Background

The consensus statement by American Diabetes Association (ADA) published in 2009 were the fundaments of diabetic ketoacidosis (DKA) management.[1] A drowsy and dehydrated diabetic with highly elevated blood sugar in conjunction with an acidotic blood gas and positive urine ketones is no stranger to a well-seasoned emergency physician, and is the classical textbook description of DKA.

It has been 14 years since ADA updated the definition of DKA, and now – problems arise. 

Hyperglycemia was a key diagnostic criterion of DKA, and the cut-off was 250mg/dL (13.9mmol/L). However, patients with a blood glucose below this cut-off often appeared just as ill.

Beta-hydroxybutyrate was a well-known ketone body formed during DKA, which can be ordered as a blood laboratory test or detected in a commercial point-of-care fingerstick instrument. Despite evidence pointing that it could be helpful in diagnosing DKA, the consensus statement was ambiguous on its utility.[2]

SGLT-2 inhibitors, now a first line pharmacological agent for treating type 2 diabetes[3], and widely prescribed for proven benefits in cardiovascular and chronic kidney disease[4-5], was not known then. Euglycemic DKA, an increasingly common complication associated with SGLT-2 inhibitors usage in patients with risk factors such as fasting, surgery and pregnancy, was not addressed in the 2009 statement.[6] A meta-analysis went further to conclude that SGLT-2 inhibitors doubled the risk of DKA.[7]

New Joint Society Statement (2023)

At the 2023 European Association for the Study of Diabetes (EASD) Conference in Hamburg, Germany, researchers unveiled an updated consensus statement on hyperglycemic crises in adults with type 2 diabetes. The new consensus report is jointly endorsed by the ADA, the EASD, the American Association of Clinical Endocrinology, the Diabetes Technology Society, and the Joint British Diabetes Societies for Inpatient Care.[8-9]

Hyperglycemia – no longer the major diagnostic criterion

For all patients with hyperglycemic crisis, the hyperglycemia cutoff is now lowered to 200 mg/dL (11.1 mmol/L) from the previous 250 mg/dL (13.9mmol/L).

For known diabetics, the glucose cutoff has been removed entirely.

Concomitant Hyperosmolar Hyperglycemic State (HHS)

The new consensus statement emphasizes on the possibility of concomitant HHS. In patients with DKA, the serum osmolality should also be checked. Moreover, the effective serum osmolality threshold for diagnosing HHS has been decreased from 320 mOsm/L to 300 mOsm/L.

Importance of Mental Status

Echoing the de-emphasis on glucose levels, it is more important to assess the patient’s clinical condition. A patient who has altered mental status, such as drowsiness, stupor and coma, is more indicative of a serious disease process such as DKA, and a predictor of poor outcome.[10]

Role of Beta-hydroxybutyrate

The new statement now recommends the use of beta-hydroxybutyrate, either via point-of-care test or serum level measured in a laboratory, using a cut-off of 3.0 mmol/L. Alternatively, a urine ketone strip value of 2+ or greater can be used. Also, the anion gap has been removed from the primary definition, although it can still be used in settings where ketone testing is unavailable.

Subcutaneous insulin

Traditionally, intravenous insulin infusion is the definitive treatment for DKA. In this new statement, subcutaneous insulin could be used to treat mild DKA.

Euglycemic DKA

The new statement now addresses the treatment of euglycemic DKA as a separate entity. Importantly, dextrose should be given simultaneously to avoid hypoglycemia. If SGLT-2 inhibitors are identified as the cause of euglycemic DKA, it should be stopped and not re-initiated upon discharge. The decision to re-start SGLT-2 inhibitors should be made on an individual basis with careful consideration in an outpatient setting.

Conclusion

From first glance, much of the new recommendations appear familiar and common-sense. These practices may have already been adopted in individual medical wards or emergency departments. Indeed, the authors acknowledge the diversity in managing DKA, which may be subject to resource limitations, physician preferences and beliefs, as well as the inadequacy of the 2009 consensus statement to cover all clinical aspects of DKA. A new consensus statement endorsed by various bodies will provide support and unify these controversial practices. For instance, point-of-care beta-hydroxybutyrate would be utilized in a broader scale, serum osmolality would be routinely checked, and more patients diagnosed with DKA would receive earlier intensive care and monitoring. Finally, further research in DKA diagnosis and management, as well as future audit on adherence to new guidelines would be just as fundamental to improve ultimate patient outcomes.

References:

1. Kitabchi AE, Umpierrez GE, Miles JM et al. 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. Sheikh-Ali M, Karon BS, Basu A et al. Can serum β-hydroxybutyrate be used to diagnose diabetic ketoacidosis? Diabetes Care 2008; 31: 643– 647

3. American Diabetes Association Professional Practice Committee. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022 Jan 1;45(Suppl 1):S125-S143. doi: 10.2337/dc22-S009. PMID: 34964831.

4. Wiviott SD, Raz I, Bonaca MP et al. DECLARE–TIMI 58 Investigators. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019 Jan 24;380(4):347-357. doi: 10.1056/NEJMoa1812389. Epub 2018 Nov 10. PMID: 30415602.

5. Heerspink HJL, Stefánsson BV, Correa-Rotter R et al. DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24. PMID: 32970396.

6. Fralick M, Schneeweiss S, Patorno E. Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor. N Engl J Med. 2017 Jun 8;376(23):2300-2302. doi: 10.1056/NEJMc1701990. PMID: 28591538.

7. Colacci M, Fralick J, Odutayo A, Fralick M. Sodium-Glucose Cotransporter-2 Inhibitors and Risk of Diabetic Ketoacidosis Among Adults With Type 2 Diabetes: A Systematic Review and Meta-Analysis. Can J Diabetes. 2022 Feb;46(1):10-15.e2. doi: 10.1016/j.jcjd.2021.04.006. Epub 2021 Apr 28. PMID: 34116926.

8. Miriam E. Tucker. New Hyperglycemia Emergency Guidance Updates DKA Definition - Medscape - Oct 09, 2023.

9. https://easd-elearning.org/new-guidance-on-managing-hyperglycaemic-crises-news/

10. Suwarto S, Sutrisna B, Waspadji S et al. Predictors of five days mortality in diabetic ketoacidosis patients: a prospective cohort study. Acta Med Indones. 2014 Jan;46(1):18-23. PMID: 24760804.