Transcranial Doppler-based assessment of cerebral autoregulation in critically ill children during diabetic ketoacidosis treatment.

OBJECTIVES: Impaired cerebral autoregulation may be associated with poor outcome in diabetic ketoacidosis. We examined change in cerebral autoregulation during diabetic ketoacidosis treatment. DESIGN: Prospective observational cohort study. SETTING: Tertiary care children's hospital. PATIENTS/SUBJECTS: Children admitted to the ICU with diabetic ketoacidosis (venous pH < 7.3, glucose > 300 mg/dL, HCO3 < 15 mEq/L, and ketonuria) constituted cases, and children with type I diabetes without diabetic ketoacidosis constituted controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between 2005 and 2009, 32 cases and 50 controls were enrolled. Transcranial Doppler ultrasonography was used to measure middle cerebral artery flow velocities, and cerebral autoregulation testing was achieved via tilt-table testing. Cases underwent two and controls underwent one cerebral autoregulation test. Cerebral autoregulation was quantified by the autoregulatory index (autoregulatory index < 0.4 = impaired and autoregulatory index 0.4-1.0 = intact autoregulation). The first autoregulation test was obtained early (time 1, 12-24 hr; median [interquartile range], 8 hr [5-18 hr]) during diabetic ketoacidosis treatment, and a second autoregulation test was obtained during recovery (time 2, 36-72 hr; median [ interquartile range], 46 hr [40-59 hr]) from time 0 (defined as time of insulin start). Cases had lower autoregulatory index at time 1 than time 2 (p < 0.001) as well lower autoregulatory index than control subjects (p < 0.001). Cerebral autoregulation was impaired in 40% (n = 13) of cases at time 1 and in 6% (n = 2) of cases at time 2. Five cases (17%) showed persistent impairment of cerebral autoregulation between times 1 and 2 of treatment. All control subjects had intact cerebral autoregulation. CONCLUSIONS: Impaired cerebral autoregulation was common early during diabetic ketoacidosis treatment. Although the majority improved during diabetic ketoacidosis treatment, 17% of subjects had impairment between 36 and 72 hours after start of insulin therapy. The observed impaired cerebral autoregulation appears specific to the diabetic ketoacidosis process in patients with type I diabetes.

Change in mean transit time, apparent diffusion coefficient, and cerebral blood volume during pediatric diabetic ketoacidosis treatment.

OBJECTIVES: Cerebral edema is a devastating complication of pediatric diabetic ketoacidosis. We examined measures describing potential causes of whole brain and regional brain edema (mean transit time, apparent diffusion coefficient, and relative cerebral blood volume) during treatment of diabetic ketoacidosis in children. DESIGN: Prospective observational study. SETTING: Regional children's hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After Institutional Review Board approval, children admitted with diabetic ketoacidosis (pH <7.3, HCO3 <15 mEq/L, glucose >300 mg/dL, and ketosis) underwent two serial paired contrast-enhanced (gadolinium) and diffusion magnetic resonance imaging scans. Change in whole brain and regional (frontal lobe, occipital lobe, and basal ganglia) mean transit time, apparent diffusion coefficient, and relative cerebral blood volume between the two time periods (12-24 hrs) and (36-72 hrs) after start of insulin treatment (time 0) were determined. Thirteen children (median age, 10.3 ± 1.1 yrs; 7 female) with diabetic ketoacidosis were examined. Overall, whole brain and regional mean transit time decreased from time 1 (first magnetic resonance imaging after time 0) to time 2 (second magnetic resonance imaging after time 0) by 51% ± 59% (p = .01), without differences between the brain regions examined. Whole brain apparent diffusion coefficient increased by 4.7% ± 3.4% (p = .001), without differences between the brain regions examined. There was no change in relative cerebral blood volume for the whole brain and for the three brain regions examined. CONCLUSIONS: In this study, whole brain mean transit time decreased and apparent diffusion coefficient increased, suggesting a vasogenic process between the two study periods during diabetic ketoacidosis treatment.

Change in blood-brain barrier permeability during pediatric diabetic ketoacidosis treatment.

OBJECTIVE: Cerebral edema is a devastating complication of pediatric diabetic ketoacidosis. We aimed to examine blood-brain barrier permeability during treatment of diabetic ketoacidosis in children. DESIGN: Prospective observational study. SETTING: Seattle Children's Hospital, Seattle, WA. PATIENTS: Children admitted with diabetic ketoacidosis (pH <7.3, HCO3 <15 mEq/L, glucose >300 mg/dL, and ketosis). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Subjects underwent two serial paired contrast-enhanced perfusion (gadolinium) and diffusion magnetic resonance imaging scans. Change in whole brain and regional blood-brain barrier permeability (permeability ratio*100 and % permeability ratio change) between illness and recovery were determined. Time 0 reflects start of insulin treatment. Thirteen children (median age 10.0 +/- 1.1 yrs; seven female) with diabetic ketoacidosis were enrolled. Permeability ratio increased from time 1 (first magnetic resonance image after time 0) to time 2 (second magnetic resonance image after time 0) in the frontal cortex (ten of 13 subjects), occipital cortex (ten of 13 subjects), and basal ganglia (nine of 13). Whole brain permeability ratio increased from time 1 to time 2 (160%) and regional increase in permeability ratio was greatest in the frontal cortex (148%) compared with the occipital cortex (128%) and basal ganglia (112%). CONCLUSIONS: Overall, whole brain and regional blood-brain barrier permeability increased in most subjects during diabetic ketoacidosis treatment. The frontal region had more blood-brain barrier permeability than other brain regions examined.

SLC20A2 Deficiency in Mice Leads to Elevated Phosphate Levels in Cerbrospinal Fluid and Glymphatic Pathway-Associated Arteriolar Calcification, and Recapitulates Human Idiopathic Basal Ganglia Calcification.

Idiopathic basal ganglia calcification is a brain calcification disorder that has been genetically linked to autosomal dominant mutations in the sodium-dependent phosphate co-transporter, SLC20A2. The mechanisms whereby deficiency of Slc20a2 leads to basal ganglion calcification are unknown. In the mouse brain, we found that Slc20a2 was expressed in tissues that produce and/or regulate cerebrospinal fluid, including choroid plexus, ependyma and arteriolar smooth muscle cells. Haploinsufficient Slc20a2 +/- mice developed age-dependent basal ganglia calcification that formed in glymphatic pathway-associated arterioles. Slc20a2 deficiency uncovered phosphate homeostasis dysregulation characterized by abnormally high cerebrospinal fluid phosphate levels and hydrocephalus, in addition to basal ganglia calcification. Slc20a2 siRNA knockdown in smooth muscle cells revealed increased susceptibility to high phosphate-induced calcification. These data suggested that loss of Slc20a2 led to dysregulated phosphate homeostasis and enhanced susceptibility of arteriolar smooth muscle cells to elevated phosphate-induced calcification. Together, dysregulated cerebrospinal fluid phosphate and enhanced smooth muscle cell susceptibility may predispose to glymphatic pathway-associated arteriolar calcification.