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Three Part Question

In [pediatric patients with diabetic ketoacidosis and evidence of cerebral edema] is [intravenous mannitol or hypertonic saline] better [in reducing neurologic disability or mortality]?

Clinical Scenario

In treating pediatric patients with diabetic ketoacidosis (DKA), minimizing the risk of cerebral edema is a mainstay of therapy. However, the pathophysiologic mechanism of cerebral edema in pediatric DKA is controversial. A literature search is performed to assess the evidence favoring the use of mannitol vs. hypertonic saline in the treatment of pediatric DKA.

Search Strategy

Medline 1950-05/07 using the OVID interface, Cochrane Library (2007), PubMed clinical queries.
[(exp diabetic ketoacidosis/) AND (exp brain edema or cerbral edema.mp or cerebral oedema.mp/). LIMIT to human AND English AND all child
PubMed: cerebral edema or oedema and hypertonic saline and mannitol and pediatric diabetic ketoacidosis
OVID: cerebral edema or oedema and hypertonic saline and mannitol and pediatric diabetic ketoacidosis

Search Outcome

129 papers were found; 10 papers addressed therapy in cerebral edema.The majority of these were small case reports or case series. None of the studies compared mannitol to hypertonic saline in pediatric DKA. One retrospective study was identified that examined outcomes in children treated with mannitol (1) and one study addressed the issue of hypertonic saline in pediatric cerebral edema, though it was not strictly limited to children with DKA (2).

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Yildizdas D, Altunbasak S, Celik U, et al 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: Recieved 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.	Mortality and duration of comatose state	Hypertonic saline more effective than mannitol in the treatment of cerebral edema	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.
Marcin, James P. MD, MPH; Glaser, Nicole MD; Barnett, Peter MB, BS; McCaslin, Ian MD; Nelson, David December, 2002 USA	Children <= 18 years old with DKA and cerebral edema were retrospectively identified from 10 pediatric centers between 1982 and 1997.	Studied relation between outcomes of children with diabetic ketoacidosis(DKA)-related cerebral edema and clinical outcome in association with therapeutic interventions for treatment of cerebral edema. Worse outcomes associated with dehydration, more profound neurologic depression at diagnosis of cerebral edema, and hyperventilation.	Effect of mannitol use on adverse neurologic sequelae	Not able to prove or disprove the harm or efficacy of mannitol.	Retrospective, small. Non-standardized dosing of mannitol. Non-standardized timing of therapeutic implementation for patients treated. Assessment of patient neurologic status subject to interobserver variability. Study limited in its ability to evaluate use of mannitol specifically.

Comment(s)

Performing a large and high-quality study to compare mannitol vs. hypertonic saline in the setting of pediatric DKA poses numerous ethical and logistical difficulties. At this time, most of the literature regarding hypertonic saline and mannitol in cerebral edema is related to patients with traumatic brain injury. More investigation is needed before definitive recommendations can be made. Marcin, et al. showed a compelling relationship between poor neurologic outcome and hyperventilation, dehydration, and worse neurologic status at time of cerebral edema diagnosis. Although Yildizdas, et al. report the advantage of hypertonic saline over mannitol in cerebral edema in general, translating these results specifically to cerebral edema in pediatric DKA would be premature.

Clinical Bottom Line

Mannitol does not appear to worsen outcomes in pediatric patients with DKA and evidence of cerebral edema. Currently, no good evidence supports the use of hypertonic saline over mannitol in this specific group of patients.

References

1. Yildizdas D, Altunbasak S, Celik U, et al Hypertonic saline treatment in children with cerebral edema. Indian Pediatrics. September, 2006;43(9):771-9
2. Marcin, James P. MD, MPH; Glaser, Nicole MD; Barnett, Peter MB, BS; McCaslin, Ian MD; Nelson, David MD; Trainor, Jennifer MD; Louie, Jeffrey MD; Kaufman, Francine MD; Quayle, Kimberly MD; Roback, Mark Factors associated with adverse outcomes in children with diabetic ketoacidosis-related cerebral edema. Journal of Pediatrics 141(6):793-797, December 2002.