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Three Part Question

[In children with DKA] is [the early use of insulin] associated with [development of cerebral oedema]?

Clinical Scenario

A 15 year old boy with type 1 DM is admitted to the ED unwell, with a BM of 29.
O/E he is pale, sweaty and lethargic with a BP of 90/40 and pulse 120. Otherwise exam is unremarkable.
You site an IV cannula and take a VBG which shows pH 7.1 and HCO3- 10.
You give a 900ml 0.9% NaCl fluid bolus (20ml/kg) and are about to start a sliding scale when the paediatric SpR tells you that local policy is to hold off insulin for the first 2-3 hours as it may increase the risk of development of cerebral oedema.
You wonder what the evidence shows.

Search Strategy

Medline, Embase and Cinahl searched.
Date range 1996-2015.
Exp Diabetic Ketoacidosis/ OR exp Ketosis/ OR exp Hyperglycemia/OR exp Diabetic Coma/AND Insulin/ OR sliding adj scale OR actrapid OR novorapid OR exp short acting insulin/ OR exp neutral insulin AND exp Brain Edema OR Cerebral ADJ ?edema.


Limited to human and English language.

Search Outcome

48 references found - 8 relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Berkley K 2004 USA	Children presenting with DKA	Clinical case and review of guideline in authors’ local Emergency Department	Development of cerebral oedema.	Too rapid correction of hyperglycaemia with fluid and insulin increases the risk of cerebral oedema. The authors’ ED defer starting insulin for 30 minutes.	Subjective report of 2 patients with DKA. No report as to how the authors’ ED developed their guideline.
Edge et al. 2006 UK	Children <16 years with DKA, defined as ‘decompensated diabetes mellitus with evidence of ketoacidosis (pH<7.3 or plasma bicarbonate level <18mmol/l or heavy ketonuria)	Large multi centre case control study	Development of cerebral oedema, reported as sudden or unexpected deterioration in conscious level in a child with DKA or any death during assessment or management of DKA.	Insulin administration in the first hour increases risk of cerebral oedema (OR 12.7 [1.41-114.5, p=0.02)	Retrospective study, cases reported by different individuals in different centres, no guarantee of standardisation
Wolfdorf et al 2007 International guidance	Children with DKA	International Society of Paediatric Diabetes Clinical Practice Consensus Guideline	Management of DKA	Start insulin infusion 1–2 h after starting fluid	No review date on guidance. No documentation regarding how guidance developed.
British Society of Paediatric Endocrinology and Diabetes 2009 UK	Children with DKA	National guidance from the British Society of Paediatric Endocrinology and Diabetes	Management of DKA	Once rehydration fluids and potassium are running, blood glucose levels will start to fall. Cerebral oedema is more likely if insulin is started early. Start insulin after IV fluids running for at least 1 hour.	No review date on guidance. No documentation regarding how guidance developed.
Datz et al. 2009 Germany	Case presentation of child with DKA	Case presentation	Development of cerebral oedema	Cerebral oedema can develop despite following current clinical guidance regarding time of starting insulin therapy	Anecdotal. Does not refer to which guidelines are used for the treatment of DKA. Development of cerebral oedema may have been secondary to other factors.
Wolfsdorf et al. 2009 International guidance	Children with DKA	ISPAD Clinical Practice Consensus Guideline	Management of DKA.	Start insulin infusion 1–2 hours after starting fluid	No review date on guidance. No documentation regarding how guidance developed. Update of 2007 guidance.
Barrios et al. 2012 USA	Paediatric patients presenting with DKA.	Retrospective case record review. 113 emergency departments reviewed.	Differences in management of DKA in different hospitals.	Insulin started after 1 hour of fluids in 77% of new-onset cases and	Retrospective review. Dependent on documentation in case records. No detail regarding association between timing of insulin administration and rate of cerebral oedema.
National Institute of Clinical Excellence 2015 UK	Children with type 1 diabetes presenting with DKA	National guidance based on systematic review of liteature	When to start insulin infusion	Start an intravenous insulin infusion 1–2 hours after beginning intravenous fluid therapy in children and young people with DKA	Search strategy and strength of recommendations not given in main guideline.

Comment(s)

Cerebral oedema occurs in 0.3 - 1% episodes of DKA, with estimates of mortality ranging from 20-50%. Its low incidence has limited the number of prospective trials carried out, and understanding of the cause remains poor. Recent evidence suggests that the early administration of insulin may increase the risk of cerebral oedema. Current guidelines therefore suggest insulin therapy should be delayed by one hour after commencement of fluids. Further high quality research is however required.

Editor Comment

Previous 2006 work on this topic at BET 1366 http://bestbets.org/bets/bet.php?id=1366

Clinical Bottom Line

Administration of insulin should be delayed until at least one hour after fluids have commenced. This is to reduce the risk of cerebral oedema in children presenting with DKA.

References

1. Berkley, K. Treating diabetic ketoacidosis in children while preventing cerebral edema: one hospital's protocol. Journal of Emergency Nursing 2004 30(6):569-571
2. Edge JA, Jakes RW, Roy Y et al. The UK case-control study of cerebral oedema complicating diabetic ketoacidosis in children. Diabetologia 2006 49, 2002-2009
3. Wolfsdorf, J., Craig, M. E., Daneman, D., et al. Diabetic ketoacidosis. Pediatric Diabetes 2007 8(1):28-43.
4. British Society of Paediatric Endocrinology and Diabetes BSPED Recommended DKA Guidelines 2009
5. Datz, N., Schuetz, W. V., Kordonouri, O., et al. Cerebral crisis in severe diabetic ketoacidosis (DKA) despite adequate fluid and insulin therapy. Pediatric Diabetes 2009. 1034.
6. Wolfsdorf, J., Craig, M. E., Daneman, D., et al Diabetic ketoacidosis Pediatric Diabetes 2007 8(1):28-43
7. Wolfsdorf, J., Craig, M. E., Daneman, D., et al. Diabetic ketoacidosis in children and adolescents with diabetes. Pediatric Diabetes 2009 10(SUPPL. 12):118-133.
8. NICE Guideline Development Group NICE NICE CG18