Type 1 diabetes is the most common endocrine health condition among youth. Healthcare professionals must consider evidence-based guidelines in managing children and adolescents with diabetic ketoacidosis (DKA). The current study aims to assess the outcomes of implementing clinical guidelines by the American Diabetes Association to manage DKA among pediatrics in an emergency department in Palestine.

A prospective cohort study was conducted among 60 children (<12 years old) with type 1 diabetes mellitus with DKA throughout February to May 2021. The children were assessed on arrival and during the next 6 h for implementing the recommended guidelines of DKA management (e.g., fluids and insulin therapy). The assessment included measurement of vital signs (blood pressure, heart rate, respiratory rate, O2 saturation), PH, HCO3-, and random blood glucose (RBG). A repeated-measure ANOVA was used to detect the difference between outcome measures during the follow-up period.

After implementing the recommended guidelines of DKA management, all vital signs improved significantly in the follow-up period (p < 0.05). Also, PH, HCO3-, and random blood glucose (RBG) were significantly enhanced in the follow-up period (p < 0.05) among children with DKA.

The study demonstrated that the recommended DKA management guidelines effectively managed children with DKA in emergency departments. Healthcare professionals should adhere to the guidelines when treating children with DKA.

This review discusses the challenges and controversies in the treatment of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). Key areas include the selection of intravenous (IV) fluids, insulin therapy, strategies for preventing and monitoring cerebral edema (CE) by managing hyperglycemia overcorrection, electrolyte replacement, timing of nutrition, use of IV sodium bicarbonate, and airway management in critically ill DKA patients. Isotonic normal saline remains the standard for initial fluid resuscitation, though balanced solutions have been shown to have faster DKA resolution. Current guidelines recommend using continuous IV insulin for DKA management after fluid status has been restored potassium levels have been achieved and subcutaneous (SQ) insulin is started only after the resolution of metabolic acidosis. In comparison, the British guidelines recommend using SQ insulin glargine along with continuous regular IV insulin, which has shown faster DKA resolution and shorter hospital stays compared to continuous IV insulin alone. Although rare, rapid overcorrection of hyperglycemia with fluids and insulin can lead to CE, seizures, and death. Clinicians should be aware of risk factors and preventive strategies for CE. DKA frequently involves multiple electrolyte abnormalities, such as hypokalemia, hypophosphatemia, and hypomagnesemia and regular monitoring is essential for DKA management. Early initiation of oral nutrition has been shown to reduce intensive care unit and overall hospital length of stay. For impending respiratory failure, Bilevel positive airway pressure is not recommended due to aspiration risks. Instead, intubation and mechanical ventilation, with monitoring and management of acid-base and fluid status, are recommended. The use of sodium bicarbonate is discouraged due to the potential for worsening ketosis, hypokalemia, and risk of CE. However, IV sodium bicarbonate can be considered if the serum pH falls below 6.9, or when serum pH is less than 7.2 and/or serum bicarbonate levels are below 10 mEq/L, pre-and post-intubation, to prevent metabolic acidosis and hemodynamic collapse that occurs from apnea during intubation. Managing DKA and HHS in critically ill patients includes using balanced IV fluid solutions to restore volume status, followed by continuous IV insulin, early use of SQ glargine insulin, electrolyte replacement, and monitoring, CE preventive strategies by avoiding hyperglycemia overcorrection, early nutritional support, and appropriate airway management.

Pediatric diabetic ketoacidosis (DKA) is often treated in a PICU, but nonsevere DKA may not necessitate PICU admission. At our institution, nonsevere DKA was treated on the floor until policy change shifted care to the PICU. We describe outcomes in pediatric mild to moderate DKA by treatment location.

Patients aged 2 to 21 with mild to moderate DKA (pH <7.3 but >7.1), treated on the floor from January 1, 2018 to July 31, 2020 and PICU from August 1, 2020 to October 1, 2022 were included. We performed a single-center, retrospective cohort study; primary outcome was DKA duration (from emergency department diagnosis to resolution), secondary outcomes included hospital length of stay, and complication rates, based on treatment location.

Seventy nine floor and 65 PICU encounters for mild to moderate pediatric DKA were analyzed. There were no differences in demographics, initial pH, or bicarbonate; PICU patients had more acute kidney injury on admission. Floor patients had a shorter DKA duration (10 hours [interquartile range 7-13] vs 11 hours [9-15]; P = .04), and a shorter median length of stay (median 43.5 hours [interquartile range 31-62] vs 49 hours [32-100]; P < .01). No patients had clinical signs of cerebral edema; other complications occurred at similar rates. PICU patients received significantly more intravenous electrolyte boluses, but there were no differences in dysrhythmia or electrolyte abnormalities on final serum chemistry.

Our study did not find a clear benefit to admitting patients with mild to moderate DKA to the PICU instead of the hospital floor. Our findings suggest that some children with nonsevere DKA may be treated safely in a non-PICU setting.

Acute kidney injury (AKI) is a recognized comorbidity in pediatric diabetic ketoacidosis (DKA), although the exact etiology is unclear. The unique physiology of DKA makes dehydration assessments challenging, and these patients potentially receive excessive amounts of intravenous fluids (IVF). We hypothesized that dehydration is over-estimated in pediatric DKA, leading to over-administration of IVF and hyperchloremia that worsens AKI.

Retrospective cohort of all DKA inpatients at a tertiary pediatric hospital from 2014 to 2019. A total of 145 children were included; reasons for exclusion were pre-existing kidney disease or incomplete medical records. AKI was determined by change in creatinine during admission, and comparison to a calculated baseline value. Linear regression multivariable analysis was used to identify factors associated with AKI. True dehydration was calculated from patients' change in weight, as previously validated. Fluid over-resuscitation was defined as total fluids given above the true dehydration.

A total of 19% of patients met KDIGO serum creatinine criteria for AKI on admission. Only 2% had AKI on hospital discharge. True dehydration and high serum urea levels were associated with high serum creatinine levels on admission (p = 0.042; p < 0.001, respectively). Fluid over-resuscitation and hyperchloremia were associated with delayed kidney recovery (p < 0.001). Severity of initial AKI was associated with cerebral edema (p = 0.018).

Dehydration was associated with initial AKI in children with DKA. Persistent AKI and delay to recovery was associated with hyperchloremia and over-resuscitation with IVF, potentially modifiable clinical variables for earlier AKI recovery and reduction in long-term morbidity. This highlights the need to re-address fluid protocols in pediatric DKA.

Diabetic ketoacidosis (DKA), a common onset modality of type 1 diabetes mellitus (T1DM), can lead, in rare instances, to the development of cerebral edema, which is the leading cause of mortality in T1DM. Aside from the identification of several demographic and clinical risk factors for cerebral edema, attention has also been drawn to the possible link between systemic inflammation and neuroinflammation. This single-center retrospective study of 98 children with severe DKA aimed to investigate the possible relationship between neutrophil-to-lymphocyte ratio NLR) levels and the presence of cerebral edema. Patients were classified into three groups: alert (n = 28), subclinical cerebral edema (n = 59), and overt cerebral edema (n = 11). Lower blood pH and elevated NLR and blood urea were correlated with the presence of cerebral edema (p < 0.001). After a multivariable risk adjustment for possible confounding factors, such as age, pH, corrected sodium, and BUN, the NLR remained positively associated with cerebral edema (p = 0.045). As such, NLR may be an additional instrument to help practitioners target patients with a higher risk of severe cerebral edema. These patients would benefit from more rigorous neurologic surveillance, enabling the prompt identification of early signs of cerebral edema.

Diabetic ketoacidosis (DKA) is a common, serious acute complication in children with diabetes mellitus (DM). DKA can accompany new-onset type 1 insulin-dependent DM, or it can occur with established type 1 DM, during the increased demands of an acute illness or with decreased insulin delivery due to omitted doses or insulin pump failure. In addition, DKA episodes in children with type 2 DM are being reported with greater frequency. Although the diagnosis is usually straightforward in a known diabetes patient with expected findings, a sizable proportion of patients with new-onset DM present with DKA. The purpose of this comprehensive review is to acquaint clinicians with details regarding the pathophysiology, treatment caveats, and potential complications of DKA.

The incidence of pediatric diabetic ketoacidosis (DKA) increased during the peak of the COVID-19 pandemic. The objective of this study was to investigate whether rates of hyperosmolar therapy administration for suspected clinically apparent brain injury (CABI) complicating DKA also increased during this period as compared to the three years immediately preceding the pandemic and to compare the characteristics of patients with suspected CABI before the pandemic, patients with suspected CABI during the peak of the pandemic, and those with DKA but without suspected CABI during the pandemic. Patients aged ≤18 years presenting with DKA before (March 11, 2017-March 10, 2020) and during the peak of the pandemic (March 11, 2020-March 10, 2021) were identified through a rigorous search of two databases. Predefined criteria were used to diagnose suspected CABI. Biochemical, clinical, and sociodemographic data were collected from a comprehensive review of the electronic medical record. The proportion of patients with DKA who received hyperosmolar therapy was significantly higher (P = 0.014) during the pandemic compared to the prepandemic period; however, this was only significant among patients with newly diagnosed diabetes. Both groups with suspected CABI had more severe acidosis, lower Glasgow Coma Scale scores, and longer hospital admissions (P< 0.001 for all) than cases without suspected CABI. During the pandemic, the blood urea nitrogen concentration was significantly higher in patients with suspected CABI than those without suspected CABI, suggesting they were more severely dehydrated. The clinical, biochemical, and sociodemographic characteristics of patients with suspected CABI were indistinguishable before and during the pandemic. In conclusion, administration of hyperosmolar therapy for suspected CABI was more common during the peak of the COVID-19 pandemic, possibly a result of delayed presentation, highlighting the need for increased awareness and early recognition of the signs and symptoms of diabetes and DKA, especially during future surges of highly transmissible infections.

Cerebral edema (CE) remains one of the most feared complications of diabetic ketoacidosis (DKA) with severe morbidity and mortality. The use of computerized tomography (CT) scan in the setting of suspected cerebral edema in DKA has been minimally studied. The objective of our study was to evaluate the utility of CT scans in children with suspected cerebral edema, and secondarily to analyze the various patient characteristics of those with and without cerebral edema.

We performed a retrospective chart review of all the children with DKA secondary to T1DM admitted to our tertiary PICU in order to obtain demographic data, laboratory results, and their treatment course. Differences between the groups of suspected CE and no suspected CE were compared using linear and logistic regression for continuous and binary variables respectively.

We identified 251 patients with DKA, 12 of which had suspected CE; 67% (8/12) of those patients received head CT and 87.5% (7/8) of them were read as normal. On the other hand, 33% (4/12) did not receive CT scan of head, and yet three of the four patients were treated for CE.

In our cohort of patients, CT results did not influence CE treatment or lack thereof; most patients with suspected CE were treated with or without head CT findings of CE, indicating that imaging has very little utility in our cohort of patients. In some cases, the use of head CT delayed the onset of treatment for CE.

To compare clinical management and key outcomes of critically ill children with diabetic ketoacidosis (DKA) in two cohorts (2015 cohort: managed according to the 2015 British Society of Paediatric Endocrinology and Diabetes (BSPED) guidelines; 2020 cohort: managed according to the 2020 BSPED guidelines).

Retrospective cohort study using prospectively collected data.

A critical care advice and transport service based in London, and referring hospitals within the critical care network.

All children 0-17 years referred for advice and/or critical care transport with a clinical diagnosis of DKA over a 30-month period (from September 2018 to March 2021).

None.

Admission to intensive care unit (ICU), clinically diagnosed cerebral oedema and death.

There were significant differences in fluid and insulin administration practices between the 2015 and 2020 cohorts (fluid bolus >20 mL/kg: 3% vs 30%, p<0.001; median total fluid given in the first 24 hours: 84 mL/kg vs 117 mL/kg, p<0.01; starting insulin infusion rate 0.1 U/kg/hour: 54% vs 31%, p<0.01). However, these differences were consistent with guideline recommendations (initial fluid infusion rate within 5% of guideline-recommended rate: 80% in the 2015 group vs 84% in the 2020 group). There were no significant differences in outcomes (ICU admission: 26% vs 35%, p=0.2; cerebral oedema: 21% vs 23%, p=0.8).

Our study findings indicate that changes to fluid and insulin administration occurred after the 2020 BSPED guideline publication, with strong adherence to the guideline, but these changes were not associated with changes in key outcomes.

Suspected cerebral edema diabetic ketoacidosis (SCEDKA) is more common than perceived with symptoms including altered mentation, headache with vomiting, depressed Glasgow coma scale (GCS), abnormal motor or verbal responses, combativeness, and neurological depression. Suspected cerebral edema diabetic ketoacidosis has been associated with initial diabetic ketoacidosis (DKA) presentation and at start of DKA therapy.Cerebral oximetry (bihemispheric regional cerebral oxygen saturation [rcSO2] and cerebral blood volume index [CBVI]) can detect increased intracranial pressure (ICP)-induced altered bihemispheric cerebral physiology (rcSO2) (Crit Care Med 2006;34:2217-2223, J Pediatr 2013;163: 1111-1116, Curr Med Chem 2009;16:94-112, Diabetologia 1985;28:739-742, Pediatr Crit Care Med 2013;14:694-700). In pediatrics, rcSO2 of less than 60% or rcSO2 of greater than 85% reflects increased ICP and cerebral edema (Crit Care Med 2006;34:2217-2223, J Pediatr 2013;163: 1111-1116, Curr Med Chem 2009;16:94-112, Diabetologia 1985;28:739-742, Pediatr Crit Care Med 2013;14:694-700). Cerebral oximetry can detect increased ICP-induced altered bihemispheric cerebral physiology (rcSO2, CBVI) and cerebral physiological changes (rcSO2, CBVI changes) during therapeutic mechanical cerebral spinal fluid removal to decrease increased ICP (Crit Care Med 2006;34:2217-2223, J Pediatr 2013;163: 1111-1116, Curr Med Chem 2009;16:94-112, Diabetologia 1985;28:739-742, Pediatr Crit Care Med 2013;14:694-700).In the pediatric intensive care units, SCEDKA patients with nonbihemispheric cerebral oximetry showed an initial rcSO2 of greater than 90%. Bihemispheric rcSO2 with CBVI in SCEDKA patients has the potential to detect the abnormal cerebral physiology and disruptive autoregulation while detecting 3% hypertonic saline solution (HTS) effects on the SCEDKA altered cerebral physiology (rcSO2).

The purposes of this study were to analyze and compare 3% HTS effect on bihemispheric rcSO2 readings, neurological and biochemical parameters in SCEDKA with 3% HTS infusion to non-SCEDKA patients in pediatric emergency department (PED).

An observational retrospective comparative analysis study of bihemispheric rcSO2 readings, neurological and biochemical parameters in 2 groups of PED DKA patients were performed: PED DKA patients with SCEDKA +3% HTS infusions versus non-SCEDKA without 3% HTS infusions.

From 2008 to 2013, of the 1899 PED DKA patients, 60 SCEDKA patients received 3% HTS (5 mL/kg via peripheral intravenous) infusion (median age of 5 years [range, 3.7-7 years]), with 42 new DKA insulin dependent diabetes mellitus onset. Suspected cerebral edema diabetic ketoacidosis patients had GCS of 11 (range, 11-12), with consistent SCEDKA signs and symptoms (severe headaches with vomiting, confusion, blurred vision, altered speech, lethargy, and combativeness). Suspected cerebral edema diabetic ketoacidosis patients' initial (0-5 minutes) left rcSO2 readings were 91.4% (range, 88.4%-94.1%) and right was 90.3% (range, 88.6%-94.1%) compared with non-SCEDKA patients' left rcSO2 readings of 73.2% (range, 69.7%-77.8%) and right of 73.2% (range, 67.6%-77%) (P < 0.0001). The rcSO2 monitoring time before 3% HTS infusion was 54.9 minutes (range, 48.3-66.8 minutes) with 3% HTS time effect change: pre-3% HTS (54.9 minutes [range, 48.3-66.8 minutes]). Before 3% HTS infusion, the left rcSO2 readings were 90.0% (range, 89%-95%) and right was 91% (range, 86%-95%). The 30 to 45 minutes post-3% HTS showed that left was 64% (range, 62%-69%) and right was 65.4% (range, 63%-70%) (P < 0.0001). rcSO2 Δ change for post-3% HTS (0-20 minutes) to pre-3% HTS was as follows: left, -26.58 (-29.5 to -23.7) (P < 0.0001); right, -25.2 (-27.7 to -22.6) (P < 0.0001). Post-3% HTS GCS (14,15) and biochemistry compared with pre-3% HTS infusions all improved (P < 0.001).

In PED SCEDKA patients, the pre-3% HTS bihemispheric rcSO2 readings were greater than 90% and had lower GCS than non-SCEDKA patients. The post-3% HTS infusion rcSO2 readings showed within minutes a substantial reduction compared with non-SCEDKA patients, with no complications. Changes in rcSO2 readings after 3% HTS correlated with improved SCEDKA indicators (improved mental status, headache, and GCS) without any complications. We showed that cerebral oximetry in PED SCEDKA patients has shown an initial bihemispheric of greater than 90% readings signifying abnormal bihemispheric cerebral physiology. We also showed the cerebral oximetry's functionality in detecting 3% HTS therapeutic effects on SCEDKA's abnormal cerebral physiology and the beneficial therapeutic effects of 3% HTS infusion in SCEDKA patients. Using cerebral oximetry in pediatric DKA patients' initial cerebral assessment could have a significant impact in detecting SCEDKA patients. Further SCEDKA research using cerebral oximetry should be considered.

How to cite this article: Williams V, Mohandoss V. Portending Complications in Pediatric Diabetic Ketoacidosis. Indian J Crit Care Med 2021;25(12):1339-1340.

Hyperosmolar diabetic ketoacidosis (H-DKA), a distinct clinical entity, is the overlap of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS).

We describe the clinical presentation, metabolic aberrations, and associated morbidity/mortality of these cases with H-DKA. We highlight the problem areas of medical care which require particular attention when caring for pediatric diabetes patients presenting with H-DKA.

In our study we reviewed the literature back to 1963 and retrieved twenty-four cases meeting the criteria of H-DKA: glucose >600 mg/dL, pH < 7.3, bicarbonate <15 mEq/L, and serum osmolality >320 mOsm/kg, while adding three cases from our institution.

Average age of presentation of H-DKA was 10.2 years ± 4.5 years in females and 13.3 years ± 4 years in males, HbA1c was 13%. Biochemical parameters were consistent with severe dehydration: serum osmolality = 394.8±55 mOsm/kg, BUN = 48±22 mg/dL, creatinine = 2.81±1.03 mg/dL. Acute kidney injury, present in 12 cases, was the most frequent end-organ complication.

Multi-organ involvement with AKI, rhabdomyolysis, pancreatitis, neurological and cardiac issues such as arrhythmias, are common in H-DKA. Aggressive fluid management, insulin therapy and supportive care can prevent acute and long term adverse outcomes in children and adolescents.

Diabetic ketoacidosis (DKA) is a potentially life-threatening metabolic disorder that can occur with manifestation of type 1 diabetes mellitus (T1D). The aim of this study was to analyze the incidence of DKA at the time of the diagnosis of T1D in childhood and adolescence, the risk factors, and regional approaches to reduce the incidence of ketoacidosis.

We investigated the proportion of patients under 18 years of age with DKA (defined as pH <7.3, severe DKA pH <7.1) at the manifestation of T1D in Germany in the period 2000-2019, based on data from the German-Austrian registry of diabetes (Diabetes-Patienten-Verlaufsdokumentation, DPV). The influence of the following factors was evaluated: year of manifestation, age, sex, family history of migration (MiH), and distance from the hospital. Moreover, data from the region with and the region without a pilot screening project from 2015 onwards were compared.

Of the 41 189 patients with manifestation of T1D, 19.8% presented with DKA (n = 8154, slight increase [p <0.001] over the study period) and 6.1% (n = 2513) had severe DKA. Children under 6 years of age had DKA more often than adolescents (12-17 years) (21.7% versus 18.6%, OR 1.22 {95% CI: [1.14; 1.30]}). Girls had a higher rate of DKA than boys (20.5% versus 19.2%, OR 1.10 [1.03; 1.14]), and patients with MiH were more likely to have DKA than those without MiH (21.4% versus 18.2%, OR 1.40 [1.32; 1.48]). In the region with a pilot screening project, the DKA rate stayed the same, at 20.6%, while in the control region the rate was 22.7% with a decreasing tendency.

The frequency of DKA at the time of diagnosis of T1D did not decrease between 2000 and 2019 and increased towards the end of the observation period. Children with MiH, children under 6, and girls were at a higher risk of DKA.

Often thought to be a nutritional issue limited to low- and middle-income countries (LMICs), pediatric thiamine deficiency (PTD) is perceived as being eradicated or anecdotal in high-income countries (HICs). In HICs, classic beriberi cases in breastfed infants by thiamine-deficient mothers living in disadvantaged socioeconomic conditions are thought to be rare. This study aims to assess PTD in HICs in the 21st century. Literature searches were conducted to identify case reports of PTD observed in HICs and published between 2000 and 2020. The analyzed variables were age, country, underlying conditions, clinical manifestations of PTD, and response to thiamine supplementation. One hundred and ten articles were identified, totaling 389 PTD cases that were classified into four age groups: neonates, infants, children, and adolescents. Eleven categories of PTD-predisposing factors were identified, including genetic causes, lifestyle (diabetes, obesity, and excessive consumption of sweetened beverages), eating disorders, cancer, gastrointestinal disorders/surgeries, critical illness, and artificial nutrition. TD-associated hyperlactatemia and Wernicke encephalopathy were the most frequent clinical manifestations. The circumstances surrounding PTD in HICs differ from classic PTD observed in LMICs and this study delineates its mutiple predisposing factors. Further studies are required to estimate its magnitude. Awareness is of utmost importance in clinical practice.

Fluid and electrolyte therapy in childhood diabetic ketoacidosis (DKA) management has been controversial. Previous National Institute for Health and Care Excellence (NICE) 2015 guidance advocated a restricted fluid regimen while more recent guidelines have advocated a more liberal approach to fluid replacement in DKA. At the core of the debate is the need to avoid developing cerebral oedema as a complication. Although subtle asymptomatic cerebral oedema is common in children presenting in DKA, clinically apparent cerebral oedema is rare and has been reported in approximately 0.5%-1% of DKA cases in children. Recent research evidence has shown that there was no clear evidence of a difference in rates of clinically apparent cerebral injury in children in DKA managed with a range of fluid volumes and rates of rehydration. In view of this, NICE has updated its guideline. In this paper, we review literature evidence underpinning the current understanding of the pathophysiology of cerebral oedema in children and discuss the rationale for the new NICE guidance.

Diabetic ketoacidosis (DKA) is a serious complication of complete insulin deficiency and insulin resistance in Type 1 diabetes (T1D). This results in the body producing high levels of serum ketones in an attempt to compensate for the insulin deficiency and decreased glucose utilization. DKA's metabolic and immunologic dysregulation results in gradual increase of systemic and cerebral oxidative stress, along with low grade systemic and cerebral inflammation and the development of pretreatment subclinical BE. During treatment the early progression of oxidative stress and inflammation is hypothesized to advance the possibility of occurrence of crisis of clinical brain edema (BE), which is the most important cause of morbidity and mortality in pediatric DKA. Longitudinal neurocognitive studies after DKA treatment show progressive and latent deficits of cognition and emphasize the need for more effective DKA treatment of this long-standing conundrum of clinical BE, in the presence of systemic osmotic dehydration, metabolic acidosis and immune dysregulation. Candidate biomarkers of several systemic and neuroinflammatory pathways prior to treatment also progress during treatment, such as the neurotoxic and neuroprotective molecules in the well-recognized tryptophan (TRP)/kynurenine pathway (KP) that have not been investigated in DKA. We used LC-MS/MS targeted mass spectrometry analysis to determine the presence and initiation of the TRP/KP at three time points: A) 6-12 hours after initiation of treatment; B) 2 weeks; and C) 3 months following DKA treatment to determine if they might be involved in the pathogenesis of the acute vasogenic complication of DKA/BE. The Trp/KP metabolites TRP, KYN, quinolinic acid (QA), xanthurnenic acid (XA), and picolinic acid (PA) followed a similar pattern of lower levels in early treatment, with subsequent increases. Time point A compared to Time points B and C were similar to the pattern of sRAGE, lactate and pyruvic acid. The serotonin/melatonin metabolites also followed a similar pattern of lower quantities at the early stages of treatment compared to 3 months after treatment. In addition, glutamate, n-acetylglutamate, glutamine, and taurine were all lower at early treatment compared to 3 months, while the ketones 3-hydroxybutaric acid and acetoacetate were significantly higher in the early treatment compared to 3 months. The two major fat metabolites, L-carnitine and acetyl-L-carnitine (ALC) changed inversely, with ALC significantly decreasing at 2 weeks and 3 months compared to the early stages of treatment. Both anthranilic acid (AA) and 3-OH-anthranilic acid (3OH-AA) had overall higher levels in the early stages of treatment (A) compared to Time points (B and C). Interestingly, the levels of AA and 3OH-AA early in treatment were higher in Caucasian females compared to African American females. There were also differences in the metabolite levels of QA and kynurenic acid (KA) between genders and between races that may be important for further development of custom targeted treatments. We hypothesize that the TRP/KP, along with the other inflammatory pathways, is an active participant in the metabolic and immunologic pathogenesis of DKA's acute and chronic insults.

Bedside sonographic assessment of the optic nerve sheath has gained popularity for evaluating intracranial pressure in recent years.

To investigate the bedside sonographic measurements of optic nerve sheath diameter (ONSD) and ONSD/eyeball diameter ratios, which are related with cerebral edema (CE), in children with diabetic ketoacidosis (DKA) before and after treatment.

Children aged 12 months to 18 years, who were diagnosed with DKA were included. The ONSD was measured at 3 mm posterior to the globe in the anterior axial transbulbar view. The eyeball transverse diameter (ETD) and eyeball vertical diameter (EVD) were measured and ratios of ONSD/ETD and ONSD/EVD were calculated. Bedside ultrasound (US) examinations were performed at the beginning and at the end of fluid therapy.

About 43 patients were enrolled. About 12 (27.9%) patients had mild, 14 (32.6%) moderate, and 17 (39.5%) severe DKA. At baseline, the ONSD measurements and ratios were significantly higher in severe DKA group than in those with mild or moderate DKA group. All ONSD measurements, ONSD/ETD, and ONSD/EVD ratios at the end of therapy were significantly lower compared with baseline measurements. At the end of therapy, ONSD measurements and ratios were similar among DKA severity groups.

The ONSD measurements and ratios decreased from the beginning of DKA treatment, which could be considered as an indicator of an increase in intracranial pressure at the time of admission. Ocular US may serve as a promising tool to perform further risk stratification of children with DKA and to identify DKA-related CE.

Cerebral edema (CE) is a potentially devastating complication of diabetic ketoacidosis (DKA) that almost exclusively occurs in children. Since its first description in 1936, numerous risk factors have been identified; however, there continues to be uncertainty concerning the mechanisms that lead to its development. Currently, the most widely accepted hypothesis posits that CE occurs as a result of ischemia-reperfusion injury, with inflammation and impaired cerebrovascular autoregulation contributing to its pathogenesis. The role of specific aspects of DKA treatment in the development of CE continues to be controversial. This review critically examines the literature on the pathophysiology of CE and attempts to categorize the findings by types of brain injury that contribute to its development: cytotoxic, vasogenic, and osmotic. Utilizing this scheme, we propose a multifactorial pathway for the development of CE in patients with DKA.

Acute kidney injury (AKI) occurs commonly during diabetic ketoacidosis (DKA) in children, but the underlying mechanisms and associations are unclear.

To investigate risk factors for AKI and its association with neurocognitive outcomes in pediatric DKA.

This cohort study was a secondary analysis of data from the Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation in DKA Study, a prospective, multicenter, randomized clinical trial comparing fluid protocols for pediatric DKA in 13 US hospitals. Included DKA episodes occurred among children age younger than 18 years with blood glucose 300 mg/dL or greater and venous pH less than 7.25 or serum bicarbonate level less than 15 mEq/L.

DKA requiring intravenous insulin therapy.

AKI occurrence and stage were assessed using serum creatinine measurements using Kidney Disease: Improving Global Outcomes criteria. DKA episodes with and without AKI were compared using univariable and multivariable methods, exploring associated factors.

Among 1359 DKA episodes (mean [SD] patient age, 11.6 [4.1] years; 727 [53.5%] girls; 651 patients [47.9%] with new-onset diabetes), AKI occurred in 584 episodes (43%; 95% CI, 40%-46%). A total of 252 AKI events (43%; 95% CI, 39%-47%) were stage 2 or 3. Multivariable analyses identified older age (adjusted odds ratio [AOR] per 1 year, 1.05; 95% CI, 1.00-1.09; P = .03), higher initial serum urea nitrogen (AOR per 1 mg/dL increase, 1.14; 95% CI, 1.11-1.18; P < .001), higher heart rate (AOR for 1-SD increase in z-score, 1.20; 95% CI, 1.09-1.32; P < .001), higher glucose-corrected sodium (AOR per 1 mEq/L increase, 1.03; 95% CI, 1.00-1.06; P = .001) and glucose concentrations (AOR per 100 mg/dL increase, 1.19; 95% CI, 1.07-1.32; P = .001), and lower pH (AOR per 0.1 increase, 0.63; 95% CI, 0.51-0.78; P < .001) as variables associated with AKI. Children with AKI, compared with those without, had lower scores on tests of short-term memory during DKA (mean [SD] digit span recall: 6.8 [2.4] vs 7.6 [2.2]; P = .02) and lower mean (SD) IQ scores 3 to 6 months after recovery from DKA (100.0 [12.2] vs 103.5 [13.2]; P = .005). Differences persisted after adjusting for DKA severity and demographic factors, including socioeconomic status.

These findings suggest that AKI may occur more frequently in children with greater acidosis and circulatory volume depletion during DKA and may be part of a pattern of multiple organ injury involving the kidneys and brain.

Cognitive decline is common in patients with type 1 diabetes and has been attributed to the effects of chronic hyperglycemia and severe hypoglycemia. Diabetic ketoacidosis (DKA) has only recently been suspected to be involved in causing cognitive decline. We hypothesized that DKA triggers both acute and chronic neuroinflammation, contributing to brain injury.

We measured concentrations of cytokines, chemokines and matrix metalloproteinases (MMP) in serum and brain tissue lysates in juvenile rats during and after DKA (during acute DKA, 24 hours and 7 days after DKA), and compared these to healthy controls and hyperglycemic controls. We also measured cytokine, chemokine and MMP concentrations in serum and brain tissue of adult rats (70 days) that had experienced DKA as juveniles and compared these measurements to those of adult diabetic rats without exposure to DKA.

During acute DKA in the juvenile rats, serum concentrations of CCL3, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and MMP-9 were significantly increased. Serum concentrations of IL-2 and IL-17A increased 7 days after DKA recovery. In brain tissue lysates, concentrations of CCL3, CCL5, interferon (IFN)-γ and MMP-9 were significantly elevated during acute DKA. In adult rats that had DKA as juveniles (28 days previously), serum concentrations of IL-1ß and brain concentrations of IL-10 and IL-12p70 were elevated in comparison to diabetic rats without prior DKA. Composite scores for highly correlated cytokines and chemokines (mean z-scores for IL-10, IL-1ß, TNF-α, IL-17A, IFN-γ, CXCL-1 and CCL5) were also significantly elevated in adult rats with prior DKA.

These data confirm that DKA causes acute systemic inflammation and neuroinflammation in a rat model. Importantly, the neuroinflammatory response triggered by DKA is long-lasting, suggesting the possibility that DKA-induced chronic neuroinflammation could contribute to long-term cognitive decline in individuals with diabetes.

This study assessed whether a single diabetic ketoacidosis (DKA) episode is associated with cognitive declines in children with newly diagnosed type 1 diabetes and whether the same is true in children who had previously been diagnosed after accounting for variations in glycemic control and other relevant factors.

We prospectively enrolled 758 children, 6-18 years old, who presented with DKA in a randomized multisite clinical trial evaluating intravenous fluid protocols for DKA treatment. DKA was moderate/severe in 430 children and mild in 328 children. A total of 392 children with DKA had new onset of type 1 diabetes, and the rest were previously diagnosed. Neurocognitive assessment occurred 2-6 months after the DKA episode. A comparison group of 376 children with type 1 diabetes, but no DKA exposure, was also enrolled.

Among all patients, moderate/severe DKA was associated with lower intelligence quotient (IQ) (β = -0.12, P < 0.001), item-color recall (β = -0.08, P = 0.010), and forward digit span (β = -0.06, P = 0.04). Among newly diagnosed patients, moderate/severe DKA was associated with lower item-color recall (β = -0.08, P = 0.04). Among previously diagnosed patients, repeated DKA exposure and higher HbA_1c were independently associated with lower IQ (β = -0.10 and β = -0.09, respectively, P < 0.01) and higher HbA_1c was associated with lower item-color recall (β = -0.10, P = 0.007) after hypoglycemia, diabetes duration, and socioeconomic status were accounted for.

A single DKA episode is associated with subtle memory declines soon after type 1 diabetes diagnosis. Sizable IQ declines are detectable in children with known diabetes, suggesting that DKA effects may be exacerbated in children with chronic exposure to hyperglycemia.

Diabetic ketoacidosis (DKA) is the end result of insulin deficiency in type 1 diabetes mellitus (T1D). Loss of insulin production leads to profound catabolism with increased gluconeogenesis, glycogenolysis, lipolysis, and muscle proteolysis causing hyperglycemia and osmotic diuresis. High levels of counter-regulatory hormones lead to enhanced ketogenesis and the release of 'ketone bodies' into the circulation, which dissociate to release hydrogen ions and cause an overwhelming acidosis. Dehydration, hyperglycemia, and ketoacidosis are the hallmarks of this condition. Treatment is effective repletion of insulin, fluids and electrolytes. Newer approaches to early diagnosis, treatment, and prevention may diminish the risk of DKA and its childhood complications including cerebral edema. However, the potential for some technical and pharmacologic advances in the management of T1D to increase DKA events must be recognized.

To characterize hemodynamic alterations occurring during diabetic ketoacidosis (DKA) in a large cohort of children and to identify clinical and biochemical factors associated with hypertension.

This was a planned secondary analysis of data from the Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation in DKA Study, a randomized clinical trial of fluid resuscitation protocols for children in DKA. Hemodynamic data (heart rate, blood pressure) from children with DKA were assessed in comparison with normal values for age and sex. Multivariable statistical modeling was used to explore clinical and laboratory predictors of hypertension.

Among 1258 DKA episodes, hypertension was documented at presentation in 154 (12.2%) and developed during DKA treatment in an additional 196 (15.6%), resulting in a total of 350 DKA episodes (27.8%) in which hypertension occurred at some time. Factors associated with hypertension at presentation included more severe acidosis, (lower pH and lower pCO₂), and stage 2 or 3 acute kidney injury. More severe acidosis and lower Glasgow Coma Scale scores were associated with hypertension occurring at any time during DKA treatment.

Despite dehydration, hypertension occurs in a substantial number of children with DKA. Factors associated with hypertension include greater severity of acidosis, lower pCO_2, and lower Glasgow Coma Scale scores during DKA treatment, suggesting that hypertension might be centrally mediated.

Diabetic Ketoacidosis (DKA) is one of the most commonly encountered diabetic complication emergencies. It typically affects people with type 1 diabetes at the onset of the disease. It can also affect people with type 2 diabetes, although this is uncommon.

Research and online content related to diabetes online activity is reviewed. DKA is caused by a relative or absolute deficiency of insulin and elevated levels of counter-regulatory hormones.

Goals of therapy are to correct dehydration, acidosis, and to reverse ketosis, gradually restoring blood glucose concentration to near normal.

It is essential to monitor potential complications of DKA and, if necessary, to treat them and any precipitating events.

To determine the time relationships of soluble receptor for glycation end-products (sRAGE), [a decoy of the advanced glycation end-products (AGE)-RAGE axis] and D-lactate, (a metabolite of methylglyoxal) in the inflammatory response to diabetic ketoacidosis (DKA).

Sixteen children and adolescents with type 1 diabetes (T1D) had blood samples obtained, 6-12 hours into treatment, at three weeks and three months post start of treatment. sRAGE and D-lactate concentrations at three months were considered baseline. Expression of RAGE was investigated in the myocardium of a newly diagnosed and untreated young person with fatal T1D/DKA.

sRAGE 6-12 hours after the start of treatment was 39% lower than the values at two weeks (p=0.0036) and at three months (p=0.0023) post treatment. D-lactate was higher during treatment than at three weeks (p=0.04) and at three months (p=0.035).

sRAGE concentration was decreased during treatment, compared to concentrations at two weeks and three months after treatment. The increased D-lactate during treatment was in keeping with the known increase in dicarbonyls at this time. The finding of RAGE expression in a young myocardium prior to DKA treatment suggested cardiovascular inflammation pre-treatment and at a young age.

Diabetic ketoacidosis (DKA) is a serious complication of diabetes. DKA is associated with poorer cognition in children with type 1 diabetes (T1D), but whether this is the case in older adults with T1D is unknown. Given the increasing life expectancy in T1D, understanding the role of DKA on brain health in older adults is crucial.

We examined the association of DKA with cognitive function in 714 older adults with T1D from the Study of Longevity in Diabetes. Participants self-reported lifetime exposure to DKA resulting in hospitalization; DKA was categorized into 0 hospitalization, 1 hospitalization or ≥2 hospitalizations (recurrent DKA). Global and domain-specific cognition (language, executive function/psychomotor speed, episodic memory and simple attention) were assessed. The association of DKA with cognitive function was evaluated via linear and logistic regression models.

Twenty-eight percent of participants (mean age=67 years; mean age at diagnosis=28 years; average duration of diabetes=39 years) reported a lifetime history of DKA resulting in hospitalization (18.5% single DKA; 9.7% recurrent DKA). In fully adjusted models, those with recurrent DKA had lower global cognitive function (β=-0.13; 95% CI -0.22 to 0.02) and lower scores on the executive function/psychomotor speed domain (β=-0.34; 95% CI -0.51 to 0.17). Individuals with recurrent DKA were also more likely to have the lowest level of cognitive function on the executive function/psychomotor speed domain (defined as 1.5 SD below the population mean; OR=3.26, 95% CI 1.43 to 7.42).

Among 714 older adults with T1D, recurrent DKA was associated with lower global cognitive function, lower scores on the executive function/psychomotor speed domain and 3.3 times greater risk of having the lowest level of cognitive function in our sample on the executive function/psychomotor speed domain. These findings suggest that recurrent DKA may negatively impact the brain health of older patients with T1D and highlight the importance of DKA prevention.

Diabetic ketoacidosis (DKA) in patients with type 1 diabetes mellitus (T1DM) is known to affect memory function, but little is known about its impact on executive function. This study aimed to determine whether a history of DKA was associated with changes in executive function in children with T1DM.

The sample consisted of 99 patients with T1DM with histories of DKA, 82 patients with T1DM without DKA, and 100 healthy controls aged 7 to 18 years. Neuropsychological function and emotion assessments were performed in all participants. The Wisconsin Card Sorting Test (WCST) was used to assess executive function.

Compared with healthy controls, the DKA group (but not the non-DKA group) had a significantly lower mean intelligence quotient (IQ; p = .006, Cohen d = 0.528) and a significantly higher rate of WCST perseverative errors (p = .006, Cohen d = 0.475). In the DKA group, the age at DKA onset was significantly associated with the IQ (p = .001) and the number of completed WCST categories (p = .046). Higher hemoglobin A1c levels were associated significantly with lower IQ (p < .001), increased rate of WCST perseverative errors (p = .015), and completion of fewer WCST categories (p = .027).

DKA has implications for executive function in children with T1DM. These findings emphasize the importance of DKA prevention in patients with known T1DM, especially younger children with newly diagnosed T1DM.

Neuron-specific enolase (NSE) and S100 calcium-binding protein B (S100B) are markers of different neurological disorders. The aim was to investigate the relationship between NSE and S100B serum concentrations and the severity of diabetic ketoacidosis (DKA) in diabetic children.

Eighty children with DKA, 40 with type 1 diabetes mellitus (T1DM) without DKA and 40 healthy controls were enrolled. Severity of DKA was assessed according to blood pH and bicarbonate concentration. Serum NSE and S100B were measured in all participants. In the DKA group serum NSE and S100B were measured at three time points, at admission and at 12 hours and 24 hours after starting treatment.

Children with DKA showed significantly higher serum levels of NSE at all time points compared to children with T1DM without DKA and controls (p<0.01), while serum S100B concentrations did not differ between the three cohorts. Children with T1DM but without DKA also had significantly higher serum levels of NSE (p<0.01) compared to healthy controls. Patients with low Glasgow Coma Scale score (GCSS) and those with moderate and severe DKA had significantly higher levels of NSE at all time points (p<0.01 for each) compared to patients with normal GCSS and those with mild DKA. No significant differences were found in serum S100B levels according to the severity of DKA and GCS (p>0.05). Younger age, lower GCSS, higher glucose and HbA1c, lower pH and lower serum bicarbonate were the risk factors associated with elevated NSE.

Serum NSE is elevated in all patients with type 1 DM and, in patients with DKA, correlates with severity of DKA. However, serum S100B concentration did not differ between T1DM with or without DKA and healthy controls.

Background Cerebral edema is a fatal complication that can occur in children with diabetic ketoacidosis (DKA). Its clinical signs are generally not explicit, and subclinical cerebral edema can occur. This study is one of the few longitudinal studies conducted to identify cerebral edema in patients with DKA by measuring the optic nerve sheath diameter (ONSD). The aim of this study was to investigate cerebral edema in children with DKA with serial measurement of ONSD, which is an early and reliable indicator of cerebral edema, and to monitor changes in ONSD during therapy. Methods The study was conducted by measuring ONSD ultrasonographically at baseline and during the course of therapy in patients with DKA. All participants were diagnosed and received therapy at our unit between May 2016 and June 2017. The study was registered with the Clinical Trials database, with a study number of NCT02937441. Measurements were obtained while the patients were in the supine position with their eyes closed, and axial transbulbar images of both eyes were obtained with a 6-15-MHz linear probe. Results The ONSD values of children with DKA changed during the treatment, reaching the highest values at 12-16 h of therapy, and the greatest ONSD was observed in children who had moderate and severe DKA. Conclusions During treatment of children with DKA, it is possible to predict cerebral edema by measuring ONSD, and this may contribute to clinical management, especially fluid treatment.

Cerebral edema (CE) is a rare but potentially fatal complication of diabetic ketoacidosis (DKA) in children with type 1 diabetes. CE is frequently mentioned as being more common in young children. The primary objective of this study was to review the evidence suggesting that younger age is a risk factor for the development of CE during DKA. The secondary objective was to assess if younger children are at a higher risk of DKA and severe DKA. A literature review was performed, and studies which reported the frequency of CE, DKA and severe DKA in children <3 and 3 to 5 years of age were included. Among the 6 studies reporting the frequency of CE that were identified, 5 good-quality studies found no significant association between younger age and higher risk of CE. Twenty-seven studies (DKA frequency: 11.3% to 54%) reported DKA frequency as a function of age. Most published studies found a higher frequency of DKA in children <5 years of age (20/25 studies), and in particular in those in the first 2 to 3 years of life (8/8 studies). There was inconclusive evidence to determine whether the severity of DKA was influenced by age. In conclusion, the commonly held view that CE is more common in younger children is not supported by the existing literature. Published data suggest that DKA (and possibly severe DKA) is more common in very young children. Regardless of age, all children with DKA should be monitored carefully for the development of CE.

The optimal fluid treatment protocol for children with diabetic ketoacidosis (DKA) has long been a subject of controversy. Until recently, there was no high-quality evidence from randomized clinical trials to support an optimal guideline, and recommendations were mainly based on theoretical considerations. As a consequence, fluid treatment protocols for children with DKA vary between institutions (and countries). In June 2018, the results from the Fluid Therapies Under Investigation in DKA Trial conducted in the Pediatric Emergency Care Applied Research Network were published. This large, factorial-designed randomized controlled trial assessed neurological outcomes of 1387 children with DKA who were treated with one of four fluid protocols that varied in infusion rate and sodium content. In this commentary, we review and discuss the results of this new study and the implications for clinical care of DKA in children.

Subclinical cerebral edema in diabetic ketoacidosis tends to manifest with subtle neurological symptoms including headache, lethargy, or disorientation and a Glasgow Coma Scale of 14-15. Treatment of subclinical cerebral edema with hyperosmolar therapy for persistent symptoms is associated with good outcomes.

Diabetic ketoacidosis (DKA) is one of the most common causes of morbidity and mortality in new onset type 1 diabetes mellitus (T1DM). Children have a higher rate of neurological complications from DKA when compared to adults. The differential for sudden focal neurological deterioration in the setting of DKA is cerebral oedema followed by ischaemic and haemorrhagic stroke. Spontaneous intracranial haemorrhages can present with non-specific features frequently, for example, impaired consciousness, even when biochemical parameters are improving in the setting of DKA. We report the case of a girl with new onset T1D who presented in severe DKA and subsequently developed intracerebral parenchymal and subarachnoid haemorrhages. Our patient is unique in that no focal neurological or neuropsychological deficits have been found at 1-year follow up, compared to the literature which suggests poor outcomes. Our case contrasts with these previous cases as none of the other case reports demonstrated subarachnoid haemorrhages with survival.

Some patients with diabetic ketoacidosis develop cerebral edema (CE) in the course of type 1 diabetes mellitus (T1D), which may result in central nervous system disorders and high mortality. The imperfection of existing neuroimaging techniques for early recognition of CE forces us to search for the new and non-invasive methods. The aim of the study was to assess the usefulness of new methods (pachymetry, transorbital ultrasonography-USG, optical coherence tomography-OCT study) in the assessment of the risk of CE occurrence in children with newly diagnosed T1D.

The study group included 50 children with newly diagnosed T1D, 54 patients with long-term T1D as a reference group and 40 children without glucose tolerance disorders as controls. In all subjects, a corneal thickness (CCT) index with pachymeter, optic nerve sheath diameter (ONSD) using transorbital USG and retinal nerve fiber layer (RNFL) during OCT study were measured and compared with selected clinical parameters of T1D.

In patients from a study group at onset of T1D, the higher CCT (p < 0.001) and ONSD (p < 0.001) values were observed as compared to the results obtained after 48 h of metabolic compensation. The ONSD correlated negatively with pH value (r = - 0.64; p < 0.001), BE (r = - 0.54, p < 0.001) and HCO^3- (r = - 0.50; p < 0.001). A positive correlation between RNFL and Na⁺ levels (r = 0.47; p < 0.005) was also observed.

Transorbital USG and pachymetry may serve as the potential promising methods for the non-invasive assessment of the increased risk of development of CE in patients with T1D.

Brain injury in diabetic ketoacidosis (DKA) is common but under recognized and affects up to 54% of patients with this complication. It's manifestations include cerebral oedema (CE) and cerebral infarction (CI). The etiology of CE in DKA has up to the present time been uncertain. Practical management had been guided by the assumption that rapid osmotic shifts due to rapid correction of hypovolemia and reduction of plasma glucose could cause a shift of water into the cells. The osmotic effect of glucose can cause inflammation by activation of inflammasomes. Recently it has been recognized that the body is in a pro-inflammatory state during DKA involving interleukin-1 production by inflammasomes. Interleukin-1 has been involved in the pathogenesis of cerebral oedema and CI.

In diabetic ketoacidosis brain injury including cerebral oedema and infarction is caused by interleukin-1.

Inflammasome activity could be quantified in peripheral blood mononuclear cells and in patients with and without clinical and/or subclinical CE and/or stroke or features of cerebral ischemia on MRI. Surrogates of brain injury in peripheral blood like neuron specific enolase could be measured and correlated with inflammasome activity. Interleukin-1 receptor antagonists and inflammasome inhibitors including telmisartan could be assessed in their effect on MRI changes consistent with CE or CI in patients with DKA in randomised placebo-controlled trials.

To investigate serum levels of brain injury markers in diabetic ketoacidosis (DKA) and the relation of these markers with clinical and radiological findings of brain injury and laboratory results.

Twenty-nine patients with DKA, 30 with type 1 diabetes mellitus (T1DM), and 35 healthy children were included. Clinical and laboratory findings, and the Glasgow Coma Scale (GCS) were recorded. In the DKA group, neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B) and glial fibrillary acidic protein (GFAP) levels were measured at baseline and 6 and 12 hours after treatment. Magnetic resonance imaging was performed in the DKA group to demonstrate any brain injury.

No clinical or radiological findings of brain injury were found in any of the patients with DKA. In the DKA group, S100B was significantly higher than the healthy control and T1DM groups, while GFAP and NSE levels were not different from controls and T1DM patients. No significant differences were found in GFAP, NSE and S100B levels according to severity of DKA, diabetes duration and GCS.

NSE and GFAP levels do not increase in DKA patients without overt brain injury. Elevated levels of S100B, which is also synthesized from non-neuronal tissues, might arise from peripheral sources. A lack of concurrent increase in serum levels of these brain injury markers might result from the yet intact blood brain barrier or a true absence of neuronal damage. In order to reveal subclinical brain injury related to DKA, there is a need for studies concurrently assessing neurocognitive functions.

This study examines temporal trends in treatment-related outcomes surrounding a diabetic ketoacidosis (DKA) performance improvement intervention consisting of mandated intensive care unit admission and implementation of a standardized management pathway, and identifies physical and biochemical characteristics associated with outcomes in this population.

A retrospective cohort of 1225 children with DKA were identified in the electronic health record by international classification of diseases codes and a minimum pH less than 7.3 during hospitalization at a quaternary children's hospital between April, 2009 and May, 2016. Multivariable regression examined predictors and trends of hypoglycemia, central venous line placement, severe hyperchloremia, head computed tomography (CT) utilization, treated cerebral edema and hospital length of stay (LOS).

The incidence of severe hyperchloremia and head CT utilization decreased during the study period. Among patients with severe DKA (presenting pH < 7.1), the intervention was associated with decreasing LOS and less variability in LOS. Lower pH at presentation was independently associated with increased risk for all outcomes except hypoglycemia, which was associated with higher pH. Patients treated for cerebral edema had a lower presenting mean systolic blood pressure z score (0.58 [95% confidence interval (CI) -0.02-1.17] vs 1.23 [1.13-1.33]) and a higher maximum mean systolic blood pressure (SBP) z score during hospitalization (3.75 [3.19-4.31] vs 2.48 [2.38-2.58]) compared to patients not receiving cerebral edema treatment. Blood pressure and cerebral edema remained significantly associated after covariate adjustment.

Treatment-related outcomes improved over the entire study period and following a performance improvement intervention. The association of SBP with cerebral edema warrants further study.