Cerebral metabolic alterations in rats with diabetic ketoacidosis: effects of treatment with insulin and intravenous fluids and effects of bumetanide.
OBJECTIVE
Cerebral edema is a life-threatening complication of diabetic ketoacidosis (DKA) in children. Recent data suggest that cerebral hypoperfusion and activation of cerebral ion transporters may be involved, but data describing cerebral metabolic alterations during DKA are lacking.


METHODS
We evaluated 50 juvenile rats with DKA and 21 normal control rats using proton and phosphorus magnetic resonance spectroscopy (MRS). MRS measured cerebral intracellular pH and ratios of metabolites including ATP/inorganic phosphate (Pi), phosphocreatine (PCr)/Pi, N-acetyl aspartate (NAA)/creatine (Cr), and lactate/Cr before and during DKA treatment. We determined the effects of treatment with insulin and intravenous saline with or without bumetanide, an inhibitor of Na-K-2Cl cotransport, using ANCOVA with a 2 x 2 factorial study design.


RESULTS
Cerebral intracellular pH was decreased during DKA compared with control (mean +/- SE difference -0.13 +/- 0.03; P < 0.001), and lactate/Cr was elevated (0.09 +/- 0.02; P < 0.001). DKA rats had lower ATP/Pi and NAA/Cr (-0.32 +/- 0.10, P = 0.003, and -0.14 +/- 0.04, P < 0.001, respectively) compared with controls, but PCr/Pi was not significantly decreased. During 2-h treatment with insulin/saline, ATP/Pi, PCr/Pi, and NAA/Cr declined significantly despite an increase in intracellular pH. Bumetanide treatment increased ATP/Pi and PCr/Pi and ameliorated the declines in these values with insulin/saline treatment.


CONCLUSIONS
These data demonstrate that cerebral metabolism is significantly compromised during DKA and that further deterioration occurs during early DKA treatment--consistent with possible effects of cerebral hypoperfusion and reperfusion injury. Treatment with bumetanide may help diminish the adverse effects of initial treatment with insulin/saline.
Glaser
Nicole
N
Department of Pediatrics, University of California, Davis, California, USA. nsglaser@ucdavis.edu
Yuen
Natalie
N
Anderson
Steven E
SE
Tancredi
Daniel J
DJ
O'Donnell
Martha E
ME
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D002034:Bumetanide / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D003404:Creatinine / Q000378:metabolism; D016883:Diabetic Ketoacidosis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004232:Diuretics / Q000494:pharmacology; D005440:Fluid Therapy; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007262:Infusions, Intravenous; D007328:Insulin / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000494:pharmacology
D004232:Diuretics; D007004:Hypoglycemic Agents; D007328:Insulin; D010725:Phosphocreatine; D002034:Bumetanide; D001224:Aspartic Acid; D019344:Lactic Acid; D012965:Sodium Chloride; C000179:N-acetylaspartate; D003404:Creatinine