CLN - Ask The Expert

Diagnosing and Managing Diabetic Ketoacidosis

Ask the Expert: September 2022

Brooke Andrews, PhD

What are the clinical diagnostic criteria for diabetic ketoacidosis (DKA)?

A: DKA can be challenging to diagnose due to conflicting clinical definitions. The American Diabetes Association (ADA) defines this condition as the triad of metabolic acidosis, hyperglycemia, and elevated ketones, with specific clinical parameters of serum glucose >250 mg/dL, arterial pH <7.3, serum bicarbonate <18 mmol/L, ketonuria or ketonemia, and anion gap >10. However, Diabetes U.K.’s criteria include ketones but exclude anion gap, and the 2018 Diabetes Canada Clinical Practice Guidelines state that “there are no definitive criteria for diagnosis of DKA.”

Which analytes have the greatest clinical utility in diagnosis and management of DKA?

The 2006 and 2009 ADA consensus guidelines require the confirmed presence of blood or urinary ketones for a diagnosis of DKA. The subsequent 2011 laboratory guidelines from ADA and AACC specifically indicate a preference for blood ketone measurement for both diagnosis and therapeutic monitoring. In particular, beta-hydroxybutyrate (BHB) represents approximately 80% of ketones present in blood during DKA, as physiologic equilibrium favors this species under acidic conditions. Monitoring BHB in plasma therefore offers a real-time indication of the severity of ketosis and reflects the impact of treatment more quickly than urinary ketone measurements. Because two-thirds of the physiologically relevant ketone bodies are strong acids, resolution of ketosis will also be reflected in normalization of pH and anion gap “closure,” or return to within the reference interval.  

What are the pros and cons of the testing options available for ketone measurements?

Ketones can be measured in urine or in blood. Urine is typically analyzed either in the clinical laboratory or at the point of care (POC) via the nitroprusside reaction, which involves the ketones acetoacetate and acetone reacting with an iron complex to generate a red-purple color on a dipstick. This method is quick and uses a noninvasive specimen, a drawback is that only the minor ketone species present during DKA are measured. Furthermore, the nitroprusside reaction is subject to interferences such as sulfhydryls from medications, and dipsticks generate a qualitative, subjective result. Alternatively, acetone can be measured in urine or blood specimens via gas chromatography headspace analysis, but this is highly specialized testing and also excludes BHB, the predominant ketone species present during DKA.

Commercially available BHB assays can be adapted to automated chemistry analyzers with open reagent channel capabilities. These assays are Food and Drug Administration (FDA)-approved for measurement of BHB in plasma via a colorimetric coupled enzymatic method. In addition, there are FDA-approved, CLIA-waived
POC ketone meters that use a strip-based, enzymatic amperometric method. Similar to POC glucometers, a whole blood capillary specimen is absorbed onto a strip docked into a device that rapidly (often within 10 seconds) determines and displays a BHB concentration.

How do POC BHB meters compare to in-lab testing methodologies?

Plasma measurement of BHB on an automated platform offers a precise assessment of ketosis along with other routine laboratory testing for DKA management in the same heparinized plasma specimen. A survey of the clinical literature shows that ketone meters compare well to in-lab measurements of BHB in plasma through a limited measurement subrange. Unfortunately, in-patient specimens are not linear through the FDA-approved analytical measurement range of 0–8 mmol/L. It is therefore recommended that results >4 mmol/L generated on a POC meter should be disregarded.

With that said, the small specimen requirement and decreased turnaround time of POC ketone meters are unique advantages of these devices. With careful implementation, use of these meters has become standard practice in many children’s hospitals across the U.S., as pediatric DKA requires swift diagnosis to avoid severe consequences.

Brooke Andrews, PhD, is a clinical chemistry fellow in the department of pathology and laboratory medicine at the University of Kentucky in Lexington, Kentucky. +Email: [email protected]