Cerebral Blood Flow and Cerebral Edema in Rats With Diabetic Ketoacidosis

Abstract

OBJECTIVE-Cerebral edema (CE) is a potentially life-threatening complication of diabetic ketoacidosis (DKA) in children. Osmotic fluctuations during DKA treatment have been considered responsible, but recent data instead suggest that cerebral hypoperfusion may be involved and that activation of cerebral ion transporters may occur. Diminished cerebral blood flow (CBF) during DKA, however, has not been previously demonstrated. We investigated CBF and edema formation in a rat model of DKA and determined the effects of bumetanide, an inhibitor of Na-K-Cl cotransport.RESEARCH DESIGN AND METHODS-Juvenile rats with streptozotocin-induced DKA were treated with intravenous saline and insulin, similar to human treatment protocols. CBF was determined by magnetic resonance (MR) perfusion-weighted imaging before and during treatment, and CE was assessed by determining apparent diffusion coefficients (ADCs) using MR diffusion-weighted imaging.RESULTS-CBF was significantly reduced in DKA and was responsive to alterations in pCO 2 . ADC values were reduced, consistent with cell swelling. The reduction in ADCs correlated with dehydration, as reflected in blood urea nitrogen concentrations. Bumetanide caused a rapid rise in ADCs of DKA rats without significantly changing CBF, while saline/insulin caused a rapid rise in CBF and a gradual rise in ADCs. DKA rats treated with bumetanide plus saline/insulin showed a trend toward more rapid rise in cortical ADCs and a larger rise in striatal CBF than those observed with saline/insulin alone.CONCLUSIONS-These data demonstrate that CE in DKA is accompanied by cerebral hypoperfusion before treatment and suggest that blocking Na-K-Cl cotransport may reduce cerebral cell swelling. Diabetes 57:2588-2594, 2008 D iabetic ketoacidosis (DKA) occurs frequently in children with type 1 diabetes. A total of 25-40 percent of children with new-onset type 1 diabetes present with DKA, and DKA can occur in children with known diabetes during episodes of illness, poor compliance, or malfunction of diabetes care equipment such as insulin pumps (1,2). Cerebral edema (CE) is the most feared complication of DKA in children (3-5). CE has a high mortality rate (21-24%), and survivors often have permanent neurological deficits (15-35%) (5,6). CE is the major diabetes-related cause of mortality in children with type 1 diabetes and is responsible for 50 -85% of diabetes-related deaths (7-9).Asymptomatic CE is thought to occur with much greater frequency than clinically apparent CE and may be present in the majority of DKA episodes in children (10 -12). Studies utilizing sequential computed tomography or magnetic resonance (MR) scanning in children with DKA without significant neurological abnormalities have shown evidence of CE at presentation (10), demonstrated by decreased size of the cerebral ventricles, and that this edema likely worsens during therapy (10 -12). Thus, the development of symptomatic CE in 1% of children with DKA may represent the most severe presentation of a more common pathophysiological phen...

Diagnosis and management of hyperglycemic emergencies

“…12 Cerebral edema occurs in 0.3-1% of children with DKA but is very rare in adults 7,77 and its mechanism is debated. 7,[77][78][79][80][81][82][83] Other reported life-threatening complications include adult respiratory distress syndrome, hydrostatic pulmonary edema, bronchial mucous plugging, ischemic intestinal necrosis and arterial and venous thromboses; 32,[84][85][86][87][88] standard low-dose unfractionated heparin or low molecular weight heparin prophylaxis is reasonable adjunctive therapy when no contra-indications are present.…”

Joint British Diabetes Societies guideline for the management of diabetic ketoacidosis

“…However, there is evidence that subclinical cerebral oedema may be present before treatment is started [43]. The exact cause of this phenomenon is unknown; recent studies suggest that cerebral hypoperfusion with subsequent re-perfusion may be the mechanism operating [38,44,45]. …”

Subclinical Cerebral Edema in Children With Diabetic Ketoacidosis Randomized to 2 Different Rehydration Protocols

“…For example, untreated DKA is characterized by low ADC values (suggesting cytotoxic edema) and low CBF. 23,24 Brain lactate levels are elevated and levels of high-energy phosphates are decreased. 25 These findings are similar to those observed during cerebral hypoxia or ischemia.…”