Copyright # Blackwell Munksgaard 2005
Pediatric Diabetes 2005: 6: 41—49 Printed in Denmark. All rights reserved
Pediatric Diabetes
Hot Topic
Cerebral edema in diabetic ketoacidosis and other acute devastating complications: recent observations Rosenbloom AL. Cerebral edema in diabetic ketoacidosis and other acute devastating complications: recent observations Pediatric Diabetes 2005: 6: 41—49. # Blackwell Munksgaard, 2005
Arlan L. Rosenbloom Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA Key words: cerebral edema — cerebral thrombosis — children — diabetic ketoacidosis — hyperglycemic hyperosmolar state. Corresponding author: Arlan L. Rosenbloom, MD Children’s Medical Services Center 1701, SW 16th Avenue Gainesville, FL 32608, USA Tel: þ1 352 334 1393; fax: þ1 352 334 1476; e-mail:
[email protected] Submitted 23 August 2004. Accepted for publication 16 November 2004
In his 2000 Hot Topic entitled, ‘Do doctors cause or prevent cerebral edema in children with diabetic ketoacidosis?’, Andrew Muir (1) emphasized the continuing conundrums and paucity of data to predict this complication or inform treatment guidelines to prevent it. The 2005 version of this topic will review reports since 2000 that have expanded understanding of the epidemiology, clinical prediction, differential diagnosis from other devastating acute complications with diabetes, and that have begun to explore the pathogenesis of cerebral edema using new imaging methods.
Retrospective analyses and case reports
Improving management of diabetic ketoacidosis in children. Felner EI, White PC (2001) Pediatrics 108: 735—740. Drawing on a large number of admissions for diabetic ketoacidosis (DKA) in children under 18 yr of age (approximately 130/year), these authors compared consecutive 2.75-yr intervals, representing change from a regi-
men of calculated fluid deficit plus 1.5 times maintenance, half of which was administered in the first 12 h and the remaining 50% over the next 24 h to a simplified regimen calculated as 2.5 times maintenance, regardless of degree of dehydration. Those patients who were treated with the revised protocol received less total fluid (4.4 vs. 5.1 L/m2/ 24 h) of higher sodium content (115 vs. 75 mmol/L), needed fewer intravenous fluid changes, were treated at lower cost, and had their acidosis resolve more rapidly than those treated under the earlier protocol. Cerebral edema occurred in one patient in each group, indicating no advantage or disadvantage to the revised protocol from the standpoint of this complication.
The risk and outcome of cerebral edema developing during diabetic ketoacidosis. Edge JA, Hawkins MM, Winter DL, Dunger DB (2001) Archives of Disease in Childhood 85: 16—22. This was the first large population-based study of cerebral edema complicating DKA, drawing on all cases
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Rosenbloom from England, Scotland, and Wales reported through the British Pediatric Surveillance Unit from October 1995 to September 1998. There were 34 cases of cerebral edema among 2940 episodes of DKA for a calculated cerebral edema risk of 6.8 in 1000 episodes of DKA (0.7%). The risk for new-onset DKA was 11.9 in 1000 episodes and for recurrent DKA 3.8 in 1000 episodes. Mortality with cerebral edema was 24%, and 35% of survivors had neurologic residua including motor deficits, visual impairment, short-term memory loss, speech problems, and convulsions.
Risk factors for cerebral edema in children with diabetic ketoacidosis. Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, Louie J, Kaufman F, Quayle K, Roback M, Malley R, Kuppermann N (2001) The New England Journal of Medicine 344: 264—269. This retrospective multicenter study identified 61 children in whom cerebral edema had developed over a 15-yr period among 6977 hospitalizations for DKA, an incidence of 0.9%. They were compared to 181 randomly selected children with DKA, and 174 youngsters matched for age, whether new-onset or established, initial serum glucose concentration, and initial venous pH. The three groups were compared for demographic characteristics and biochemical variables, and the matched groups were compared for therapeutic interventions and changes in biochemical values during treatment. Cerebral edema was significantly associated with lower initial partial pressures of arterial carbon dioxide and higher initial serum urea nitrogen concentrations. The only treatment variable associated with cerebral edema was the use of bicarbonate. Survival without sequelae occurred in 57% of those with cerebral edema, survival with permanent neurological dysfunction in 21%, and death in 21%. Rates of fluid, insulin, and sodium administration did not affect the occurrence of cerebral edema. During the study period, only two other children died as a result of DKA in the 10 centers, both from cardiac arrest associated with hypokalemia and hypocalcemia. This emphasizes the overwhelming predominance of cerebral edema in fatal outcomes from DKA. This experience, however, may be exceptional. In our own institution, over the same period of time, there were four deaths in children with diabetes 14—19 yr of age from rhinocerebral or pulmonary mucormycosis (2). Contrasting observations about the role of rate of fluid administration and sodium content in the development of cerebral edema were reported by Edge et al. (3) at the 30th Annual Meeting of the International Society for Pediatric and Adolescent Diabetes (ISPAD) in Singapore in November 2004. They ana-
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lyzed 43 cases of cerebral edema identified to the British Paediatric Surveillance Unit and compared them to 169 controls. Similar to the above study, the risk for cerebral edema was strongly related to pH or bicarbonate levels at presentation, but they also found that high concentrations of potassium and sodium conferred risk, presumably reflecting greater severity of dehydration. Higher volumes of fluid administered in the first 1, 2, 3, and 4 h independently contributed to the risk of cerebral edema, as did a shift from normal saline to more dilute fluids in the second and third hours. Odds ratios for these various factors ranged from 5 to 9.5. Early administration of insulin (during the first hour of treatment) was also a risk factor.
Factors associated with adverse outcomes in children with diabetic ketoacidosis-related cerebral edema. Marcin JP, Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, Louie J, Kaufman F, Quayle K, Roback M, Malley R, Kuppermann N (2002) The Journal of Pediatrics 141: 793—797. This report is a more detailed look at baseline clinical features and treatment interventions in the 61 children who developed cerebral edema from the previous study to determine variables associated with outcome. Poor outcome was associated with greater neurologic depression at the time of diagnosis of cerebral edema, elevated initial serum urea nitrogen concentration, and intubation with hyperventilation to a pCO2 15 mmol/L, small ketonuria, absent-to-low ketonemia, effective serum osmolality >320 mOsm/kg, and stupor or coma. This has previously been a rare condition in children with the only fatalities being in those with existing neurologic deficits. None of the previously reported pediatric patients with HHS were overweight. In a presentation at the 2003 Endocrine Society meeting, Fourtner et al. (13) reviewed 190 pediatric patients with type 2 diabetes and found that eight of them aged 10—17 yr had HHS at onset, and all were obese African-Americans. The single death was a result of multisystem organ failure and another patient had rhabdomyolysis, acute renal failure, and pancreatitis. One of the patients in the current report also had fever and rhabdomyolysis as in the report of Hollander et al. It is noteworthy that death was considered preventable in all of the patients in this report with earlier recognition of their diabetes or with more appropriate treatment on admission. Three of them had irreversible cardiac complications of iatrogenic hypokalemia. Two others had severe hypophosphatemia, and one patient had acute pancreatitis and was inadequately treated for that complication. One patient had cerebral edema as did one of the pediatric patients reported by Fourtner et al. (13), indicating that pediatric type 2 diabetes patients with HHS may be at similar risk for cerebral edema as type 1 patients with DKA. The reports of Hollander et al., Fourtner et al., and Morales & Rosenbloom indicate that children with type 2 diabetes are at risk for severe dehydration and electrolyte disturbance and that longstanding hyperglycemia and osmotic diuresis can result
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Rosenbloom in severe total body water and potassium/phosphorus deficits with the advent of vomiting. There needs to be a high index of suspicion for type 2 diabetes and recognition of the risk of HHS or DKA in obese sick children and appreciation that the diagnosis of type 2 diabetes can be as much an emergency as is that of type 1 diabetes.
Cerebral venous thrombosis during diabetic ketoacidosis. Keane S, Gallagher A, Ackroyd S, McShane MA, Edge JA (2002) Archives of Disease in Childhood 86: 204—226. A 5-yr old girl with established diabetes had mild ketoacidosis with moderate dehydration and microcytic anemia. Following initial improvement, but 12 h following admission, she became increasingly confused and progressed to unconsciousness with posturing and response only to painful stimuli. She was given mannitol for suspected cerebral edema and received a transfusion of packed red cells. Brain CT scan showed thrombosis in the straight sinus and the vein of Galen with ischemic changes in the thalamus. She received anticoagulant therapy and made a full recovery with very mild learning disability as a residual.
Fatal cerebral infarctions in diabetic ketoacidosis in a child with previously unknown heterozygosity for factor V Leiden deficiency. Rosenbloom AL (2004) The Journal of Pediatrics 145: 561—562 Heterozygosity for factor V Leiden deficiency has a prevalence of approximately 5% in the general population of European ancestry, conveying a two- to sevenfold increased risk of venous thromboembolism. An 11-yr old boy with poorly controlled diabetes developed a painful swollen vein in his calf and at about the same time headache with nausea and vomiting. A few days later he was found unconscious with fixed dilated pupils. MRI 2 h after his collapse showed acute infarction affecting multiple areas of the brain without hemorrhage or edema. Right-sided acute deep venous thrombosis involving the common and superficial femoral and popliteal veins was identified by Doppler ultrasound. He was found to be heterozygous for factor V Leiden mutation. Aside from this mutation, there were no coagulation factor abnormalities that could not be attributed to his thrombotic state. It was thought that his dehydration exacerbated the thrombotic tendency. He died 9 d after his collapse. While the leading cause of diabetes-related death and disability in type 1 diabetes mellitus in children is cere-
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bral edema, other intracerebral complications account for an estimated 10% of neurological collapse, including subarachnoid hemorrhage, basilar artery thrombosis, dural sinus thrombosis, cerebral venous thrombosis (as above), meningoencephalitis, and disseminated intravascular coagulation. Although it is essential to urgently intervene on the basis of clinical diagnosis with intravenous mannitol, fluid restriction, and respiratory support as indicated when cerebral edema is suspected, cranial imaging is appropriate following acute treatment and stabilization to rule out thrombotic or hemorrhagic phenomena that may benefit from specific therapy. The patient in this report did not have a clinical picture that is typical of idiopathic cerebral edema, in which respiratory arrest would be expected with his unconsciousness and fixed dilated pupils as a reflection of brainstem herniation or compression from edema.
Treatment of extreme hyperglycemia monitored with intracerebral microdialysis. Ahisson F, Gedeborg R, Hesselager G, Tuvemo T, Enblad P (2004) Pediatric Critical Care Medicine 5: 89—92. An 11-yr old boy with new-onset diabetes was severely dehydrated with a weight loss of 29% over the previous month. Blood glucose concentration was 100 mmol/L and osmolality 448 mOsm/kg. His fluid and insulin treatment was quite conservative, less than usual recommendation. With serum bicarbonate 17 mmol/L and mild ketonuria, he met the criteria for HHS. Sixteen hours after initiation of treatment, he became confused and agitated. He was treated with mannitol and was sedated and mechanically ventilated; CT scan of the brain showed no signs of edema. Brain and subcutaneous tissue glucose concentrations were measured by microdialysis, the brain microdialysis catheter being inserted with the intraventricular pressure catheter into the right frontal cortex. This was to monitor brain/blood glucose ratio to control for rapid changes in osmolar ratios. The child made a full recovery without neurologic sequelae. Rapid decrease in blood glucose increases the brain/subcutaneous glucose ratio, which may be a potential risk factor for osmotic brain edema. It is difficult to imagine that this is a useful approach, as ventricular pressure monitoring is rarely, if ever, indicated for DKAassociated cerebral edema. This report provides another instance of normal brain CT scan in the face of clinical cerebral edema. It is especially noteworthy for the unusual occurrence of HHS at onset of type 1 diabetes, with further demonstration that cerebral edema can occur with HHS in children, despite its rarity in adults with HHS (14). Pediatric Diabetes 2005: 6: 41—49
Cerebral edema in diabetic ketoacidosis
European Society for Paediatric Endocrinology/Lawson Wilkins Pediatric Endocrine Society consensus statement on diabetic ketoacidosis in children and adolescents. Dunger DB, Sperling MA, Acerini CL, Bohn DJ, Daneman D, Danne TPA, Glaser NS, Hanas R, Hintz RL, Levitsky LL, Savage MO, Tasker RC, Wolfsdorf JI (2004). Pediatrics 113: e133—140 (www.pediatrics.org/CGI/content/full/113/2/e133). Although this consensus conference dealt broadly with DKA, the opening paragraph emphasizes the importance of the problem of cerebral edema and that its etiology, pathophysiology, and ideal method of treatment are poorly understood. All of the discussions in this report used the American Diabetes Association evidence grading system, wherein ‘‘A’’ is the level of clear evidence with well-conducted, generalizable, randomized, controlled trials that are adequately powered, ‘‘B’’ indicates supportive evidence from well-conducted cohort studies, ‘‘C’’ is supportive evidence from poorly controlled or uncontrolled studies, or conflicting evidence with the weight of evidence supporting the recommendations, and ‘‘E’’ expert consensus or clinical experience. In this context, the occurrence of cerebral edema before treatment was given an evidence level of B, and the signs typically associated with the condition a level of C. Demographic risk factors of new-onset disease, younger age, and longer duration of symptoms with greater severity of DKA were considered at the level of C. Risk factors at diagnosis or during treatment included an attenuated rise in serum sodium concentration during therapy (C). It was noted that little evidence supported an association between the volume or sodium content of administered fluids or the rate of change in serum glucose concentration and risk for cerebral edema (C). It is unclear whether the association between less rise in serum sodium and cerebral edema reflects a variation in fluid administration or is a result of cerebral injury affecting renal salt handling. Severity of acidosis may increase the risk of cerebral edema (C), as may bicarbonate treatment for correction of acidosis (C). The association of greater hypocapnia, after adjustment for the degree of acidosis, with risk for cerebral edema, was noted above and considered to have an evidence level of C, as was the association with elevated serum urea nitrogen which reflects degree of dehydration. The degree of hyperglycemia at the start of treatment was not thought to relate to the risk for cerebral edema (C). Suspicion of cerebral edema was considered sufficient to warrant treatment with reduction in the rate of fluid administration. The experience with mannitol was described as ‘‘possible beneficial effects in case reports’’, Pediatric Diabetes 2005: 6: 41—49
and its prompt administration, before respiratory arrest, suggested in a dose of 0.25—1.0 g/kg over 20 min (C, E). Repeat was suggested in 2 h, if there is no initial response, but most would repeat in a half hour or so after completion of the initial dose if there were no response. There have been two reports of the use of 3% saline, as noted above, and it was proposed that a study of the comparative efficacy of HS and mannitol be carried out. Although such a study is a daunting prospect, the suggestion of Curtis et al. is certainly reasonable, that if there is no improvement after giving mannitol, a trial of HS is warranted. The association of aggressive hyperventilation with poor outcome in the study of Marcin et al. above and in other conditions such as head trauma and high-altitude exposure was noted.
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