Cerebral Metabolic Alterations in Rats With Diabetic Ketoacidosis

Abstract

OBJECTIVECerebral 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.RESEARCH DESIGN AND METHODSWe 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 × 2 factorial study design.RESULTSCerebral 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.CONCLUSIONSThese 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.

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

“…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. [26][27][28][29] During DKA treatment with insulin and saline, CBF is elevated, and vasogenic edema develops.…”

“…Brain levels of high-energy phosphates and ratios of N-acetylaspartate to creatine (an indicator of neuronal health) decline during initial treatment with insulin and saline. 25 These changes are similar to those observed during reperfusion after a hypoxic/ischemic insult. 6 to -0.6), P = .80.…”

The Impact of Diabetes on Brain Function in Childhood and Adolescence

“…56,84 Brain lactate levels are elevated and levels of high-energy phosphates are decreased. 85 However, after resuscitation has commenced, cerebral blood flow and ADC increase and high-energy phosphates and ratios of N-acetylaspartate to creatinine (an indicator of neuronal health) decline in a similar fashion to that which occurs during the phases of cerebral injury from hypoxia-ischemia. 85 These MR changes do not seem to correlate with speed of rehydration during resuscitation.…”

Simulated diabetic ketoacidosis therapy in vitro elicits brain cell swelling via sodium-hydrogen exchange and anion transport

“…BBB dysfunction may be secondary to DKA-associated inflammation and leukocyte adherence to the brain microvascular endothelium (16,45). DKA-induced BBB permeability may exacerbate increases in brain glucose, lactate, and ketone levels during DKA (13,28,55) and underlie the vasogenic edema observed on brain MRI with apparent diffusion coefficients (19, 23, 29). In this study, we examined the potential for cellular DKA-CE to be mediated by changes in CSF composition during DKA therapy.…”

“…One study on a mixed population of adults and adolescents demonstrated that DKA CSF had increased glucose, ketones, lactate, and osmolality, whereas the bicarbonate was reduced (44); during DKA treatment, all values approached normal values. Noninvasive NMR and MRS imaging have also demonstrated altered CSF composition during DKA, which included elevated glucose, lactate, and ketones, and reduced intracerebral pH (8,13,28,55). Thus, experimental aCSF was approximated to these studies.…”