Nicole Glaser

Risk factors for cerebral edema in children with diabetic ketoacidosis

BACKGROUND Cerebral edema is an uncommon but devastating complication of diabetic ketoacidosis in children. Risk factors for this complication have not been clearly defined. METHODS In this multicenter study, we identified 61 children who had been hospitalized for diabetic ketoacidosis within a 15-year period and in whom cerebral edema had developed. Two additional groups of children with diabetic ketoacidosis but without cerebral edema were also identified: 181 randomly selected children and 174 children matched to those in the cerebral-edema group with respect to age at presentation, onset of diabetes (established vs. newly diagnosed disease), initial serum glucose concentration, and initial venous pH. Using logistic regression we compared the three groups with respect to demographic characteristics and biochemical variables at presentation and compared the matched groups with respect to therapeutic interventions and changes in biochemical values during treatment. RESULTS A comparison of the children in the cerebral-edema group with those in the random control group showed that cerebral edema was significantly associated with lower initial partial pressures of arterial carbon dioxide (relative risk of cerebral edema for each decrease of 7.8 mm Hg [representing 1 SD], 3.4; 95 percent confidence interval, 1.9 to 6.3; P<0.001) and higher initial serum urea nitrogen concentrations (relative risk of cerebral edema for each increase of 9 mg per deciliter [3.2 mmol per liter] [representing 1 SD], 1.7; 95 percent confidence interval, 1.2 to 2.5; P=0.003). A comparison of the children with cerebral edema with those in the matched control group also showed that cerebral edema was associated with lower partial pressures of arterial carbon dioxide and higher serum urea nitrogen concentrations. Of the therapeutic variables, only treatment with bicarbonate was associated with cerebral edema, after adjustment for other covariates (relative risk, 4.2; 95 percent confidence interval, 1.5 to 12.1; P=0.008). CONCLUSIONS Children with diabetic ketoacidosis who have low partial pressures of arterial carbon dioxide and high serum urea nitrogen concentrations at presentation and who are treated with bicarbonate are at increased risk for cerebral edema.

ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents

Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (TIDM). Mortality is predominantly related to the occurrence of cerebral oedema; only a minority of deaths in DKA are attributed to other causes. Cerebral oedema occurs in about 0.3–1% of all episodes of DKA, and its aetiology, pathophysiology, and ideal method of treatment are poorly understood. There is debate as to whether physicians treating DKA can prevent or predict the occurrence of cerebral oedema, and the appropriate site(s) for children with DKA to be managed. There is agreement that prevention of DKA and reduction of its incidence should be a goal in managing children with diabetes.

Diabetic Ketoacidosis in Infants, Children, and Adolescents

The adage “A child is not a miniature adult” is most appropriate when considering diabetic ketoacidosis (DKA). The fundamental pathophysiology of this potentially life-threatening complication is the same as in adults. However, the child differs from the adult in a number of characteristics. 1 ) The younger the child, the more difficult it is to obtain the classical history of polyuria, polydipsia, and weight loss. Infants and toddlers in DKA may be misdiagnosed as having pneumonia, reactive airways disease (asthma), or bronchiolitis and therefore treated with glucocorticoids and/or sympathomimetic agents that only compound and exacerbate the metabolic derangements. Because the diagnosis of diabetes is not suspected as it evolves, the duration of symptoms may be longer, leading to more severe dehydration and acidosis and ultimately to obtundation and coma. Even in developed countries, some 15–70% of all newly diagnosed infants and children with diabetes present with DKA (1–8). Generally, the rates of DKA are inversely proportional to rates of diabetes in that community, but throughout the U.S., the overall rates of DKA at diagnosis have remained fairly constant at ∼25% (6). DKA, defined by blood bicarbonate 14 years but did not differ significantly by sex or ethnicity (6). 2 ) The higher basal metabolic rate and large surface area relative to total body mass in children requires greater precision in delivering fluids and electrolytes. The degree of dehydration is expressed as a function of body weight, i.e., 10% dehydration implies 10% loss of total body weight as water. However, the calculation of basal requirements, although a constant per unit …

Evidence of Increased Inflammation and Microcirculatory Abnormalities in Patients With Type 1 Diabetes and Their Role in Microvascular Complications

OBJECTIVE—Type 1 diabetes is associated with increased microvascular complications and inflammation. The monocyte-macrophage is a pivotal cell in atherogenesis. There are scanty data on noninvasive measures of microvascular abnormalities and inflammation in type 1 diabetic subjects with microvascular complications. Thus, we examined systemic and cellular biomarkers of inflammation in type 1 diabetic patients with microvascular complications (T1DM-MV patients) and type 1 diabetic patients without microvascular complications (T1DM patients) compared with matched control subjects and determined the microcirculatory abnormalities in the T1DM and T1DM-MV patients using computer-assisted intravital microscopy (CAIM). RESEARCH DESIGN AND METHODS—Fasting blood, 24-h urine, and CAIM measurements were obtained from the T1DM and T1DM-MV patients and matched control subjects. C-reactive protein, E-selectin, nitrotyrosine, monocyte superoxide, and cytokines were elevated in the T1DM and T1DM-MV patients compared with control subjects (P < 0.01). RESULTS—Severity index, as assessed by CAIM, was significantly increased in the T1DM and T1DM-MV patients compared with the control subjects (P < 0.001). There was a significant increase in C-reactive protein, nitrotyrosine, vascular cell adhesion molecule and monocyte superoxide anion release, and interleukin-1 release in T1DM-MV compared with T1DM patients (P < 0.05). T1DM-MV patients had significantly increased CAIM severity index and microalbumin-to-creatinine ratio compared with T1DM patients (P < 0.05). Furthermore, pp38MAPK, pp65, and pERK activity were significantly increased in monocytes from the T1DM and T1DM-MV patients compared with those from the controls subjects, and pp38MAPK and pp65 activity were significantly increased in the T1DM-MV compared with the T1DM patients (P < 0.01). CONCLUSIONS—T1DM-MV patients have increased inflammation compared with T1DM patients. CAIM provides an effective biomarker of microvascular complications, since it is significantly elevated in T1DM-MV compared with T1DM patients and can be monitored following therapies targeted at improving inflammation and/or microvascular complications of type 1 diabetes.

Diabetic ketoacidosis and hyperglycemic hyperosmolar state

aDivision of Endocrinology, Boston Children’s Hospital, Boston, MA, USA; bBarts Health NHS Trust, Royal London Hospital, London, UK; cInstitute of Endocrinology and Diabetes, The Children’s Hospital at Westmead; School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia; dOxfordshire Children’s Diabetes Service, Oxford Children’s Hospital, Oxford, UK; eSection of Endocrinology, University of California, Davis School of Medicine, Sacramento, CA, USA; fPediatric Endocrinology Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India; gEndocrinology Service, Department of Paediatrics, KK Women’s and Children’s Hospital, Singapore; hDepartment of Paediatrics and Child Health, University of Nairobi, Nairobi, Kenya ; iDepartment of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; jDivision of Endocrinology, Diabetes and Metabolism, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA and kDepartment of Pediatrics, NU Hospital Group, Uddevalla and Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden

Frequency of sub‐clinical cerebral edema in children with diabetic ketoacidosis

Abstract:  Symptomatic cerebral edema occurs in approximately 1% of children with diabetic ketoacidosis (DKA). However, asymptomatic or subclinical cerebral edema is thought to occur more frequently. Some small studies have found narrowing of the cerebral ventricles indicating cerebral edema in most or all children with DKA, but other studies have not detected narrowing in ventricle size. In this study, we measured the intercaudate width of the frontal horns of the lateral ventricles using magnetic resonance imaging (MRI) in children with DKA during treatment and after recovery from the DKA episode. We determined the frequency of ventricular narrowing and compared clinical and biochemical data for children with and without ventricular narrowing. Forty‐one children completed the study protocol. The lateral ventricles were significantly smaller during DKA treatment (mean width, 9.3 ± 0.3 vs. 10.2 ± 0.3 mm after recovery from DKA, p < 0.001). Children with ventricular narrowing during DKA treatment (22 children, 54%) were more likely to have mental status abnormalities than those without narrowing [12/22 vs. 4/19 with Glasgow Coma Scale (GCS) scores below 15 during therapy, p = 0.03]. Multiple logistic regression analysis revealed that a lower initial PCO2 level was significantly associated with ventricular narrowing [odds ratio (OR) = 0.88, 95% confidence interval (95% CI) = 0.78–0.99, p = 0.047). No other variables analyzed were associated with ventricular narrowing in the multivariate analysis. We conclude that narrowing of the lateral ventricles is evident in just over half of children being treated for DKA. Although children with ventricular narrowing did not exhibit neurological abnormalities sufficient for a diagnosis of ‘symptomatic cerebral edema’, mild mental status abnormalities occurred frequently, suggesting that clinical evidence of cerebral edema in children with DKA may be more common than previously reported.

Predicting the likelihood of remission in children with graves' disease: A prospective, multicenter study

OBJECTIVE. The optimal treatment for Graves’ disease in children is controversial. Antithyroid medications are often used initially, but many children eventually require alternative therapies. We evaluated predictors of remission after 2 years of antithyroid medication use. METHODS. We prospectively studied children who had Graves’ disease and were treated with antithyroid medications. We compared children who achieved remission after 2 years with those who had persistent disease to determine which variables were associated with remission; multiple logistic regression and binary recursive partitioning analyses were used to evaluate interactions among predictive variables. RESULTS. Of 51 children who completed the study, 15 (29%) achieved remission. Children who achieved remission had lower thyroid hormone concentrations at presentation than those with persistent disease (free thyroxine: 6.17 ± 3.10 vs 9.86 ± 7.54 ng/dL; total triiodothyronine: 431 ± 175 vs 561 ± 225 ng/dL). Children who achieved remission were also more likely to be euthyroid within 3 months of initiating propylthiouracil (82% vs 29%). Binary recursive partitioning analysis identified rapid achievement of euthyroid status after initiation of propylthiouracil, lower initial triiodothyronine, and older age as significant predictors of remission. CONCLUSIONS. Thyroid hormone concentrations at diagnosis, age, and initial response to propylthiouracil can be used to stratify patients according to the likelihood of remission after 2 years of antithyroid medication use. These data provide a useful guide for clinical decision-making regarding Graves’ disease in children.

Correlation of Clinical and Biochemical Findings with Diabetic Ketoacidosis-Related Cerebral Edema in Children Using Magnetic Resonance Diffusion-Weighted Imaging

OBJECTIVE To determine clinical and biochemical factors influencing cerebral edema formation during diabetic ketoacidosis (DKA) in children. STUDY DESIGN We used magnetic resonance diffusion-weighted imaging to quantify edema formation. We measured the apparent diffusion coefficient (ADC) of brain water during and after DKA treatment in 26 children and correlated ADC changes with clinical and biochemical variables. RESULTS Mean ADC values were elevated during DKA treatment compared with baseline (8.13 +/- 0.47 vs 7.74 +/- 0.49 x 10(-4) mm(2)/sec, difference in means 0.40, 95% CI: 0.25 to 0.55, P < .001). Children with altered mental status during DKA had greater elevation in ADC. ADC elevation during DKA was positively correlated with initial serum urea nitrogen concentration (correlation coefficient 0.41, P = .03) and initial respiratory rate (correlation coefficient 0.61, P < .001). ADC elevation was not significantly correlated with initial serum glucose, sodium or effective osmolality, nor with changes in glucose, sodium or osmolality during treatment. Multivariable analyses identified the initial urea nitrogen concentration and respiratory rate as independently associated with ADC elevation. CONCLUSIONS The degree of edema formation during DKA in children is correlated with the degree of dehydration and hyperventilation at presentation, but not with factors related to initial osmolality or osmotic changes during treatment. These data support the hypothesis that CE is related to cerebral hypoperfusion during DKA, and that osmotic fluctuations during DKA treatment do not play a primary causal role.

Cerebral Blood Flow and Cerebral Edema in Rats With Diabetic Ketoacidosis

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 pCO2. 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.

Hyperglycemic hyperosmolar syndrome in children: Pathophysiological considerations and suggested guidelines for treatment

A.H. received support from the Alberta Diabetes Institute and the Women & Children’s Health Research Institute at University of Alberta. These Clinical Practice Guideline are endorsed by the Lawson Wilkins Pediatric Endocrine Society. They were developed to be of assistance to endocrinologists by providing guidance and yperglycemic hyperosmolar syndrome (HHS), characterized by extreme elevations in serum glucose concentrations andhyperosmolalitywithout significant ketosis, has historically been infrequent in children. However, recent case reports and series describing HHS in children suggests that the incidence of this disorder may be increasing. The epidemiology of HHS in children and adolescents has been reviewed recently. HHS has a high mortality rate, and an understanding of the unique pathophysiology (Figure 1) of this condition is important to guide clinical decision-making. However, although treatment of diabetic ketoacidosis (DKA) in children is familiar to most clinicians, the management of HHS in youth presents a unique set of clinical challenges for which little guidance is currently available. The aim of this review is to discuss the pathophysiology of HHS and to provide broad treatment recommendations on the basis of the available literature and known physiological principles. Criteria for the diagnosis of HHS are listed in Table I. Although HHS is distinct from DKA (Table II; available at www.jpeds.com), patients may present with features of both conditions. HHS occurs less frequently in children than DKA, and some children with DKA can have severe hyperosmolality, complicating the recognition of HHS as a distinct entity. As a result, children with HHS are often treated with DKA protocols. However, the pathophysiology of HHS differs from DKA, and these differences should be considered in planning a rational therapeutic approach. Unlike the usual symptoms of DKA (hyperventilation, vomiting, and abdominal pain), which typically bring children to medical attention, the gradually increasing polyuria and polydipsia of HHS may go unrecognized. As a result, both dehydration and electrolyte loss are profound in HHS; in adults, fluid losses in HHS have been estimated to be twice those of DKA. Furthermore, obesity and hyperosmolality can make the clinical assessment of dehydration unreliable. It has been suggested on the basis of information from small case series that intake of copious quantities of carbonated sugar-enriched drinks before presentation may be a common feature of patients presenting with severe hyperglycemia. Because these case series lack control data, however, it is unclear whether this finding is specific to these patients.