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Source: Glaser N, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med 2001;344:264-269.
This retrospective study from the pediatric emergency medicine Collaborative Research Committee of the American Academy of Pediatrics examines the risk factors for cerebral edema (CE), an uncommon yet devastating complication in children with diabetic ketoacidosis (DKA). The authors identified 61 children with DKA complicated by CE who presented to 10 pediatric centers over 15 years. DKA with CE was defined as a serum glucose less than 300 mg/dL, venous pH less than 7.25 or serum bicarbonate less than 15, ketonuria, alteration in mental status, and either radiographically or pathologically confirmed CE or clinical improvement following specific treatment for CE (hyperosmolar therapy or controlled hyperventilation). For each child with CE, the authors identified six children as controls, three in each of two control groups. The first control group ("random controls") consisted of children with DKA who were selected randomly from all children with DKA at each center during the study period. The second group ("matched controls") consisted of children with DKA who were matched with the children with CE according to age (within 2 years), onset of diabetes mellitus (new vs established), venous pH (within 0.1), and serum glucose (within 200 mg/dL).
Data from each child’s medical record were collected including demographics, serum chemistry results, treatment regimen, and changes in laboratory values during treatment. Comparison of the children with CE to the children in the random control group demonstrated that CE was significantly associated with lower initial pCO2 (relative risk for each decrease of 7.8 mmHg was 3.4; 95% CI 1.9-6.3) and higher initial blood urea nitrogen (BUN) (relative risk for each increase of 9 mg/dL was 1.7; 95% CI 1.2-2.5). Comparison of the children with CE to the matched control group also showed that CE was associated with lower initial pCO2 and higher initial BUN.
Examination of therapeutic variables revealed that after adjustment for other covariates, treatment with bicarbonate was associated with an increased risk of CE (relative risk, 4.2; 95% CI 1.5-12.1). Smaller increases in the serum sodium concentration during therapy also were associated with CE. Interestingly, the rates of fluid or sodium administration were not associated with an increased risk of CE after adjustment for covariates.
Comment by Jacob W. Ufberg, MD
The results of this excellent study agree with several previous studies showing that the initial pCO2 and smaller increases in serum sodium concentration during therapy predict increased risk of cerebral edema. This study also refutes the belief that the rate of fluid administration and the change in serum glucose during therapy are associated with increased risk of cerebral edema. Therefore, cerebral edema in children with DKA may not be caused by a rapid decrease in extracellular osmolarity during treatment, as has been theorized previously.
Despite this study’s findings, we should not jump to the conclusion that bicarbonate therapy causes cerebral edema. Cerebral edema occurs in some children prior to the initiation of any therapy. Additionally, there is the possibility that bicarbonate therapy was instituted in response to a change in the clinical status of some of the children who eventually were diagnosed with cerebral edema, even though the authors attempted to control for this. The authors note that although this is a relatively large study, it is still limited in its ability to detect some associations of smaller magnitude. They also note, "confounding factors that were not analyzed may have influenced the detected associations, particularly related to the use of bicarbonate treatment." Therefore, it remains unclear whether bicarbonate therapy, or any therapy for that matter, necessarily causes cerebral edema. What seems crystal clear is that this study, in conjunction with the prior literature, should put to rest the routine use of bicarbonate therapy in children with DKA.