MONITORING KETOSIS


acetoacetic acid. A colour chart is used for reading the ketone concentrations.2 Quantitative enzymatic assays for the


determination of ßHB have been available for many years. A report from the University of Wisconsin Hospital and Clinics, Madison, WI, describes the development of an optimised method for the determination of serum ßHB for use on a Cobas FARA.3


Umpierrez4 reported


on the clinical utility determined by a reflectance meter in the management of diabetic ketoacidosis in 1995. The instrument was developed commercially as a bench top analyser (Ketosite; GDS technologies, Elkhart, IN).The test uses a simple slide and requires 20 µl of serum. The reaction is shown in Figure 3. The comparison of the determination


of ßHB vs Nitroprusside (Acetest or Ketostix)is shown below:


ßHB • Quantitative • Measures largest component of ketones.


• Best and earliest indicator of ketosis. • Best predictor of resolution of ketoacidosis.


Acetest • Only measures acetoacetic acid and acetone (weakly).


• Qualitative assay often requiring multiple manual dilutions.


• Increase lags behind symptoms of ketosis.


• Decrease begins 2-4 hours after resolution of ketoacidosis.


Several reports conclude that the use of Acetest may be misleading and should be avoided because the fall of acetoacetate lags behind the resolution of ketoacidosis. ßHB levels correlate better with acid-base changes during the course of treatment for DKA than changes in acetoacetate concentrations. The study by Umpierrez4 highlights that all patients with ßHB levels of 1.1 mmol/Lor less had resolved their ketosis. In contrast, 8 out of 15 patients in whom ketosis had been resolved as demonstrated by blood gas and acid-base parameters still had positive Acetest results for up to 24 hours after resolution. Studies at Henry Ford Hospital5 demonstrated that at ßHB levels of 1.0-1.5 mmol/Land resolution of ketoacidosis, the Acetest procedure still gave positive results. Furthermore, in the same study, ßHB levels were just as sensitive as blood pH for demonstrating resolution of ketoacidosis. Rapid determinations of ßHB levels


were useful in establishing the diagnosis of DKA and in the management of patients with prolonged metabolic acidosis, combined diabetic and lactic acidosis and


48 THE CLINICAL SERVICES JOURNAL


‘Several reports conclude that the use of Acetest may be misleading and should be avoided because the fall of acetoacetate lags behind the resolution of ketoacidosis.’


other mixed acid–base disorders. Direct measurement of ßHB in serum improved laboratory turnaround time and replaced a subjective, qualitative result with a method that is quantitative and less subject to observer bias.6


In addition, the


nitroprusside method has demonstrated susceptibility to false positive results from drugs containing free – sulfhydryl groups and false negative results from reagent deterioration.7,8


Blood testing for ketones


is superior to urine testing because fluid intake can affect concentrationrendering urinetesting unreliable.9


outcomes and enhanced cost efficiency have been attributed to blood testing of ßHB.5


Improvements were seen in the


following areas: • Earlier detection of clinically significant ketosis.


• Improved turnaround times. • Significant reduction in laboratory testing.


• Faster resolution of ketoacidosis with significant reduction in the patients’ length of stay in the clinical decision unit.


Alternatives are now available for ßHB testing on multichannel chemistry analysers and several point-of-care devices. A recent web search found a number of companies that manufacture or distribute kits for the determination of ßHB.


Summary As discussed in this paper, assays for ßHB in blood are superior to Acetest or Ketostixin a number of respects. Physicians and medical facilities should no longer be performing nitroprusside- based testing to diagnose or monitor ketoacidosis. Numerous assays for small point-of-care devices and liquid reagents for automated analysers are highly reliable and have been in use for two decades. For example, the University of Wisconsin has used an automated enzymatic assay


Improved clinical


References 1 Laffel L. Ketone bodies: a review of physiology, pathophysiology and Application of monitoring to diabetes. Diabetes Metab Res Rev 1999; 15: 412-26.


2 Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, Burtis, Ashwood, Bruns, editors. (2006). Chapter 25, “Carbohydrates”, 837-902.


3 Koch D, Feldbruegge D. Optimized method for automated determination of Beta- Hydroxybutyrate. 1987; 33(10): 1761-6.


4 Umpierrez G,Watts N, Phillips L. Clinical utility of Beta-Hydroxybutyrate determined by reflectance meter in the management of diabetic ketoacidosis. Diabetes Care 1995; 18(1): 137-8.


5 Foreback C, Former Director of Clinical Chemistry, Henry Ford Hospital, Detroit, MI. White Paper. Clinical effectiveness of Beta- Hydroxybutryate assays in a clinical decision unit (1998).


6 Foreback C. Beta-Hydroxybutyrate and acetoacetic acid levels. Am J ClinPathol 1997; 602-4.


7 Csako G. Unrecognised false – positive ketones from drugs containing free-sulfhydryl groups. JAMA 1993; 269(13): 1364.


8 Csako G. False-positive results for ketones with the drug mesna and other free- sulfhydryl compounds. ClinChem 1987; 33: 289-92.


9 Goldstein, D, Little R, Lorenz R et al. Tests of glycemia in diabetes. Technical Review. Diabetes Care 1995; 18(6): 896-909.


About the author


Chemical structures of various ketone bodies – acetone, acetoacetic acid, and ß-hydroxybutyric acid.


Craig C. Foreback PhD, is a senior lecturer, CLS Program at the Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI. 53711, USA. Gary Dowthwaite, PhD, is product manager (Diabetes) at EKF Diagnostics


NOVEMBER 2012


for ßHB since 1988. Healthcare organisations need to rediscover and implement the diagnostic treasures available to them.


• This article is based upon a paper published in Treatment Strategies: Diabetes by Craig C. Foreback PhD andGary Dowthwaite PhD in November 2012.


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