Cerebral Edema In Diabetic Ketoacidosis Research Articles

Severe diabetic ketoacidosis complicated with severe dyslipidemia, cerebral edema and acute kidney injury in a pediatric girl with type 1 diabetes mellitus: a case study

Diabetic ketoacidosis (DKA) is a life-threatening acute metabolic complication occurring in patients with type 1 diabetes, due to an insulin deficiency. Moderate hypertriglyceridemia is commonly observed in DKA but severe hypertriglyceridemia with a triglyceride level exceeding 10 g/l is very rarely reported. Acute kidney injury (AKI) is a serious condition which still carries a mortality of around 50%. Cerebral edema is a devastating complication of DKA which is leading cause of diabetes-related death in the pediatric population. Newly diagnosed diabetes, younger age, first episode of DKA, severity of DKA at presentation, and administration of bicarbonate are predictive of cerebral edema in DKA. We present a case of 8-year-old girl who presented with severe DKA, whose clinical course was complicated by renal failure, severe dyslipidemia and cerebral edema.

Utility of head CT scan in treatment decisions for suspected cerebral edema in children with DKA.

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.

Acute respiratory distress syndrome in a case of diabetic ketoacidosis requiring ECMO support.

SummaryAcute respiratory distress syndrome (ARDS) is a rare but life-threatening complication of diabetic ketoacidosis (DKA). We present the case of a young female, with no previous diagnosis of diabetes, presenting in DKA complicated by ARDS requiring extra corporeal membrane oxygenation (ECMO) ventilator support. This case report highlights the importance of early recognition of respiratory complications of severe DKA and their appropriate management.Learning pointsARDS is a very rare but life-threatening complication in DKA.The incidence of ARDS remains unknown but less frequent than cerebral oedema in DKA.The mechanism of ARDS in DKA has multifactorial aetiology, including genetic predisposition.Early recognition and consideration of rare pulmonary complication of DKA can increase survival rate and provide very satisfactory outcomes.DKA patients who present with refractory ARDS can be successfully rescued by ECMO support.

Cerebral Oedema in Diabetic Ketoacidosis

Cerebral oedema in diabetic ketoacidosis (CODKA) is a controversial subject both in medical and forensic practice as well as in the specialized literature, in the light of the non-homogeneous theories regarding the pathophysiological mechanisms. It would seem that the ground of CEDKA would be a combination/fusion of processes that affect both metabolic changes in diabetic ketoacidosis (DKA) and aggressive therapy to combat DKA. This article wants to underline the importance of knowing and deepening the pathophysiological mechanism that leads to the installation of cerebral oedema (CO) in DKA, focusing on the potential of the thanatogenerator mechanism.

Factors Associated With Cerebral Edema at Admission in Indian Children with Diabetic Ketoacidosis

To evaluate the time course and predictors of cerebral edema in diabetic ketoacidosis (DKA). Review of hospital records of 107 episodes of DKA between January 2013 to March 2019. Cerebral edema was identified in 26 (24.3%; 22 at presentation and 4 during treatment). Cerebral edema at presentation was associated with lower (<10 mmHg) arterial carbon dioxide (OR 3.6, 95% CI 1.0,12.7; P=0.04), prior fluid treatment (OR 4.7, 95% CI 1.8,12.7; P=0.001) and new onset diabetes (OR 3.5, 95% CI 1.1,11.1; P=0.03). Prior fluid was the only significant predictor on multivariate analysis (P=0.013). Cerebral edema resulted in a longer ICU stay [4.1 (2.3) vs 1.8 (0.9) d; P<0.001]. Cerebral edema at admission is common in Indian children with DKA and should be suspected with severe metabolic acidosis and inappropriate prior fluid treatment.

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

BackgroundBrain 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. HypothesisIn diabetic ketoacidosis brain injury including cerebral oedema and infarction is caused by interleukin-1. Confirmation of hypothesis and implicationsInflammasome 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.

Emergency Medicine Myths: Cerebral Edema in Pediatric Diabetic Ketoacidosis and Intravenous Fluids

BackgroundPediatric diabetic ketoacidosis (DKA) is a disease associated with several complications that can be severe. One complication includes cerebral edema (CE), and patients may experience significant morbidity with this disease. ObjectiveThis review evaluates the myths concerning CE in pediatric DKA including mechanism, presentation of edema, clinical assessment of dehydration, and association with intravenous (i.v.) fluids. DiscussionMultiple complications may occur in pediatric DKA. CE occurs in < 1% of pediatric DKA cases, though morbidity and mortality are severe without treatment. Several myths surround this disease. Subclinical CE is likely present in many patients with pediatric DKA, though severe disease is rare. A multitude of mechanisms likely account for development of CE, including vasogenic and cytotoxic causes. Clinical dehydration is difficult to assess. Literature has evaluated the association of fluid infusion with the development of CE, but most studies are retrospective, with no comparator groups. The few studies with comparisons suggest fluid infusion is not associated with DKA. Rather, the severity of DKA with higher blood urea nitrogen and greater acidosis contribute to CE. Multiple strategies for fluid replacement exist. A bolus of 10 mL/kg of i.v. fluid is likely safe, which can be repeated if hemodynamic status does not improve. ConclusionsPediatric CE in DKA is rare but severe. Multiple mechanisms result in this disease, and many patients experience subclinical CE. Intravenous fluids are likely not associated with development of CE, and 10-mL/kg or 20-mL/kg i.v. bolus is safe.

Suspected Cerebral Edema in Diabetic Ketoacidosis: Is There Still a Role for Head CT in Treatment Decisions?

Neurologic deterioration associated with cerebral edema in diabetic ketoacidosis is typically sudden in onset, progresses rapidly, and requires emergent treatment. The utility of brain imaging by head CT in decisions to treat for cerebral edema has not been previously studied. The objective of this study was to describe the characteristics of pediatric patients with diabetic ketoacidosis who develop altered mental status and evaluate the role of head CT in this cohort. Retrospective analysis of clinical, biochemical, and radiologic data. Tertiary care children's hospital (2004-2010). Six hundred eighty-six admissions of patients (< 26 yr) with diabetic ketoacidosis. None. Altered mental status was documented during 96 of 686 diabetic ketoacidosis admissions (14%). Compared with alert patients, those with altered mental status were younger (median, 12.0 vs 13.1 yr; p = 0.007) and more acidotic (pH, 7.04 vs 7.19; p < 0.001), with higher serum osmolality (328 vs 315 mOsm/kg; p < 0.001) and longer hospital length of stay (4.5 vs 3 d; p = 0.002). Head CT was performed during 60 of 96 diabetic ketoacidosis admissions with altered mental status (63%), 16 (27%) of which had abnormal results. Hyperosmolar therapy for cerebral edema was given during 23 of the 60 admissions (38%), during which 12 (52%) had normal head CT results, eight of these 12 (67%) after cerebral edema treatment and four (33%) before. Of the 11 admissions with abnormal head CT results that received hyperosmolar therapy, four head CT scan (36%) occurred after hyperosmolar treatment and seven (64%) before. For the 11 admissions with head CT before cerebral edema treatment, there was a median 2-hour delay between head CT and hyperosmolar therapy. In this single-center retrospective study, there was no evidence that decisions about treatment of patients with diabetic ketoacidosis and suspected cerebral edema were enhanced by head CT, and head CT may have led to a significant delay in hyperosmolar therapy.

Serial optic nerve sheath diameter ultrasonography during pediatric diabetic ketoacidosis management: A pilot study

ObjectiveIntracranial hypertension is an infrequent but serious acute complication of pediatric diabetic ketoacidosis (DKA). Subclinical elevations of intracranial pressures however, may be more common, and can be indirectly evaluated with ultrasonography of the optic nerve sheath diameter (ONSD). In this pilot study, we report serial data on ONSD trajectories from five pediatric patients with DKA to generate hypotheses for future studies. MethodsFive pediatric patients with type 1 diabetes presented to our emergency department with DKA and enrolled in our study <3h after initiation of treatment. Ultrasonographic evaluation of the ONSD was conducted at presentation, every three hours until resolution of acidosis, and finally 24h post presentation. Following each interval evaluation, a clinical bedside neurologic tool developed for detecting cerebral edema in DKA was utilized. ResultsFour of the five patients exhibited a similar “bell” shaped trajectory — an increase of ONSD after initiation of treatment followed by a return to admission baseline. Patients demonstrated peak ONSDs nine and twelve hours after DKA therapy was initiated, at resolution of acidosis, and at admission. No children exhibited clinical signs suggestive of cerebral edema. ConclusionsPeak ONSDs cannot be reliability determined in children with DKA unless serial investigations are conducted. Practices to mitigate risks for intracranial hypertension may require constant surveillance during DKA management.

Increased activity of inflammasomes as osmosensors as cause of cerebral edema in diabetic ketoacidosis

Increased activity of inflammasomes as osmosensors as cause of cerebral edema in diabetic ketoacidosis

Increasing Use of Hypertonic Saline Over Mannitol in the Treatment of Symptomatic Cerebral Edema in Pediatric Diabetic Ketoacidosis

Cerebral edema in diabetic ketoacidosis is a devastating complication with significant morbidity and mortality. This entity has traditionally been treated with mannitol, but use of 3% hypertonic saline has become an accepted alternative. We sought to assess if changes in the use of hyperosmolar therapies for treatment of cerebral edema in diabetic ketoacidosis may have influenced mortality over the last decade. Retrospective cohort study. Patients discharged between 1999 and 2009 from 41 children's hospitals that provided data to the Pediatric Health Information System database. A total of 43,107 children (age < 19) with diagnosis codes related to diabetic ketoacidosis were identified and further classified as having cerebral edema if treated with mannitol and/or 3% hypertonic saline. None. Billing for 3% hypertonic saline and mannitol was quantified, and mortality associated with both diabetic ketoacidosis and cerebral edema in diabetic ketoacidosis was examined. Overall mortality in diabetic ketoacidosis was 0.25% and significantly decreased (p < 0.001) over the study period, whereas the frequency of treatment with hyperosmolar agents (3.8%) was unchanged. Use of mannitol as a sole agent decreased from 98% to 49%, 3% hypertonic saline as a sole agent increased from 2% to 39%, and combined therapy increased from 0% to 10%. Use of 3% hypertonic saline alone was associated with a higher mortality than mannitol alone (adjusted odds ratio, 2.71 [95% CI, 1.01-7.26]) in patients treated for cerebral edema. Similar results were obtained after adjustment for the propensity to receive hypertonic saline (adjusted odds ratio, 2.33 [95% CI, 1.07-5.07]) and in the subset of subjects receiving mechanical ventilation (adjusted odds ratio, 3.27 [95% CI, 1.12-9.60]). Hypertonic saline has replaced mannitol as the most commonly used agent at many institutions for treatment of cerebral edema in diabetic ketoacidosis. In our analysis, however, use of hypertonic saline as a sole agent was associated with an increased risk of mortality. Recognizing the limitations of administrative data, we conclude that equipoise regarding choice of therapy for treatment of cerebral edema in diabetic ketoacidosis should be maintained until a more definitive study is performed to guide therapy of this potentially lethal complication.

Treating Cerebral Edema in Diabetic Ketoacidosis

Treating Cerebral Edema in Diabetic Ketoacidosis

Risk factors for cerebral edema in diabetic ketoacidosis in a developing country

To study the clinical profile and risk factors of cerebral edema in children with diabetic ketoacidosis with specific reference to fluid refractory shock. Retrospective review of medical records. Twelve-bed pediatric intensive care unit of a teaching hospital. Seventy-seven patients admitted to pediatric intensive care unit with a diagnosis of diabetic ketoacidosis over 5 yrs. Medical records were reviewed, and data with respect to patients' age, clinical features, biochemical profile (blood glucose, osmolality, electrolytes, urea, creatinine, arterial pH, PaCO(2), and HCO(3) at admission, 6-12 hrs, 24 hrs, and beyond 24 hrs), cerebral edema, presence of sepsis and shock, treatment details, and primary outcome in terms of survival or death were retrieved. Patients with and without cerebral edema were compared. Variables that were significant on univariate analysis were entered in a multiple logistic regression analysis to determine the predictors for cerebral edema. Odds ratio and 95% confidence interval were calculated using SPSS version 15. Mean age of the patients was 5.6 (standard deviation, 3.8) years. Fifty-five (71.4%) patients had new-onset diabetes mellitus. Cerebral edema was seen in 20 patients (26%). Blood glucose, serum osmolality, and CO(2) values at admission and rate of decline in glucose and osmolality during the first 12 hrs were similar in the cerebral edema and noncerebral edema groups. On multiple logistic regression analysis, fluid refractory shock (odds ratio, 7.3; 95% confidence interval, 1.3-41; p = .025) and presence of azotemia (odds ratio, 4.3; 95% confidence interval, 1.1-16; p = .034) at admission were predictors for development of cerebral edema. Mortality in cerebral edema group was 25% as compared to 3% in the noncerebral edema group. Patients with fluid refractory shock and azotemia at admission had higher odds for development of cerebral edema. Initial blood glucose, effective osmolality, or decline in glucose and osmolality had no association with cerebral edema.

An In Vitro Paradigm for Diabetic Cerebral Oedema and its Therapy: A Critical Role for Taurine and Water Channels

The pathophysiology of cerebral oedema (CE) in diabetic ketoacidosis (DKA) remains enigmatic. We investigated the role of the idiogenic osmol taurine and aquaporin channels in an in vitro model, the SH-SY5Y neuroblastoma cell line, by sequentially mimicking DKA-like hyperglycemia/hypertonicity and hypotonic fluid therapy. Exposure to DKA-like hyperosmolarity led to shrinkage, while hypotonic fluid exposure led to cell swelling and impaired viability. Low sodium compensated in part for elevated glucose, pointing to a critical role for overall osmolality. Taurine, was synthesized and retained intracellularly during DKA-like hypertonicity, and released during hypotonicity, in part mitigating neuronal swelling. Metabolic labeling showed that the rate of taurine release was inadequate to fully prevent neuronal swelling during hypotonic fluid therapy following DKA-like hypertonicity. Under these conditions, Aquaporin4 & 9 channels were respectively down and up-regulated. Our study provides further novel insights into molecular mechanisms contributing to CE in DKA and its therapy.

The temporal relationship between glucose-corrected serum sodium and neurological status in severe diabetic ketoacidosis

ObjectiveCerebral oedema is a potentially devastating complication of diabetic ketoacidosis (DKA). The relationship between osmolar changes, acid–base changes and development of cerebral oedema during therapy is unclear.DesignRetrospective cohort study on...

Understanding the pathophysiology of cerebral edema in diabetic ketoacidosis: Another brick in the wall?*

The Hospital for Sick Children; Toronto, ON, Canada The author has not disclosed any potential conflicts of interest. For information regarding this article, E-mail: [email protected]

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.

Cerebral edema in diabetic ketoacidosis

To review the causes of cerebral edema in diabetic ketoacidosis (CEDKA), including pathophysiology, risk factors, and proposed mechanisms, to review the diagnosis, treatment, and prognosis of CEDKA and the treatment of diabetic ketoacidosis as it pertains to prevention of cerebral edema. A MEDLINE search using OVID was done through 2006 using the search terms cerebral edema and diabetic ketoacidosis. RESULTS OF SEARCH: There were 191 citations identified, of which 150 were used. An additional 42 references listed in publications thus identified were also reviewed, and two book chapters were used. The citations were reviewed by the author. All citations identified were used except 25 in foreign languages and 16 that were duplicates or had inappropriate titles and/or subject matter. Of the 194 references, there were 21 preclinical and 40 clinical studies, 35 reviews, 15 editorials, 43 case reports, 29 letters, three abstracts, six commentaries, and two book chapters. The data are summarized in discussion. The causes and mechanisms of CEDKA are unknown. CEDKA may be due as much to individual biological variance as to severity of underlying metabolic derangement of the child's state and/or treatment risk factors. Treatment recommendations for CEDKA and diabetic ketoacidosis are made taking into consideration possible mechanisms and risk factors but are intended as general guidelines only in view of the absence of conclusive evidence.

Cerebral edema in DKA: First do no harm!

The development of cerebral edema during the acute treatment of diabetic ketoacidosis (DKA) is a rare but potentially devastating complication. Over the past few years, The Journal has published a number of studies that have attempted to elucidate the cause and prevention of this life-threatening disturbance. In the current issue, our knowledge about cerebral edema in DKA is expanded upon with a careful observational study by Hoorn et al. These workers undertook a retrospective examination of data from cohorts of children treated at their center for DKA who either did or did not develop cerebral edema. The major difference noted between the two groups was an early drop in effective plasma osmolality in the cerebral edema group. The group that did not develop this fall in osmolality had either a smaller drop in plasma glucose, a slight rise in plasma sodium, or both. The cerebral edema group tended to receive more fluid early in treatment. These observations are put into a very helpful perspective in an accompanying editorial by Friedman. Although it is likely that there are a host of causes of cerebral edema in DKA—indeed there may be vascular abnormalities at presentation that are predisposing—these publications suggest that the initial fluid therapy may play a role as well. This observation is somewhat in conflict with current consensus statements on the topic. From a practical standpoint, the thrust of these articles suggests that avoiding precipitous drops in plasma glucose, and avoiding overly aggressive rehydration, particularly with less-than-isotonic fluid, are important strategies in the management of DKA.

Combined Insulin and Bicarbonate Therapy Elicits Cerebral Edema in a Juvenile Mouse Model of Diabetic Ketoacidosis

Cerebral edema in diabetic ketoacidosis (DKA-CE) occurs primarily in children and can develop during DKA therapy. The treatment factors contributing to DKA-CE remain elusive. Our objectives were to characterize an age-appropriate DKA mouse model and to determine which DKA therapies contribute to DKA-CE. Juvenile mice were briefly fed a high-fat diet and injected with two pancreatic beta-cell toxins: streptozocin and alloxan. Severe insulin and leptin deficiencies associated with hyperosmolar ketoacidosis rapidly developed, indicating DKA. DKA mice were treated with re-hydration +/- insulin and brain water content (BWC) measured as an indicator of DKA-CE. As expected, glucose and beta-OH-butyrate corrected in DKA mice that received rehydration and insulin. BWC significantly increased above control levels only in DKA mice that received combined insulin and bicarbonate therapy, indicating the development of DKA-CE. Microscopically, DKA-CE brains had perineuronal and perivascular edema, with microvacuolation in the white matter tracts. These results indicate that insulin-deficient juvenile mice develop biochemical changes that are similar to those of DKA in children. Increased BWC was observed only in DKA mice that received combined insulin and bicarbonate therapy, suggesting that rapid systemic alkalinization in the presence of insulin may contribute to DKA-CE.