Gregory G. Passmore

Diabetic ketoacidosis promotes a prothrombotic state

Cerebrovascular accidents are one of the life‐threatening complications of diabetic ketoacidosis (DKA) in children and adolescents. Our objective was to evaluate the effect of DKA and its treatment on factors known to affect thrombotic activity (protein C; protein S; von Willebrand factor; fibrinogen; homocysteine; and folate) by comparing seven adolescents with DKA prior to treatment and at 6, 24, and 120 hours after initiation of treatment. We found that protein C activity was significantly decreased by DKA, but normalized slowly following treatment. Free protein S was low throughout the study. Protein C antigen and protein S antigen showed varying degrees of change within the first 24 hours, but remained in the normal range, with the exception of the initial value of protein C antigen, which was elevated. von Willebrand factor (vWF) antigen and vWF activity were both significantly increased prior to treatment, but decreased with treatment. However, vWF activity remained elevated at 120 hours. Fibrinogen concentrations showed no significant changes throughout the study. Homocysteine was significantly decreased prior to treatment and increased with the initiation of treatment. Folate was significantly increased prior to treatment, and decreased to high normal levels. The increased vWF and the decreased levels of protein C activity and of free protein S support the hypothesis that DKA and its treatment results in a prothrombotic state and activation of the vascular endothelium, which, in turn, predispose to cerebrovascular accidents.

Receptor for advanced glycation end products and neuronal deficit in the fatal brain edema of diabetic ketoacidosis.

Radiologic and neuropsychologic studies suggest that diabetes mellitus causes structural changes in the brain and adversely effects cognitive development. Experimental animal models of type 1 diabetes mellitus (T1DM) have advanced these findings by demonstrating duration-related neuronal and cognitive deficits in T1DM BB/Wor rats. We studied the expression of receptor for advanced glycation end products (RAGE) and neuronal densities in the brains of two patients who died as the result of clinical brain edema(BE)that developed during the treatment of severe diabetic ketoacidosis (DKA). RAGE was markedly and diffusely expressed in blood vessels, neurons, and the choroid plexus and co-localized with glial fibrillary acidic protein (GFAP) in astrocytes. Significant neuronal loss was seen in the hippocampus and frontal cortex. Astrocytosis was present and white matter was atrophied in both cases when compared to age-matched controls. Our data supports that a neuroinflammatory response occurs in the BE associated with DKA, and that even after a relatively short duration of poorly controlled T1DM, the pathogenesis of primary diabetic encephalopathy can be initiated.

Interstitial pulmonary edema in children and adolescents with diabetic ketoacidosis

The acute complications of diabetic ketoacidosis in children and adolescents are well recognized but not completely understood. Clinical studies have focused primarily on brain edema. We have investigated the prevalence and course of interstitial pulmonary edema in patients with severe diabetic ketoacidosis all of whom had uneventful clinical courses. High resolution computed tomography scans of the lungs were analyzed by determining the Hounsfield attenuation level and then converting to physical density values. All seven patients had evidence of interstitial pulmonary edema on the first scan, which was performed within 1 h of hydration and prior to receiving insulin; six of the seven patients had increased pulmonary density 6-8 h into treatment, and all had complete resolution of the interstitial changes at discharge. Our study suggests that subclinical interstitial pulmonary edema may be a frequent occurrence in children and adolescents with severe diabetic ketoacidosis and may very well be present prior to treatment. The study also supports the philosophy of cautious rehydration and the close monitoring of children and adolescents with diabetic ketoacidosis until a more complete understanding of this pathophysiologic event is achieved.

Acetoacetate increases expression of intercellular adhesion molecule-1 (ICAM-1) in human brain microvascular endothelial cells.

It has been hypothesized that ketone bodies cause activation of brain endothelial cells and that this is a factor in the intracerebral crises of diabetic ketoacidosis (DKA). In this study we used cultured human brain microvascular endothelial cells (HBMEC) to investigate the effect of beta hydroxybutyrate (BOHB) and acetoacetate (AcAc) on the expression of the adhesion molecule, intercellular adhesion molecule-1 (ICAM-1). Increasing concentrations of AcAc, but not BOHB, caused a significant upregulation of ICAM-1 in comparison to unstimulated cells. Glucose concentrations of 10 and 30 mM, but not 50 mM, also resulted in increased expression of ICAM-1. These results support the hypothesis that activation of HBMEC is involved in the acute complications of DKA, and that ketone bodies and hyperglycemia are factors in the perturbed membrane function.

Acute activation of peripheral lymphocytes during treatment of diabetic ketoacidosis

Activated peripheral T-lymphocytes are increased in both pre-insulin-dependent diabetes mellitus (IDDM) patients and in recently diagnosed IDDM patients, as well as in various forms of acute stress. We studied the in vivo T-lymphocyte activation in six patients in severe diabetic ketoacidosis (DKA) prior to treatment, after 24 h of treatment and > or =5 days after admission. Five of the six patients showed an increased percentage of activated T-lymphocytes based on the expression of HLA-DR at 24 h of treatment when compared to the admission percentage of activation (P<.05). There was no correlation to the admission serum glucose, osmolality, or electrolytes. Serum pH showed a trend toward an inverse correlation, but was not statistically significant. We speculate that T-lymphocyte activation plays a role in the progression of the acute complications of subclinical brain edema and interstitial pulmonary edema of DKA. This process could also be another factor in the progression of the chronic complications of IDDM in addition to the well-established effects of hyperglycemia and hypertension.

Diabetic ketoacidosis and its treatment increase plasma 3-deoxyglucosone

OBJECTIVES Highly reactive dicarbonyl compounds are known to be increased by hyperglycemia, ketone bodies and lipid peroxidation. This study was carried out to investigate the effect of diabetic ketoacidosis (DKA) and its treatment on the plasma concentration of 3 deoxyglucosone (3-DG) one of the dicarbonyl compounds. DESIGN AND METHODS 3-DG was measured in 7 children before, during and following correction of severe DKA. 3-DG was elevated before treatment (610 nmol/L +or/- 70) in comparison to baseline (120 h) (200 nmol/L+/or- 17) (p < 0.05). At 6 to 24 h into treatment 3-DG was further elevated (1080 nmol/L +or/- 80) in comparison to both pretreatment (p < 0.05) and baseline (p < 0.05). CONCLUSION 3-DG is significantly elevated before the treatment of DKA and increases further during the treatment of DKA. The time course of the increase of 3-DG coincides with the time of progression of subclinical brain edema, which occurs in DKA.

Study of subclinical cerebral edema in diabetic ketoacidosis by magnetic resonance imaging T2 relaxometry and apparent diffusion coefficient maps.

Cerebral edema is the most significant complication in children with diabetic ketoacidosis (DKA). Our goal was to study whether subclinical cerebral edema was preferentially vasogenic or cytotoxic. Magnetic resonance imaging (MRI)—diffusion-weighted imaging (DWI) and T2 relaxometry (T2R)—were obtained in pediatric patients presenting with severe diabetic ketoacidosis (DKA) 6–12 hours after initial DKA treatment and stabilization and 96 hours after correction of DKA. T2 relaxometry was significantly increased during treatment in both white and gray matter, in comparison to the absolute T2R values 96 hours after correction of DKA (p = .034). Classic intracellular cytotoxic edema could not be detected, based on the lack of a statistically significant decrease in ADC values. ADC values were instead elevated, implying a large component of cell membrane water diffusion, correlating with the elevated white and gray matter T2R. We discuss the findings in relation to cerebral blood volume, cerebral vasoregulatory dysfunction, and cerebral hyperemia.

Insulin and IGF-1 receptors, nitrotyrosin and cerebral neuronal deficits in two young patients with diabetic ketoacidosis and fatal brain edema

Gray and white matter structural deficits may accompany type 1 diabetes. Earlier experimental studies have demonstrated neuronal deficits associated with impaired neurotrophic support, inflammation and oxidative stress. In this study we demonstrate in two patients with histories of poorly controlled type 1 diabetes and fatal brain edema of ketoacidosis neuronal deficits associated with a decreased presence of insulin and IGF-1 receptors and accumulation of nitrotyrosin in neurons of affected areas and the choroid plexus. The findings add support to the suggested genesis of T1DM encephalopathy due to compromised neurotrophic protection, oxidative stress, inflammation and neuronal deficits, as demonstrated in T1DM encephalopathy in the BB/Wor-rat.

Development of a Concept Map to Convey Understanding of Patient and Family-Centered Care

&NA; Even though the expression “Patient and Family‐Centered Care (PFCC)” is widely used, there remains a lack of clarity regarding how the fundamental tenets of PFCC fit with our current model of healthcare. The purpose of this manuscript was to describe the first step in developing an organizational understanding of the operational construct for PFCC utilizing a concept map and the fundamental concept mapping learning theories. The overall goals were to build a more robust organization‐wide understanding of the basic PFCC tenets guided by the philosophy of concept mapping. The long‐range aspirations of this process are to improve safety and quality of life by incorporating the PFCC philosophy in the career development path of our students and healthcare professionals.

Computer Analysis of Magnetic Resonance Imaging of the Brain in Children and Adolescents After Treatment of Diabetic Ketoacidosis

Cerebral vascular accidents are one of the causes of morbidity and mortality in children with diabetic ketoacidosis. We investigated the possible occurrence of asymptomatic cerebrovascular infarcts and the course of subclinical brain edema in six patients. Neurologic examinations and computer analysis of magnetic resonance imaging were performed immediately after, and again at 14 days after, correction of DKA. None of the patients had clinical evidence of a neurologic deficit. Neither radiologic evaluation nor computer analysis of MRI identified changes indicating asymptomatic ischemic events. However, a computer analysis of the MRI identified a significant increase of the total ventricle area between Day one and Day 14. Our study does not establish whether this change is a return to the baseline prior to DKA or a new baseline, representing an early manifestation of diabetic encephalopathy.