This study showed that tight glycemic control, as compared with standard care in the cardiac ICU, did not change the rate of health care–associated infections, mortality, the length of stay in the cardiac ICU, or several organ-specific end points. Glucose control was achieved in the intervention group quickly and with low rates of severe hypoglycemia in our study as compared with previous studies.
The present trial assessed the benefits of tight glycemic control in infants and young children recovering from cardiac surgery, on the basis of published studies indicating that tight glycemic control improved important clinical outcomes in adult cardiac medical and surgical patients.4–7
We enrolled high-risk, relatively homogeneous, critically ill children in our study because this is the pediatric population that would be most likely to benefit from tight glycemic control. Mortality was an inadequate end point for this trial because in this patient population, deaths are largely attributable to underlying cardiac anatomy and the technical quality of surgical repair.3,29
Furthermore, low mortality at high-volume pediatric cardiac surgical centers would necessitate a prohibitively large sample to achieve adequate power with this end point. The rate of health care–associated infections was chosen as the primary outcome because of its relevance with respect to clinical outcomes and health care costs.30
Our infection rate proved to be similar to the rates in other cohorts.31,32
The biologic plausibility of reducing infection rates with tight glycemic control is supported by previous clinical trials and in vitro models.33–35
In contrast to previous trials involving adults, our study showed no benefit of tight glycemic control in critically ill children who had undergone cardiac surgery, though the reasons are unclear. Unlike the findings in adults, normoglycemia was achieved in virtually all the children in our standard-care group without insulin therapy in the first 48 hours after surgery. This is a limited window to produce a benefit of tight glycemic control as compared with standard care. Whether there are age-related differences in the biologic sequelae of hyperglycemia in pediatric and adult populations of cardiac surgical patients is unknown. One meta-analysis suggested that the high proportion of nutrition delivered parenterally as dextrose was an important positive predictor of a beneficial effect of tight glycemic control.36
However, despite extensive use of dextrose for parenteral nutrition in our study population, similar benefits were not observed.
Our results also differ from those of the one previous randomized trial of tight glycemic control in children, which showed reductions in mortality, length of stay in the ICU, and rate of infection in a mixed critical care population of medical and surgical patients.19
This study did not lead to widespread adoption of tight glycemic control in children, in part because of an unacceptably high rate of severe hypoglycemia resulting from the extremely low target glucose values specified by the study protocol. We chose normal, accepted glucose targets for our study, achieved with the use of a structured, explicit, and easily replicable insulin-dosing algorithm that incorporated data from continuous subcutaneous glucose monitoring. Though not directly comparable, the time-weighted glucose average in our study was similar to the average of all values measured in the intensive-insulin cohort in the previous study, in which the glucose target was 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter).19
As in the previous trial, the children in our study had a relatively high reliance on parenteral nutrition, and the majority of the children received all parenteral calories as dextrose at similar rates of infusion in the two trials. Marked differences between the two studies in the rate of infection (33% in the previous study vs. 5% in our study) and 30-day mortality (4% vs. 1%) and in the amount of insulin administered in the glycemic-control groups (median amount during the first full day in the ICU, approximately 1.5 units per kilogram vs. 0.2 units per kilogram). These differences suggest important dissimilarities between study populations and settings in these two trials.
The strengths of our study include high adherence to the study protocol and the fact that nearly all patients received the treatment to which they were randomly assigned. To minimize bias, the study investigators, intraoperative care teams, and adjudicators of the primary outcome were unaware of the treatment-group assignments until the study had been completed. Blood glucose management was relatively uniform in the intervention group, as guided by a detailed dosing algorithm, and very few patients in the standard-care group received insulin. The rate of severe hypoglycemia was the lowest reported in any prospective trial to date, at or below the background rate among critically ill children not enrolled in a trial.37–39
The key features of our trial design that were implemented specifically to minimize hypoglycemic episodes were an explicit insulin-dosing algorithm, continuous glucose monitoring, and the use of a blood-sampling device to eliminate dilution as a source of measurement error. Investigators in future trials might consider incorporating these components to maximize safety, reproducibility, and success.
Certain limitations of this trial must be considered. Bedside clinicians in the cardiac ICU were aware of the study-group assignments because of the requirement to closely monitor blood glucose concentrations during insulin infusion. It was not feasible to use a placebo in the standard-care group, owing to potential harm with excess fluid administration. In addition, the protocol did not specify glucose control or fluid administration in the standard-care cohort; instead, we monitored practice patterns, which were reported on a regular basis to the data and safety monitoring board, and did not detect any changes in terms of either an increase in insulin use or a reduction in dextrose administration. Bedside glucose meters, though helpful in maximizing timeliness and minimizing cost, are less accurate than blood gas analyzers or central laboratory devices40
and may have detracted from our ability to achieve ideal glycemic control.
In summary, our trial showed that tight glycemic control targeting a glucose level of 80 to 110 mg per deciliter did not change the rate of health care–associated infections, mortality, or length of stay in the cardiac ICU as compared with standard care. Postoperative pediatric patients who have undergone cardiopulmonary bypass surgery, although perhaps the most likely among critically ill children to benefit from tight glycemic control, are unique; thus, results from this study cannot be extrapolated to other pediatric critical care populations. Moreover, the study was conducted in two large pediatric cardiovascular programs, and the findings may not be generalizable to other centers, where infection and complication rates and mortality may differ.