Risk factors for cerebral oedema in children and adolescents with diabetic ketoacidosis

Abstract

Cerebral oedema (CO) is a rare life-threatening complication of diabetic ketoacidosis (DKA) in children. We analysed the biochemical and therapeutic risk factors for CO in DKA by a retrospective review of 256 children hospitalized for DKA between February 2003 and March 2015. The demographic characteristics, biochemical variables and therapeutic interventions were compared between the patients with and without CO. CO was observed in 22 (8.6%) of the 256 subjects included in the study. One of these patients (5%) had a fatal outcome and two patients (9%) survived with neurological consequences. CO was significantly associated with severe DKA: lower initial venous pH (p < 0.001) and bicarbonate (p < 0.001), higher initial blood glucose (p < 0.01), urea level (p < 0.05) and baseline serum osmolality (p < 0.05). During the treatment of DKA, low serum phosphate level was found to be significantly associated with CO (p < 0.05). We also found significant dependence between the development of CO and the initiation of treatment for DKA in another facility before hospitalization in our hospital (p < 0.05), bicarbonate application (p < 0.001), higher fluid volume infused initially (p < 0.01) and delayed potassium substitution (p < 0.01). Severe ketoacidosis, hyperglycaemia and dehydration at presentation, and low serum phosphate during treatment are significantly related to CO formation in children with DKA. The initial severe acidosis and hyperglycaemia probably cause brain injury which progresses into CO in the course of developing hypophosphatemia and cerebral hypervolemia.

Brain injury in children with diabetic ketoacidosis: Review of the literature and a proposed pathophysiologic pathway for the development of cerebral edema

“…Several studies have found that patients with DKA who develop CE present with more severe hyperglycemia than those without overt CE 13,14,36‐39 . Hyperglycemia has been suggested to augment cerebral injury via a number of mechanisms, including the production of osmolytes (such as sorbitol), induction of cerebral acidosis, reduction of cerebral blood flow (CBF), and accumulation of lactate and glutamate 40 .…”

“…Development of CE in DKA has been associated with several factors known to affect cerebral perfusion, including uremia, 4,14,37‐39,49,56 hyperosmolality, 36,38,39 hyperventilation, 37 hypocapnia, 4,37 and acidosis 13,14,37‐39,49 . Acidosis, 57,58 hyperosmolality, 59 and a synergistic combination of the two 38 have been implicated in causing altered sensorium in patients with DKA.…”

“…An exaggerated action of vasopressin has been proposed to exacerbate these shifts 48 . In humans, several retrospective studies have implicated higher fluid volume, lower fluid tonicity, and rapid correction of hyperglycemia in the development of overt CE 37,39,48,49,56,122‐130 . One study suggested an inverse relationship between the rate of fluid administration (> 4 L/m2/day) and time to brain herniation 48 .…”

“…It is possible that patients with more severe clinical and metabolic derangements on presentation (who were at higher risk of developing CE) were treated more aggressively. A related concern is referral bias in some of the studies that included patients transferred from outside centers to the institutions' pediatric intensive care units and were thus more likely to have severe DKA 39,56,125 …”

“…In addition, it has been hypothesized that insulin may have deleterious effects on the BBB 61,76 ; however, no study in humans has been able to directly implicate this mechanism. Despite the observation that CE rarely occurs in the absence of insulin therapy, 19 other studies have failed to directly implicate insulin administration in its development, 4,13,37,39,131 and the role of insulin in causing CE remains unclear.…”