Insulin administration for treatment of pediatric diabetic ketoacidosis: are lower rates of infusion beneficial?

I n this issue of Pediatric Critical Care Medicine, Drs. Al Hanshi and Shann report laboratory data from 67 children treated for diabetic ketoacidosis (DKA) (1). The data were collected retrospectively from the charts of 34 children treated with an insulin infusion of 0.1 unit/kg/hr and 33 children treated with an insulin infusion of 0.05 unit/kg/hr. The treatment protocols were not randomly assigned, and the authors used analysis of covariance methods to compare the two groups on laboratory values obtained approximately 12 hrs after initiation of treatment, controlling for age and for laboratory values obtained at presentation. The authors conclude that effective osmolality declined more gradually in children treated with the lower rate of insulin infusion, despite similar rates of resolution of acidosis and ketosis. The etiology of DKA-related cerebral edema, and the optimal protocol for treatment of pediatric DKA (which is greatly focused on the prevention of cerebral edema) has been and continues to be a subject of controversy. There are very few data in the literature comparing treatment regimens, and treatment recommendations are mainly based on expert opinion and physiologic principles. Prospective data from randomized trials in pediatric DKA are almost nonexistent. In the current study, Drs. Al Hanshi and Shann present information on an important topic. However, the study is limited by the lack of randomization of treatment protocols and resulting issues with the analytical methods used to compare treatment groups, so the findings must be interpreted with caution. Furthermore, the authors’ premise that cerebral edema is a result of changes in serum osmolality is not uniformly accepted, and contrary to what the authors state, recent data (2–4) suggested that the pathophysiology of DKA-related cerebral edema may involve cerebral hypoperfusion and reperfusion leading to vasogenic edema. Previous studies (5) have demonstrated that the decline in serum glucose concentration during DKA treatment is dependent on the rate of insulin infusion across a range of insulin dosages from 0.01 unit/kg/hr to 1.0 unit/kg/hr. The finding that a lower rate of insulin infusion might lower the plasma glucose more slowly, therefore, is not surprising. Other factors, however, also influence the rate of decline in serum glucose concentration, including the initial degree of compromise in renal function caused by dehydration, rate of infusion of intravenous fluid, and the timing and amount of dextrose administration. These and other factors may have a substantial impact on the initial and subsequent serum glucose concentrations. The severity of dehydration and rate of rehydration may have a particularly important effect on the decline in serum glucose concentration during the early stages of treatment. It is, therefore, important to note that intravenous fluid therapy was not standardized among patients in the study. In addition, it is unclear how many patients received glucose infusions, which is common during the first 12 hrs of DKA therapy. This would also affect the data and results of the analysis. As noted by the authors, the lack of randomization in the choice of insulin dosages means that only very tentative comparisons can be made regarding the observed associations. Important confounders, both known and unknown, may partially or fully account for the observed between-group differences. The analysis of covariance model specified by the authors, which is well suited for comparing randomized treatment groups on posttreatment outcomes, is not optimal for between-group comparison of overtime changes in laboratory values when treatment group is not independent of pretreatment laboratory values, a phenomenon known as “Lord’s Paradox. ” This phenomenon is named after a famous demonstration that analysis of covariance can produce statistically significant treatment effects even when treatment groups do not differ in mean changes from baseline (6–8). Hence, the p values reported in their Table 2 must be interpreted with caution, as their pertinence to the changes in laboratory values that they accompany requires that treatment be independent of initial values, a questionable assumption for nonrandomized data. Absent this assumption, the p values pertain only to whether, after adjusting for the initial value and patient age, the treatment groups differ in posttreatment values, an analysis that could be confounded by many factors that differ between the groups (6–9). According to the data presented in Table 1 in the study by Drs. Al Hanshi and Shann, at least one fourth of the patients receiving high insulin dosages presented with glucose levels of 68 mmol/L. Although a formal statistical comparison was not made, the data in Table 1 suggest that the initial effective osmolality of patients in the higher insulin dosage group was higher than that shown for the patients in the lower dosage group. Given that osmolality would likely be within or close to the normal range at 12 hrs of treatment for most patients, it is also questionable whether the analysis of covariance model used to control for baseline differences was sufficient to adjust for the effects of between group differences in initial effective osmolality, as the model specifies only a linear relationship between initial and final values of the outcome. Nonrandomized assignment of treatment protocols may have resulted in other important differences between groups. Very high initial glucose concentrations in children with DKA are associ*See also p. 137.