directions. Serum mannose binding lectin and membrane attack complex were measured using in-house developed assays [24, 25].

Protein Levels of Signal Transduction Pathways in Tissue Biopsies
Homogenates and immunoprecipitates of tissue samples were immunoblotted with specific Ab against eNOS, phospho-eNOS, Akt, and phosphor-Akt and analyzed with Image Master Software (Amersham Biosciences, Piscataway, NJ).

Clinical Endpoints
Hemodynamic performance was assessed by the need for temporary pacing (PM), incidence of delayed sternal closure (DSC), and a predefined inotrope score (Table 1). We also evaluated time to extubation, days in PICU and hospital as well as prolonged PICU and hospital stay.


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  		Table 1 Inotrope Score
 
Statistical Analysis
Baseline and outcome variables were compared using repeated measures analysis of variance (nonnormally distributed data are log-transformed prior to analysis of variance testing), the Student's t test, or the Mann-Whitney U test. Data are presented as means (± SD) or medians (25th to 75th percentiles). Two-sided p values less than 0.05 were considered statistically significant. Statistical tests were performed with Statview version 5.0.1 (SAS Institute, Inc, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Demography and Clinical Outcome
Fourteen neonates were included, 7 in each group. There were no differences between groups in baseline characteristics and CPB variables. Median time to extubation tended to be shorter in the TGC group. There were no significant differences in renal function and duration of stay in PICU and the hospital. There were no early or late deaths. The lower incidence of DSC (29% vs 0%) and need for PM (57% vs 14%) in the first 48 hours in the TGC group was not significant (Table 2).


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  		Table 2 Demography and Clinical Outcome
 
Glucose and Insulin
In the TGC group BG was within target range and significantly different from the CIT group. During surgery there were no hypoglycemic events in both groups. In the postoperative period, 4 hypoglycemic events (range, 23 to 30 mg/dL) occurred in 2 patients (28%) in the TGC group, representing 0.7% of all BG measurements No hypoglycemic events occurred in the CIT group. Glucose administration was similar in both groups, while insulin infusion significantly differed. Infusion of exogenous insulin in the TGC group suppressed the endogenous production of insulin and C-peptide. The endogenous production of insulin with CIT, reflected by increased levels of C-peptide, was insufficient to counter hyperglycemia, reflecting insulin resistance (Table 3).


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  		Table 3 Data of Metabolic, Cardiac, and Inflammatory Parameters at Different Times
 
Myocardial Function and Damage
Tight glycemic control reduced blood lactate and the need for hemodynamic support, reflected by the inotrope score. The cTnI, HFABP, and NT-proBNP release were also significantly lowered by TGC (Table 3). On postoperative day 1 a significant correlation existed between cTnI and HFABP, and NT-proBNP (Fig 1).


Figure 1
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  		Fig 1. (A) (B). Correlation between markers of myocardial damage and function. (D1 = first postoperative day regression line with 95% confidence interval; cTnI = cardiac troponin-I; HFABP = heart fatty acid binding–protein; NT–proBNP = N–terminal pro brain natriuretic peptide.) ({blacksquare} = tight glycemic control [TGC]; {ballotbox} = conventional insulin therapy [CIT].)

 
Inflammation
The rise in C-reactive protein in the postoperative period was significantly lower with TGC. A similar dampening of a rise in IL-6 and IL-8 was observed (Table 3). The time course of tumor necrosis factor-alpha, other measured cytokines, serum mannose binding lectin, and serum membrane attack complex was not significantly different between groups.

Endothelial Activation
The measured changes of E-selectin and intercellular adhesion molecule-1 levels in serum did not differ between the two groups (data not shown).

Protein Levels of Akt and eNOS
In atrial biopsies, myocardial tissue exposed to I-R, TGC did not change concentrations of Akt, eNOS, and their phosphorylated forms as compared with CIT. In skeletal muscle biopsies, tissue not exposed to I-R during the surgical procedure, levels of Akt, pAkt, eNOS, and p-eNOS, were likewise similar for both groups (Fig 2).


Figure 2
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  		Fig 2. The Akt and endothelial nitric oxide synthase (eNOS) protein (P) levels in skeletal muscle (A) and myocardium (B). Data are presented as mean (± standard error). For each signaling molecule, a representative blot is added with pre- and post-ischemia-reperfusion (I-R) samples. ({blacksquare} = tight glycemic control [TGC]; {ballotbox} = conventional insulin therapy [CIT].)

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
This study demonstrates that intraoperative and postoperative TGC in neonatal CHS protected the myocardium and attenuated the inflammatory response evoked by the surgical procedure, which may favorably affect clinical outcome. This did not appear to be mediated by direct insulin signaling effects, but to effects of preventing hyperglycemia during reperfusion.

Implementing TGC carries the risk of evoking biochemical hypoglycemia. We could not identify any deleterious symptoms of these hypoglycemic events throughout stay in PICU. In order to exclude possible longer term effects, a cardiac, neurocognitive, and developmental follow-up study of these patients is currently ongoing.

High exogenous insulin dose lowered BG to normal fasting levels and suppressed endogenous production of insulin, demonstrated by reduced C-peptide. From day 2, circulating levels of insulin were comparable in both groups despite a significant difference in BG, suggesting that insulin resistance remained more pronounced during CIT and indicating that early prevention of hyperglycemia by exogenous insulin results in maintained insulin sensitivity.

Our data strongly suggest that myocardial injury evoked by I-R was significantly reduced and myocardial function was better preserved with TGC. Release of cTnI was lower with TGC. Because surgical trauma and renal function between both groups were comparable, allowing to infer a similar cTnI clearance, reduced cTnI levels likely reflect less myocardial damage. This finding may be relevant for longer term outcome as cTnI levels early after CHS are a powerful independent predictor of outcome [26, 27]. A similar myocardial protective effect of TGC was described in adult cardiac surgery patients [28]. Circulating levels of HFABP were also reduced by TGC. In CHS, HFABP after aortic declamping reflects myocardial damage and is associated with postoperative clinical outcome [29]. Brain-natriuretic peptide is released in response to ventricular dysfunction and increased wall stress. Elevated postoperative BNP levels are also associated with postoperative cardiac dysfunction [30], prolonged hospital stay, and one-year mortality in adult cardiac surgery patients [31]. After CHS, BNP levels correlate closely with ventricular function [32], duration of mechanical ventilation, and postoperative low cardiac output [33]. Moreover, neonates after arterial switch with higher postoperative BNP values appear to have a more complicated evolution, as reflected by prolonged mechanical ventilation, inotropic support, and PICU stay [34]. Tight glycemic control reduced the rise in BNP, possibly related to the observed trends for improved clinical outcome like inotrope score and earlier extubation. However, in view of the small sample size, the clinical implications remain to be confirmed.

Postoperative PM is applied for treating arrhythmias in anticipation of recovery of normal rhythm or definitive pacemaker implantation, or to improve CO by increasing heart rate. Neonates have little inotropic reserve due to the decreased density of contractile elements and respond less to preload because of decreased ventricular compliance [35]. Therefore, they are particularly dependent on heart rate to increase CO. The increased incidence of early PM with CIT reflects decreased myocardial function and subsequent need for augmenting CO. In addition, TGC possibly decreases local inflammation and myocardial edema causing less conduction disturbances.

Delayed sternal closure is a common strategy in CHS to avoid further compromising myocardial function. The higher incidence of DSC in the CIT group, albeit not significant, possibly reflects a higher incidence of myocardial dysfunction.

Blood lactate and its time course in the immediate postoperative period correlate with outcome parameters such as inotrope score, length of stay, and mortality [36]. The observed lower lactate levels with TGC could reflect a better hemodynamic profile.

The myocardial protective effect of TGC in the context of I-R may at least partially be explained by an attenuated inflammatory response. Tight glycemic control significantly reduced inflammation, as indicated by lower C-reactive protein. The CHS, CPB, and the associated I-R injury cause an inflammatory response. Newborns are at increased risk, and higher levels of IL-6 and IL-8 after arterial switch correlate with myocardial dysfunction and damage, reflected by higher serum levels of troponin [37]. Furthermore, concentrations of IL-6 and IL-8 after CHS are associated with the degree of postoperative organ dysfunction and the need for medical intervention, including inotropic support [38]. Tight glycemic control suppressed the early release of IL-6 and IL-8 in this study. As TGC also decreased cTnI, HFABP, and NT-proBNP, this could reflect reduced myocardial damage and better preservation of myocardial function provoked by an attenuated inflammatory response. Indeed, proinflammatory cytokines are implicated in decreasing contractility and uncoupling beta-adrenergic receptors [39]. A similar effect of intraoperative TGC on the inflammatory response, reflected by decreased levels of IL-6 and IL-8, was described in adults [40].

As a potential mechanism for cardioprotection with insulin-titrated TGC, we postulated a direct action of insulin, through the insulin receptor-mediated activation of PI3K/Akt, a pathway known to evoke protection against myocardial I-R-injury. This pathway increases local nitrous oxide production resulting from phosphorylation of eNOS. Experimental animal models suggested insulin as the active component of GIK against myocardial I-R-injury [11]. However, hyperglycemia not only exacerbates myocardial I-R-injury but may also counteract any cardioprotective effect of GIK, due to myocardial PI3K/Akt inactivation [12]. In the cardiac biopsies we did not observe an effect on PI3K/Akt or eNOS. Possibly this is explained by the timing of the biopsy; 30 minutes after commencing myocardial reperfusion may have been too early to detect an effect on the studied pathway in contrast with the animal experiments where myocardial tissue was reperfused for 4 hours before being analyzed. Whether eNOS or PI3K/Akt played a role beyond the studied 30 minutes reperfusion remains unknown. Alternatively, the myocardial protection observed in this study was not mediated through this insulin-receptor mediated pathway and may point to prevention of distinct glucose toxicity.

In conclusion, this exploratory study provided arguments for a protective effect on the myocardium of insulin-titrated TGC during and after CHS. An attenuation of the early inflammatory response to CHS may have contributed to this myocardial protection. Further study is needed to unravel the molecular mechanisms involved.

Study Limitations
First, the study was not performed in a blinded fashion, as TGC requires careful BG monitoring. Second, the small sample size and the selection of CHS make that the results remain preliminary and needs confirmation in a larger, more heterogeneous population. To avoid potential interference of large differences in baseline characteristics and surgical procedures, we chose to perform this study in a population with comparable baseline and CPB characteristics and surgical trauma. Third, absence of validated serial cardiac output measurements or echocardiographic exams focusing on myocardial function limits the conclusions regarding myocardial performance. Finally, delaying the timing of myocardial tissue harvesting during reperfusion would have substantially increased the duration of the surgical procedure, which is ethically unacceptable.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
Work was supported by the Fund for Scientific Research (FWO), Belgium (G.0533.06) and the Research Council of Katholieke Universiteit Leuven (GOA2007/14). Dirk Vlasselaers is a clinical PhD Fellow (FWO), Dieter Mesotten a Postdoctoral Fellow of the Clinical Research Fund University Hospital Leuven, Lies Langouche a Postdoctoral Fellow (FWO), and Ilse Vanhorebeek a Postdoctoral Fellow of Research Fund KUL. Greet Van den Berghe, MD, PhD receives research financing through the Methusalem program funded by the Flemish Government.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Anand K, Hansen D, Hickey P. Hormonal-metabolic stress responses in neonates undergoing cardiac surgery Anesthesiology 1990;73:661-670.[Medline]
  2. Ballweg J, Wernovsky G, Ittenbach R, et al. Hyperglycemia after infant cardiac surgery does not adversely impact neurodevelopmental outcome Ann Thorac Surg 2007;84:2052-2058.[Abstract/Free Full Text]
  3. Yates A, Dyke 2nd P, Taeed R, et al. Hyperglycemia is a marker for poor outcome in the postoperative pediatric cardiac patient Pediatr Crit Care Med 2006;7:351-355.[Medline]
  4. Falcao G, Ulate K, Kouzekanani K, Bielefeld M, Morales J, Rotta A. Impact of postoperative hyperglycemia following surgical repair of congenital cardiac defects Pediatr Cardiol 2008;29:628-636.[Medline]
  5. Polito A, Thiagarajan R, Laussen P, et al. Association between intraoperative and early postoperative glucose levels and adverse outcomes after complex congenital heart surgery Circulation 2008;118:2235-2242.[Abstract/Free Full Text]
  6. Vlasselaers D, Milants I, Desmet L, et al. Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study Lancet 2009;373:547-556.[Medline]
  7. Wernovsky G, Wypij D, Jonas R, et al. Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants. A comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation 1995;92:2226-2235.[Abstract/Free Full Text]
  8. Anselmi A, Abbate A, Girola F, et al. Myocardial ischemia, stunning, inflammation, and apoptosis during cardiac surgery: a review of evidence Eur J Cardiothorac Surg 2004;25:304-311.[Abstract/Free Full Text]
  9. Deedwania P, Kosiborod M, Barrett E, et al. Hyperglycemia and acute coronary syndrome. A scientific statement from the American heart association diabetes committee of the council on nutrition, physical activity, and metabolism. Circulation 2008;117:1610-1619.[Abstract/Free Full Text]
  10. Jonassen AK, Brar BK, Mjøs OD, Sack MN, Latchman DS, Yellon DM. Insulin administered at reoxygenation exerts a cardioprotective effect in myocytes by a possible anti-apoptotic mechanism J Mol Cell Cardiol 2000;32:757-764.[Medline]
  11. Gao F, Gao E, Yue T-L, et al. Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation Circulation 2002;105:1497-1502.[Abstract/Free Full Text]
  12. Su H, Sun X, Ma H, et al. Acute hyperglycemia exacerbates myocardial ischemia/reperfusion injury and blunts cardioprotective effect of GIK Am J Physiol Endocrinol Metab 2007;293:E629-E635.[Abstract/Free Full Text]
  13. Bothe W, Olschewski M, Beyersdorf F, Doenst T. Glucose-insulin potassium in cardiac surgery: a meta-analysis Ann Thorac Surg 2004;78:1650-1657.[Abstract/Free Full Text]
  14. Kloner R, Nesto R. Glucose-insulin-potassium for acute myocardial infarction: continuing controversy over cardioprotection Circulation 2008;117:2523-2533.[Free Full Text]
  15. Van den Berghe G. Insulin vs strict blood glucose control to achieve a survival benefit after AMI? Eur Heart J 2005;26:639-641.[Free Full Text]
  16. Wessel D, Adatia I, Giglia T, Thompson J, Kulik T. Use of inhaled nitric oxide and acetylcholine in the evaluation of pulmonary hypertension and endothelial function after cardiopulmonary bypass Circulation 1993;88(5 Pt 1):2128-2138.[Abstract/Free Full Text]
  17. Langouche L, Vanhorebeek I, Vlasselaers D, et al. Intensive insulin therapy protects the endothelium of critically ill patients J Clin Invest 2005;115:2277-2286.[Medline]
  18. Ellger B, Debaveye Y, Vanhorebeek I, et al. Survival benefits of intensive insulin therapy in critical illness: impact of maintaining normoglycemia versus glycemia-independent actions of insulin Diabetes 2006;55:1096-1105.[Abstract/Free Full Text]
  19. Carvalho G, Moore A, Qizilbash B, Lachapelle K, Schricker T. Maintenance of normoglycemia during cardiac surgery Anesth Analg 2004;99:319-324.[Abstract/Free Full Text]
  20. Mosby's Diagnostic and Laboratory Test Reference. 6th edition. New York: Mosby, Elsevier Science; 2003. pp. 457.
  21. Brown T, Connelly J, Dunlop M, McDougall P, Tibballs J. Fasting plasma glucose in children Aust Paediatr J 1980;16:28-29.[Medline]
  22. Cornblath M, Hawdon JM, Williams AF, et al. Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds Pediatrics 2000;105:1141-1145.[Abstract/Free Full Text]
  23. Scott M, Bruns D, Boyd J, Sacks D. Tight glucose control in the intensive care unit: are glucose meters up to the task? Clinical Chemistry 2009;55:18-20.[Free Full Text]
  24. Hansen TK, Thiel S, Wouters PJ, Christiansen JS, Van den Berghe G. Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels J Clin Endocrinol Metab 2003;88:1082-1088.[Abstract/Free Full Text]
  25. Haahr-Pedersen S, Bjerre M, Flyvbjerg A, et al. Level of complement activity predicts cardiac dysfunction after acute myocardial infarction treated with primary percutaneous intervention J Invasive Cardiol 2009;21:13-19.[Medline]
  26. Mildh L, Pettilä V, Sairanen H, Rautiainen. Cardiac troponin T levels for risk stratification in pediatric open heart surgery Ann Thorac Surg 2006;82:1643-1649.[Abstract/Free Full Text]
  27. Imura H, Modi P, Pawade A, et al. Cardiac troponin I in neonates undergoing the arterial switch operation Ann Thorac Surg 2002;74:1998-2002.[Abstract/Free Full Text]
  28. Albacker T, Carvalho G, Schricker T, Lachapelle K. Myocardial protection during elective coronary artery bypass grafting using high-dose insulin therapy Ann Thorac Surg 2007;84:1920-1927.[Abstract/Free Full Text]
  29. Hasegawa T, Yoshimura N, Oka S, Ootaki Y, Toyoda Y, Yamaguchi M. Evaluation of heart fatty acid-binding protein as a rapid indicator for assessment of myocardial damage in pediatric cardiac surgery J Thorac Cardiovasc Surg 2004;127:1697-1702.[Abstract/Free Full Text]
  30. Provenchère S, Berroeta C, Reynaud C, et al. Plasma brain natriuretic peptide and cardiac troponin I concentrations after adult cardiac surgery: association with postoperative cardiac dysfunction and 1-year mortality Crit Care Med 2006;34:995-1000.[Medline]
  31. Hutfless R, Kazanegra R, Madani M, et al. Utility of B-type natriuretic peptide in predicting postoperative complications and outcomes in patients undergoing heart surgery J Am Coll Cardiol 2004;43:1873-1879.[Medline]
  32. Koch A, Zink S, Singer H. B-type natriuretic peptide in paediatric patients with congenital heart disease Eur Heart J 2006;27:861-866.[Abstract/Free Full Text]
  33. Shih C-Y, Sapru A, Oishi P, et al. Alterations in plasma B-type natriuretic peptide levels after repair of congenital heart defects: a potential perioperative marker J Thorac Cardiovasc Surg 2006;131:632-638.[Abstract/Free Full Text]
  34. Cannesson M, Biona C, Gostoli B, et al. Time course and prognostic value of plasma B-type natriuretic peptide concentrations in neonates undergoing the arterial switch operation Anesth Analg 2007;104:1059-1065.[Abstract/Free Full Text]
  35. Epstein D, Wetzel R. Cardiovascular physiology and shock Critical heart disease in infants and children. 2nd edition. New York: Mosby, Elsevier; 2006. pp. 17-20.
  36. Basaran M, Sever K, Kafali E, et al. Serum lactate level has prognostic significance after pediatric cardiac surgery J Cardiothorac Vasc Anesth 2006;20:43-47.[Medline]
  37. Hövels-Gürich H, Vazquez-Jimenez J, Silvestri A, et al. Production of proinflammatory cytokines and myocardial dysfunction after arterial switch operation in neonates with transposition of the great arteries J Thorac Cardiovasc Surg 2002;124:811-820.[Abstract/Free Full Text]
  38. Madhok A, Ojamaa K, Haridas V, Parnell V, Pahwa S, Chowdhury D. Cytokine response in children undergoing surgery for congenital heart disease Pediatr Cardiol 2006;27:408-413.[Medline]
  39. Blum A, Miller H. Role of cytokines in heart failure Am Heart J 1998;135(2 Pt 1):181-186.[Medline]
  40. Albacker T, Carvalho G, Schricker T, Lachapelle K. High-dose insulin therapy attenuates systemic inflammatory response in coronary artery bypass grafting patients Ann Thorac Surg 2008;86:20-28.[Abstract/Free Full Text]

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