I recently reviewed the insulin dosing recommendation by the American Diabetes Association (and UpToDate) for the treatment of diabetic ketoacidosis. Both recommend either a 0.1 U/kg bolus followed by an infusion of 0.1 U/kg/hr or no bolus and 0.14 U/kg/hr. Where does such a bizarre number come from?

0.14 units/kg/hr seems exceedingly precise, where did that number come from?

When I look at these recommendations, I like to think that someone must have done a giant study comparing outcomes in DKA patients treated with infusions at 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, etc U/kg/hr with and without a loading bolus and found that the two regimens given as options in the guideline were identified as the co-Goldilocks values – two equal sweet spots. Those two dosing regimens lead to great clinical outcomes, and all of the rest cause harm. But that’s not true.

This number came from a 2008 paper (1) that compared the following treatment regimens:

1. 0.07 U/kg/hr with a priming “load” of 0.07 U/kg/hr
2. 0.07 U/kg/hr without a load
3. 0.14 U/kg/hr without a load

These doses sound strange in isolation; however, what they represent is a unit conversion. Essentially, the investigators were studying 5 U/hr versus 10 U/hr. If you assume that a standard person is 70kg and do some math you see the following:

That’s where the number came from. Work backwards from a nice round number of 10 U/kg in a 70 kg person and you get a number that only feels odd when taken out of context.

This is the only study cited by the guidelines that uses that dosing regimen. It consisted of 37 total patients in Memphis, Tennessee.

The study must have been very convincing since it was given so much weight in the guideline, right?

Not really.

The higher dose group achieved a higher serum insulin level, but there were no differences in patient-oriented outcomes (time to improvement of the glucose, the acidosis, or the bicarbonate level). The authors state this in their results.

I do notice that the lead author of the ADA consensus statement was also the lead author on this paper. This paper was published in 2008, the consensus statement was published in 2009. Seeing as how treatment guidelines changed due to this small study with conclusions that I do not think everyone would have come to based on its results, it makes you wonder if some bias snuck into the decision making.

Does everyone do it this way?

No. The International Society for Pediatric and Adolescent Diabetes published a guideline in 2022 that recommends 0.05 – 0.1 U/kg/hr with no loading bolus (3). The Joint British Diabetes Society for Inpatient Care published a guideline in 2022 as well. They also recommend an infusion rate of 0.1 U/kg/hr with no loading bolus.

The American guideline for adults has not been updated since 2009. I suspect we may see some changes in the next iteration. For the time being, however, that is their recommendation, and now you know where it came from.

References

1. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009 Jul;32(7):1335-43. doi: 10.2337/dc09-9032. PMID: 19564476; PMCID: PMC2699725.
2. Kitabchi AE, Murphy MB, Spencer J, Matteri R, Karas J. Is a priming dose of insulin necessary in a low-dose insulin protocol for the treatment of diabetic ketoacidosis? Diabetes Care. 2008 Nov;31(11):2081-5. doi: 10.2337/dc08-0509. Epub 2008 Aug 11. PMID: 18694978; PMCID: PMC2571050.
3. Glaser N, Fritsch M, Priyambada L, Rewers A, Cherubini V, Estrada S, Wolfsdorf JI, Codner E. ISPAD clinical practice consensus guidelines 2022: Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes. 2022 Nov;23(7):835-856. doi: 10.1111/pedi.13406. PMID: 36250645.
4. Dhatariya KK; Joint British Diabetes Societies for Inpatient Care. The management of diabetic ketoacidosis in adults-An updated guideline from the Joint British Diabetes Society for Inpatient Care. Diabet Med. 2022 Jun;39(6):e14788. doi: 10.1111/dme.14788. Epub 2022 Feb 27. PMID: 35224769.