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Three Part Question

[In children presenting with diabetic ketoacidosis], [does a low dose (0.05units/kg/hour) insulin infusion, compared to a standard dose (0.1units/kg/hr) insulin infusion] [reduce the incidence of hypoglycaemia and rapid falls in serum glucose]?

Clinical Scenario

You are a Paediatric SpR in a busy DGH and a previously well 6yr old girl is brought into Paediatric resus by ambulance with blood sugar of 32 and a significant acidosis. You make a diagnosis of DKA and commence treatment in accordance with your local Paediatric DKA guideline. However, you notice that the rate of insulin infusion it instructs you to use is 0.1units/kg/hour, which is double that suggested by the South Thames Retrieval Service guideline(1) you had used in your previous hospital. You wonder what the evidence is for the possible benefits of using a lower rate and which is the more appropriate rate to use.

Search Strategy

Primary search of Medline via PubMed. Search terms: (diabetes OR diabetic ketoacidosis) AND (insulin infusion OR low dose insulin). Limits: child <18yrs, human and English language. 1373 papers were found, 9 of which were relevant.
Secondary search via the NHS Evidence National Library of Guidelines, which identified the ISPAD guideline on diabetic ketoacidosis in children and adolescents. Cochrane Database revealed no further studies. The references of articles found were searched which led to 1 further set of guidelines (ESPE/LWPES).
6 papers were excluded as they did not directly compare insulin infusions at rates of 0.5units/kg/hour and 0.1units/kg/hour or they were primarily review articles.

Search Outcome

5 relevant studies and guidelines were identified. See table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Al Hanshi et al (Ref 2) 2010 UK	All children with diabetic ketoacidosis admitted to a tertiary Paediatric Intensive care Unit during the 6-yr period from 2000 to 2005. 34 children received 0.1u/kg/hr of insulin, 33 children received 0.05 u/kg/hr of insulin	Retrospective observational study (Level 2b)	The effective plasma osmolality, plasma glucose, plasma sodium, fluid intake, and acid-base status 12 hrs after the commencement of the insulin infusion.	Children who received 0.05u/kg/hr had a more gradual reduction in the effective plasma osmolality over the first 12 hrs (p < .0005); this was because plasma glucose decreased more slowly (p =0 .004) and plasma sodium increased faster (p < .0005). Both groups had a satisfactory improvement in acidosis and ketosis, and they had a similar length of stay in the intensive care unit	Children who received 0.05u/kg/hr were younger (median age, 25 months vs. 62 months, p = .024)
Puttha et al (reference 3) 2010 UK	Data from six paediatric centres gathered on children < 16yrs with type 1 diabetes to compare 41 children who received 0.05u/kg/hr (low dose) and 52 who received 0.1u/kg/hr (standard dose)	Retrospective observational study (Level 2b)	Primary outcomes: change in blood glucose levels and pH at 6 h following admission Secondary outcome: a deterioration in Glasgow Coma Score between 1 and 6 h following admission to 13 or less compared to baseline	The low vs. standard dose groups were similar at 6 h in terms of fall in blood glucose levels [11.3 (95% confidence interval 8.6 to 13.9) vs. 11.8 (8.4 to 15.2) mmol/L, p = 0.86] and rise in pH [0.13 (0.09 to 0.18) vs. 0.11 (0.07 to 0.15), p = 0.78]. Via regression analysis, insulin dose was unrelated to the change in pH and blood glucose levels at 6. Subgroup analysis showed increased hypoglycaemia and increased frequency of GCS < 13 at 6hrs in standard dose group	Comparisons of safety data, particularly in relation to abnormal Glasgow Coma Score, were inconclusive. Authors suggest randomised controlled trials are required to show true equivalence between doses and to evaluate potential safety benefits.
International Society for Pediatric and Adolescent Diabetes (ISPAD) (Ref 4) 2009 International	Diabetic ketoacidosis in children and adolescents	Clinical Practice Consensus Guidelines		‘Extensive evidence indicates that ‘low dose’ IV insulin administration should be the standard of care’ Advise a dose of 0.1 unit/kg/ hr but suggest dose may be decreased to 0.05unit/kg/hr in patients with increased insulin sensitivity e.g younger patients	Cite 1 reference for ‘extensive evidence’ (review paper by Kitabchi 19895) Cite 2 references for advised insulin dose (Schade & Eaton, 19776, Kiabchi 19895)
American Diabetes Association, Ref 7 2006 USA	Diabetic ketoacidosis in infants, children, and adolescents	Consensus statement		‘Extensive evidence indicates that “low-dose” intravenous insulin administration should be the standard of care’. Advise a dose of 0.1 unit/kg/ hr	Cite 1 reference for ‘extensive evidence’ (review paper by Kitabchi 19895) Cite 1 reference for advised insulin dose (Schade & Eaton, 19776)
Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Paediatric Endocrino 2004 - Reference 8 European	Diabetic ketoacidosis in children and adolescents	Consensus statement		‘Extensive evidence indicates that “low dose” intravenous insulin administration should be the standard of care’ ‘Physiological studies indicate that intravenous insulin at a dose of 0.1 unit/kg/hour, which achieves steady state plasma insulin levels of around 100–200 µU/ml within 60 minutes, is effective’	Cite same 2 references as ISPAD/ADA guidelines

Comment(s)

There has been a progression over the last 20 years in Paediatric DKA towards using lower doses of insulin without an insulin bolus and starting insulin after a delay of one hour. However, it remains very unclear as to the ideal rate of insulin infusion that should be used in these children. There is some consensus between the large international guidelines from Europe(8), America(7) and worldwide(4) that 0.1unit/kg/hr is the recommended rate for most children. However, as is clear from the table this conclusion is based on very limited evidence consisting almost entirely of one review article from 1989(5) and a physiology-based paper from 1977(6), which are described by all three guidelines as ‘extensive evidence’. The British Society of Paediatric Endocrinology and Diabetes guidelines(9) (upon which the NICE guidelines(10) are based) are the only guidelines which comment on the uncertainty, remarking that ‘there are some paediatricians who believe that 0.05 units/kg/hour is an adequate dose. There is no firm evidence to support this.’ None of the above guidelines suggest that the lower dose of 0.5unit/kg/hour may be as good as the standard dose, and the question of hypoglycaemia and rapid falls in glucose which might precipitate cerebral oedema being improved by the lower dose is not addressed. This discrepancy is even more marked when we consider that some guidelines such as the South Thames Retrieval Service DKA guideline(1) advise only a rate of 0.5unit/kg/hour without comment on the evidence for this. The current evidence as described above remains insufficient for a definitive conclusion. However, the results of the studies of both Al Hanshi et al(2) and Puttha et al(3) both suggest that further work on this question, particularly with respect to abnormal Glasgow Coma Score (GCS) and ideally in the form of randomised controlled trials, may well lead us further along the path of reducing the dose of insulin for children in DKA.

Clinical Bottom Line

In children with diabetic ketoacidosis use of a low dose (0.05unit/kg/hour) or standard dose (0.1unit/kg/hour) insulin infusion are equivocal in terms of improvement in acidosis (Grade B). There is limited evidence that use of a low dose insulin infusion as compared to a standard dose insulin infusion reduces the incidence of hypoglycaemia (Grade C). There is inconclusive evidence that use of a low dose infusion prevents rapid falls in serum glucose or reductions in GCS (Grade D).

References

1. Al Hanshi S, Shann F. Insulin infused at 0.05 versus 0.1 u/kg/hr in children admitted to intensive care with diabetic ketoacidosis. Pediatr Crit Care Med 2010 May 13 [Epub ahead of print]
2. Puttha R, Cooke D, Subbarayan A, Odeka E, Ariyawansa I, Bone M, Doughty I, Patel L, Amin R; North West England Paediatric Diabetes Network Low dose (0.05 units/kg/h) is comparable with standard dose (0.1 units/kg/h) intravenous insulin infusion for the initial treatment of diabetic ketoacidosis in children with type 1 diabetes-an obser Pediatr Diabetes. 2010 Feb;11(1):12-7
3. Wolfsdorf J, Craig ME, Daneman D, Dunger D, Edge J, Lee W, Rosenbloom A, Sperling M, and Hanas R. ISPAD clinical practice consensus guidelines 2009 compendium Diabetic ketoacidosis in children and adolescents with diabetes . Pediatric Diabetes 2009 Sep;10 (Suppl. 12): 118–13
4. Wolfsdorf J, Glaser N, Sperling MA; American Diabetes Association Diabetic ketoacidosis in infants, children, and adolescents: A consensus statement from the American Diabetes Association. Diabetes Care 2006 May;29(5):1150-9
5. Dunger DB, Sperling MA, Acerini CL, Bohn DJ, Daneman D, Danne TP, Glaser NS, Hanas R, Hintz RL, Levitsky LL, Savage MO, Tasker RC, Wolfsdorf JI; ESPE; LWPES ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents Arch Dis Child 2004 Feb;89(2):188-94
6. South Thames Retrieval Service South Thames Retrieval Service DKA guideline
7. Kitabchi AE Low-dose insulin therapy in diabetic ketoacidosis: fact or fiction? Diabetes Metab Rev. 1989 Jun;5(4):337-63
8. Schade DS, Eaton RP Dose response to insulin in man: differential effects on glucose and ketone body regulation J Clin Endocrinol Metab 1977 Jun;44(6):1038-53
9. British Society of Paediatric Endocrinology and Diabetes BSPED Recommended DKA Guidelines
10. National Institute of Clinical Exellence NICE guidelines on the diagnosis and management of type 1 Diabetes in children, young people and adults