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Three Part Question

In [children with cerebral oedema in DKA] is [hypertonic (3%) saline more effective than 20% mannitol] in [improving morbidity and mortality]?

Clinical Scenario

A 4 year old girl with DKA on fluid and insulin therapy in children's ward developed altered sensorium & unequal pupils. The registrar advised to commence her on mannitol (20%) to treat cerebral oedema. Intensivist from the transport team insisted on hypertonic (3%) saline. You wonder whether hypertonic saline is better than mannitol in treating cerebral oedema in children with DKA.

Search Strategy

CINAHL, EMBASE and MEDLINE healthcare databases 1966 - August 2014
[diabetic ketoacidosis] AND [Cerebral oedema OR cerebral edema] AND [Mannitol] AND [hypertonic saline OR Saline solution, Hypertonic] LIMIT to Human

Search Outcome

1 Cohort Study, 3 Retrospective Studies and 2 Case Reports

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
DeCourcey DD, Steil GM, Wypij D, Agus MSD September 2013 USA	43,107 children <19 years of age with diagnoses codes related DKA were identified and further classified as having cerebral edema if treated with mannitol and/or 3% hypertonic saline (HS)	Retrospective cohort study of patients discharged between the years 1999-2009 from 41 children’s hospitals that provided data to the Pediatric Health Information Systems databases (2B)	Use of Hyperosmolar therapies has influenced mortality rate in last decade	Overall mortality in DKA decreased by 0.25%. Use of 3% HS alone associated with higher mortality than mannitol alone in patients treated for CE.	Retrospective study using administrative database, inherent limitations and no access to the clinical records.
Yildizdas D, Altunbasak S, Celik U, Herguner O September, 2006 Turkey	67 Pediatric intensive care unit patients with cerebral edema of varying etiologies, including meningoencephalitis, hypoxic ischemic encephalopathy, intracranial hemorrhage, meningitis, or metabolic encephalopathy.	Group I: Received only Mannitol Group II: Received only hypertonic saline Group III: Received both mannitol and hypertonic saline. This group is subdivided into IIIA and IIIB. In Group IIIB, patients with serum osmolality greater than 325 mosmol/L had mannitol discontinued, and were treated with hypertonic saline alone. (2B)	Mortality and duration of comatose state	Mortality and duration of comatose state	Small, retrospective study. Only 7/67 patients fit into the "metabolic encephalopathy" group, which would correlate best with patients in DKA. Outcomes were "duration of comatose state" and "mortality". No mention of long-term disability.
Szlam SM, Walsh M, Pfeffer A, Abramo, TJ October 2012 USA	30 patients aged 3-18 years old. 2 patients were treated with HS	Descriptive retrospective analysis of electronic records from 1/2009-2/2012 for DKA patients who received 3% HS. (2C)	Effect on clinical states and GCS after administration of 3% HS.	3% HS efficacious in improving short-term outcome without significant side effects in this population.	Retrospective study, small sample size. Larger diverse validation warranted. Only HS was used.
Roberts MD, Slover RH, Chase HP September 2001 USA	Case reports 11 instances of severe diabetic ketoacidosis (DKA) with secondary intracerebral complications (ICCs)	Retrospective Case reports study During 1989-1999 381 episodes of DKA were treated. 9 of 11 patients were treated for DKA with CE. (3C)	Effect of prompt administration of IV mannitol on complete recovery of CE	All 9 children who received early treatment with IV mannitol showed full recovery	Retrospective study, small sample size. The other 2 of 11 patients with DKA with CE died before they could be treated.
Morales AE, Daniels KA April 2009 USA	Case report – 15 year old girl	First published Case Report of DKA-related CE in a newly diabetes mellitus type 2. (3D)	Effect of early recognition and treatment with mannitol & 3% HS on patient’s recovery.	Full recovery of patient’s CE following treatment with mannitol & 3% HS solution.	Small sample size. Both mannitol and HS were used.
Curtis JR, Bohn D, Daneman D December 2001 Canada	13 year old girl with severe DKA & CE	Case report. (3D)	Complete neurological recovery	First report of successful use of HS to CE in pediatric DKA.	Both mannitol and HS were used

Comment(s)

Nearly 25% children with type 1 diabetes present with DKA. Cerebral oedema, although uncommon is a recognised and serious complication in DKA. Early recognition and effective intervention can prevent neurological complications and mortality. Accurate calculation of fluid in children with DKA is the mainstay in management. ISPAD, BSPED guidelines advise either mannitol or hypertonic saline in management of cerebral oedema. This has created confusion amongst general paediatricians and raised debate about advantages of one over the other. Josh Vander Lugt et al searched for the above answer and published in Best Bets in 2007 after finding 2 relevant papers. One study showed that hypertonic saline was more effective than mannitol in treating cerebral oedema whereas the other study was inconclusive. In one recent case report of a 9 year old child with severe DKA with cerebral oedema showed complete neurological recovery following treatment with mannitol. Curtis et al used 3% saline with remarkable result following non-response to very high dose of mannitol. They hypothesise that correction of sodium level and preservation of intravascular volume might have contributed to this dramatic response. DeCourcey et al observed in a retrospective study that there is a trend of low mortality in DKA children. Interestingly they found that use of hypertonic saline as a sole agent was associated with increased risk of mortality. A large prospective randomised comparative study of 200 children was conducted by Upadhyay et al in Paediatric Intensive Care Unit (PICU) setting to compare the efficacy and side effects of 3% hypertonic saline and mannitol in raised intracranial pressure (ICP) in non-diabetic children. They found no difference in osmolality and mortality in both groups. However, they found that the clinical response and decrease in coma hours was significant in the group receiving 3% saline. The serum osmolality remained similar in both groups. In their review article on hypertonic saline use in the emergency department; Banks & Furyk discussed the mechanism of action of hypertonic saline (HS). It increases the mean arterial pressure with less volume than isotonic fluids. The effect of rapidly infused 3% HS lasts longer than mannitol. Extremely rare side effects of hypertonic saline include osmotic demyelination syndrome (ODS) and hypernatraemic haemorrhagic encephalopathy (HHE). Hyperchloraemic metabolic acidosis is also known to occur with hypertonic saline. Marcin et al conducted a retrospective analysis of 61 children with DKA related cerebral oedema over a period of 15 years. They identified 3 variables such as increased BUN (Blood urea Nitrogen), profound neurological deterioration at the time of diagnosis of cerebral oedema and intubation & ventilation with poor prognosis. In a recent letter Tasker et al supported that intubation and ventilation is a major factor contributing to higher mortality in children with DKA related cerebral oedema. There are anecdotal reports of increased use of hypertonic saline to treat cerebral oedema as it has theoretical advantage over mannitol in preserving intravascular volume. Due to lack of uniform advice in the management of cerebral oedema, more trial study results are required to inform paediatricians about rational use of hypertonic saline in cerebral oedema in DKA.

Clinical Bottom Line

Cerebral oedema is a potential complication during management of diabetic ketoacidosis in children. BSPED and ISPAD guidelines advise either mannitol or hypertonic saline to treat cerebral oedema in DKA (Diabetic Ketoacidosis). Further future studies are required to establish the clinical effectiveness of hypertonic saline over mannitol in children with cerebral edema.

References

1. DeCourcey DD, Steil GM, Wypij D, Agus MSD Increasing use of hypertonic saline over mannitol in the treatment of symptomatic cerebral edema in pediatric diabetic ketoacidosis: an 11-year retrospective analysis of mortality Pediatric Critical Care Medicine 2013;14(7):694-700
2. Yildizdas D, Altunbasak S, Celik U, Herguner O Hypertonic saline treatment in children with cerebral edema Indian Pediatrics 2006;43(9):771-9
3. Szlam SM, Walsh M, Pfeffer A, Abramo, TJ Use of 3% hypertonic saline in pediatric patients in diabetic ketoacidosis with clinically evident cerebral edema Pediatric Emergency Care 2012;28(10):1104-1105
4. Roberts MD, Slover RH, Chase HP Diabetic ketoacidosis with intracerebral complications Pediatric Diabetes 2001;2(3):109-114
5. Morales AE, Daniels KA Cerebral edema before onset of therapy in newly diagnosed type 2 diabetes. Pediatric Diabetes 2009;10(2):155-157
6. Curtis JR, Bohn D, Daneman D Use of hypertonic saline in the treatment of cerebral edema in diabetic ketoacidosis (DKA) Pediatric Diabetes 2001;(4):191-194