Glycemic Control in the Preoperative Period for patients with Congenital Heart Disease
By Jennifer Hernandez, MD1 and James Steven, MD2
1Children’s Health, Dallas
2Children’s Hospital of Philadelphia
Over the past few decades, innovations and advancements in surgery, anesthetic techniques, and perioperative care have resulted in a substantial decrease in mortality following congenital heart disease (CHD) surgery.1-3 Approximately 85% of children who are born with CHD are now surviving into adulthood.4 With this dramatic improvement in survival, the focus of significant research in recent years has centered on the identification of potentially modifiable risk factors in an effort to decrease perioperative morbidity and further improve outcomes. Stress hyperglycemia, which often runs parallel to critical illness, became an increasingly important area of research following the landmark publication by Van den Berghe et al.5 These researchers were among the first to identify glycemic control with insulin as a strategy to reduce adverse outcomes. Their findings challenged the conventional belief that hyperglycemia was an adaptive response to critical illness and surgical stress, rather an independent predictor of adverse outcomes. It has been reported that up to 90% of children undergoing cardiac surgery are at risk for the development of hyperglycemia in the post-operative period.6 Given this high prevalence of stress hyperglycemia with potential deleterious consequences, this new appreciation for the negative outcomes associated with hyperglycemia prompted a series of investigations on the topic.
Acute illness and surgery are often associated with a hypermetabolic stress response involving the dysregulation of metabolic, endocrine and inflammatory homeostatic pathways. This physiological reaction involves the release of counterregulatory hormones (cortisol, glucagon, and growth hormones), endogenous catecholamines, and inflammatory cytokines.7,8 These mediators result in derangements in glucose metabolism characterized by a catabolic state of increased endogenous hepatic glucose production and peripheral insulin resistance. Additionally, hyperglycemia is frequently exacerbated by several common peri-operative iatrogenic interventions such as the administration of inotropes, vasopressors, glucocorticoids and dextrose infusions.
Hyperglycemia was historically viewed as an adaptive response to physiological stress and critical illness. High levels of circulating glucose during times of stress were considered beneficial by providing both additional metabolic substrate for cells that predominantly rely on glucose for energy needs and by preserving intravascular volume with increased serum osmolarity.7,9 Glycemic control with insulin was not usually instituted until glucose concentrations exceeded the renal threshold of 220mg/dl and glycosuria occurred.10 The change in this perception likely began when clinical associations between hyperglycemia and adverse neurologic outcomes were first reported following out-of-hospital cardiac arrest.11 Numerous subsequent studies in a variety of clinical settings have since associated hyperglycemia with an increased risk of infection and mortality.5,12-15 A number of morbidity indicators such as prolonged mechanical ventilation, renal replacement therapy, incidence of new organ failure, transfusion requirements, increased length of intensive care unit (ICU) and hospital stay have also been implicated.5,16,17 Mechanistically, hyperglycemia may contribute to these adverse outcomes by causing direct cellular toxicity and increased cellular apoptosis. Biological and cellular compartments that exhibit insulin-independent glucose uptake such as the nervous and immune systems, hepatocytes, and endothelial cells are particularly vulnerable. Additionally, indirect cellular toxicity can also occur as a result of enhanced mitochondrial production of reactive oxygen species in the setting of intracellular hyperglycemia.18
Following the development of a growing body of literature associating hyperglycemia with adverse outcome in both adult and pediatric critically ill patients, the role of perioperative glycemic control in pediatric cardiac patients was assessed in a number of prospective studies. The first randomly controlled trial (RCT) was conducted by the Leuven group.19 The study included 700 infants and children from a mixed critical care population, 75% percent of which had undergone cardiac surgery. Primary endpoints were duration of PICU stay and inflammation (as measured by the inflammatory marker C-reactive protein (CRP)). Patients were randomly assigned to either intensive insulin therapy (IIT) or to conventional insulin therapy (CIT). In the IIT group, insulin was used to target normal age-adjusted fasting values in infants (50-80 mg/dl in ages 0-1 year) and children (70-100 mg/dl in ages 1-16 years) throughout the PICU stay. The CIT group received standard glucose management, which restricted the use of insulin therapy for glycemic control to patients who exhibited blood glucose (BG) concentrations greater than 215 mg/dl at least twice (insulin was stopped when BG decreased below 180 mg/dl). The IIT group was found to have a statistically significant reduction in both primary endpoints. IIT also derived several additional benefits in the secondary outcomes (rate of nosocomial infections and ICU survival).
In a later study by the same group, IIT was shown to significantly reduce levels of pro-inflammatory cytokines, CRP, circulating biomarkers of myocardial injury and the need for vasoactive support.20 Despite these favorable results, the clinical benefits of IIT in this population was called into question given the reported 25% rate of severe hypoglycemia (<40 mg/dl) in the intervention arm, with a 45% incidence rate in infants alone.19 It is noteworthy that a subsequent long-term follow-up study of the cohort at four years revealed reassuring neurocognitive results indicating that neither hypoglycemia nor IIT resulted in worse neurodevelopmental sequelae compared to standard care.21
The Safe Pediatric Euglycemia after Cardiac Surgery study (SPECS) trial subsequently assessed the benefits of tight glucose control (TGC) in a two-centered RCT.22 The study enrolled 980 children (aged 0-36 months) who had undergone cardiopulmonary bypass (CPB) for repair of CHD. An insulin dosing algorithm was used to target normoglycemia (80-110 mg/dl) in the intervention arm, a higher BG concentration range as compared to the pediatric Leuven study.19 Patients randomized to standard care in the cardiac ICU (CICU) had no pre-set target range for glucose management and received insulin at the discretion of the treating physician. The primary outcome measure was the development of any nosocomial infection. Secondary outcome measures included mortality; measures of organ function; indices of nutritional balance, immunologic, endocrinologic, and neurologic function; CICU and hospital length of stay; and neurodevelopmental outcomes. Continuous glucose monitoring (CGM) technology, which had been shown to reduce the detrimental effects of insulin-induced hypoglycemia in previous studies, was used to guide the frequency of blood glucose measurements and to detect impending hypoglycemia in both groups.23 Study results demonstrated that CGM was associated with much lower rates of hypoglycemia as compared to the previous randomized trial of IIT in children. The rate of severe hypoglycemia (<40 mg/dl) was 3% in the TGC and 1% in the standard care group. Despite the more acceptable risk/benefit profile, the researchers found that TGC did not confer any advantage relative to standard care with regard to the rate of nosocomial infections, mortality, hospital length of stay, duration of mechanical ventilation, vasoactive support requirement, or other surrogate markers of organ failure.
The control of hyperglycemia in paediatric intensive care (CHIP) trial was a subsequent multicenter randomized study involving 1369 critically ill children (60% of whom had undergone cardiac surgery) admitted across 13 pediatric ICUs.24 Patients who were expected to require mechanical ventilation and vasoactive medications for at least 12 hours underwent randomization to either TGC (targeted BG range of 72-126 mg/dl) or to conventional glycemic control (targeted BG level below 216 mg/dl). The study failed to find a significant difference between the two groups with respect to mechanical ventilation-free survival at 30 days post-randomization, the primary outcome in this study. Some differences between the two groups were observed in certain secondary outcomes. TGC was associated with a reduced incidence of kidney failure, shorter length of stay in the hospital and lower total health care costs at 12 months post-randomization. These latter findings appeared to be driven by results in the non-cardiac surgery subgroup. Similar to the pediatric Leuven study, hypoglycemia occurred in a higher proportion of children in the TGC group. Severe hypoglycemia (BG < 36 mg/dl) occurred in 7.3% of these children compared to 1.5% in the control group. A total of 135 patients had at least one hypoglycemic episode, 5.9% of which had a seizure on the same day. Interestingly, all patients that exhibited seizures were in the TGC group.
Important differences between these studies related to target BG concentrations complicate the interpretation of the available research findings. In the pioneering article by Vlasselaers et al., 99% of patients in the IIT group received insulin as a result of the target age-adjusted fasting values.19 The glycemic targets in the interventional groups of both the SPECS and the CHIP trial were much higher in comparison. Although these target values are generally accepted as normal for fasting adults, in actuality they are reflective of hyperglycemia with respect to age-adjusted thresholds.25,26 In the SPECS trial, 91% of children assigned to TGC received insulin as compared to 66% in the CHIP trial, which had a somewhat broader target glycemic range. Some of the advantages of insulin administration described in previous studies that extend beyond glycemic control such as immunomodulation, oxidative stress reduction, prevention of endothelial dysfunction, favorable anabolic effects and anti-thrombotic properties may not have been recognized in all interventional group subjects in the latter studies.27-29 Theoretically, this may have contributed to the inconsistent findings to some degree. Additionally, the majority of subjects in the control groups of the two latter studies spontaneously reached the BG targets of the intervention arms without insulin therapy in a short amount of time. Curiously, BG values of 80-110 mg/dl were reached spontaneously in the control group of the Leuven study within 48 hours of study enrollment as well. Taken together, these findings suggest that the expected treatment effect size in the SPECS and CHIP trials may have been overestimated. It appears as though there is a limited interval of time where TGC can mitigate the effects of stress hyperglycemia in pediatric patients as compared to adults. Factors influencing the pattern of insulin requirement that are unique to children may be involved. Larger sample sizes may be required in order to be statistically powered to detect benefits in the setting of such small and transient differences in BG concentrations when designated target glycemic ranges are greater than age-adjusted values.
Practice guidelines for glucose management in adults undergoing cardiac surgery were issued by the Society of Thoracic Surgeons (STS) in 2009.27 According to the guidelines, glycemic control is best achieved with continuous insulin infusions rather than intermittent intravenous boluses or subcutaneous injections (class 1a). Intraoperative glycemic control is not necessary in non-diabetic patients, provided that glucose values remain < 180 mg/dl. In contrast, insulin infusions to maintain glucose values < 180 mg/dl should be initiated in the operating room and continued for at least 24 hours post-operatively in all diabetic patients (class 1b). In non-diabetic patients, intermittent doses of intravenous insulin may be administered for BG > 180 mg/dl during CPB. However, if glucose concentrations remain persistently greater than 180 mg/dl after CPB, continuous insulin infusions should be instituted in these patients and an endocrinology consult should be obtained (class 1b). Infusions initiated during the preoperative period in both diabetics and non-diabetics alike, should be continued according to institutional protocols throughout the intraoperative and early post-operative period to maintain BG < 180 mg/dl (class 1c). The guidelines additionally state that BG concentrations in patients receiving intravenous insulin therapy should be monitored every 30 to 60 minutes. During periods of rapidly fluctuating insulin sensitivity, such as administration of cardioplegia and systemic cooling/rewarming, the STS suggests that there should be more frequent monitoring.
Currently, there are no specific criteria for defining hyperglycemia in children with CHD and the optimal perioperative glucose target range remains unclear. Maturational differences in glucose metabolism and the sequelae of hyperglycemia between adults and children limit the information that can be extrapolated from adult studies and guidelines. At present, use of insulin therapy targeting glycemic control in the perioperative management of children with CHD has not been widely adopted. Aggressive glucose control strategies should be used with caution given the greater susceptibility of hypoglycemia in pediatric patients. STS practice guidelines for blood glucose management may be more pertinent to adult CHD patients, with the caveat as to whether these recommendations apply to this population that is usually younger than the majority of adult cardiac surgical patients and free of coronary artery and vascular disease associated with adult diabetic patients.
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