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ORIGINAL ARTICLE
Year : 2013  |  Volume : 3  |  Issue : 4  |  Page : 335-340

Role of measurement of blood ketone bodies in the management of diabetic ketoacidosis


1 Biochemistry and Cell Biology, Biomedical Research Group, BIRDEM, Dhaka, Bangladesh
2 Department of Pharmacy, Southeast University, Dhaka, Bangladesh
3 Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh

Date of Submission25-May-2013
Date of Acceptance14-Aug-2013
Date of Web Publication15-Oct-2013

Correspondence Address:
Md Abdur Rashid
Lab of Molecular Signaling, National Institute on Alcohol Abuse and Alcoholism (NIAAA), 5625 Fisher Lane, Room # 3S-O2, Maryland 20852, USA

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0738.119840

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   Abstract 

Objective: The present study was designed to investigate whether early detection of blood ketone bodies help in diagnosing Diabetic ketoacidosis (DKA) and also to explore whether early changes in blood β-hydroxybutyrate is associated with serum electrolytes and acid-base abnormalities. Research Design and Methods: A total of 122 consecutive type 2 diabetic patients (age 39 ± 15 yrs and body mass index 20.3 ± 2.4 kg/m 2 , mean ± SD) were included in the study. Plasma glucose was measured by glucose oxidase method, glycosylated haemoglobin (HbA 1C ) by high-performance liquid chromatography method, blood β-hydroxybutyrate by biosensor method; urinary acetone was measured by strip based on nitroprusside reaction. Serum urea and creatinine were measured by enzymatic method. Serum electrolytes were measured by ion sensitive electrode technique. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for urinary ketone method were calculated against the blood ketone. Results: The relative frequencies of DKA, using urinary ketone and blood ketone criteria, were 15.6% (19 out of 122) and 13.9% (17 out of 122), respectively. In contrast, 50% (61 out of 122) patients showed hyperketonemia. Using blood ketone as the reference method, the sensitivity of urinary ketone measurement was found to be 32.6% and specificity was 93.7%. PPV and NPV of urinary ketone against blood ketone were 73.68% and 71.84%, respectively. The DKA subjects, diagnosed by blood ketone criteria, showed significant biochemical derangements as compared to Non-DKA subjects [serum urea (P < 0.001), creatinine (P = 0.02), sodium (P < 0.001), potassium (P < 0.001), total carbon dioxide (P = 0.02), and osmolality (P = 0.02)]. Correlation analysis shows that electrolytes, blood gas, and acid-base status have highly significant correlation with blood ketone levels (Na + - r = −0.303, P < 0.001; K + - r = 0.449, P < 0.001; Mg 2+ - r = −0.174, P < 0.05; TCO 2 - r = −0.573, P < 0.001; venous blood pH- r = −0.659, P < 0.001, and osmolality- r = −0.273, P < 0.002). No such correlation was found with plasma glucose except that for serum sodium (r = −0.301, P < 0.001). Conclusions: Measurement of ketonuria by nitroprusside reaction has considerable limitations with an error of about 25-30% in detecting the ketonemic status of type 2 diabetic patients. The present data also demonstrated that severity of hyperketonemia, but not that of hyperglycemia, reflects the underlying biochemical derangements in type 2 diabetic patients better.

Keywords: Hyperglycemia, diabetic ketoacidosis, type 2 diabetes mellitus


How to cite this article:
Rashid MA, Chowdhury HS, Haque M, Faruque MO, Chowdhury MR, Ali L. Role of measurement of blood ketone bodies in the management of diabetic ketoacidosis. Int J Nutr Pharmacol Neurol Dis 2013;3:335-40

How to cite this URL:
Rashid MA, Chowdhury HS, Haque M, Faruque MO, Chowdhury MR, Ali L. Role of measurement of blood ketone bodies in the management of diabetic ketoacidosis. Int J Nutr Pharmacol Neurol Dis [serial online] 2013 [cited 2019 Aug 22];3:335-40. Available from: http://www.ijnpnd.com/text.asp?2013/3/4/335/119840


   Introduction Top


Diabetic ketoacidosis (DKA) remains a major problem of uncontrolled diabetes with significantly morbidity and mortality. Although in the last 3 decades, the average worldwide immediate mortality, related to DKA, has decreased from 10% to 5%, survival has not improved strikingly. [1] Reported frequencies range between 15% and 67% in Europe and North America and may be more common in developing countries. [2],[3] In the pathogenesis of ketoacidosis, relative insulin deficiency and counter-regulatory hormones excess lead to overproduction and underutilization of glucose resulting in hyperglycemia. [4],[5] Increased lipolysis leads to excessive formation of ketone bodies, which accumulate to produce a metabolic acidosis. Traditionally, ketonuria has been used to diagnose DKA. The development of inexpensive quantitative tests of capillary blood β-hydroxybutyrate levels was recently motivated by the unreliability of the urinary ketone tests in their role as DKA diagnosis and management tools. [6] Recently, rapid and specific enzymatic tests that measure blood β-hydroxybutyrate in small volume samples have been made available. It has been shown that the biosensor method for measuring capillary blood ketone body levels gave results similar to the spectrophotometric method used to measure plasma ketone body levels and that capillary blood β-hydroxybutyrate levels were highly and significantly correlated with plasma β-hydroxybutyrate. [7] These systems measure blood β-hydroxybutyrate levels in 30 seconds with a detection range of 0-6 mmol/l. [8]

The best way to early diagnosis of DKA or an impending DKA is still debatable and a matter of further investigation. DKA is a medical emergency and test methods that allow home-monitoring of blood ketones have been developed recently. As these have been available very recently, not many studies have reported its comparative usefulness against ketonuria measurement. No large-scale study has been reported addressing these questions. A clinical study has shown that elevation of blood β-hydroxybutyrate levels are extremely common in patients with poorly controlled diabetes, even in the absence of positive urinary ketones. [9] A study has reported that the ketone sensor has a higher sensitivity and provides an earlier diagnosis of ketosis than measurement of ketosis according to ketonuria. It also reported that the sensitivity and negative predictive values of capillary ketonemia were higher than those of ketonuria. [8] However, another report questions the added value of blood β-hydroxybutyrate level measurement. [10] Thus, how to diagnose early is still an open question that remains too answered. Using the rapid monitoring tools, the present study was designed to investigate whether early detection of blood ketone bodies help in diagnosing DKA.


   Research Design and Methods Top


Patients

A total of 122 consecutive type 2 diabetic patients (age 39 ± 15 yrs and body mass index (BMI) 20.3 ± 2.4 kg/m 2 , mean ± SD) requiring emergency admission in Bangladesh Institute of Research and Rehabilitation for Diabetes, Endocrine and Metabolic Disorders (BIRDEM) hospital (the tertiary hospital of the Diabetic Association of Bangladesh) were included in the study. DKA was defined as the combination of hyperglycemia (>12 mmol/l) and urinary large ketonuria or ketonemia with acidosis (venous blood pH < 7.3 or serum total carbon dioxide < 17 mmol/l). Urinary large ketonuria was defined as urinary ketone (≥3 + mmol//) and ketonemia was defined as plasma β-hydroxybutyrate >3.0 mmol/l. Hyperketonemia was defined as plasma β-hydroxybutyrate >1.0 mmol/l.

Biochemical measurements

Plasma glucose was measured by glucose oxidase method, glycosylated haemoglobin (HbA 1C ) by High-performance liquid chromatography (HPLC) method (Bio-Rad variant), blood β-hydroxybutyrate by biosensor method (Medisense, USA); urinary acetone was measured by strip-based on nitroprusside reaction. Serum urea and creatinine were measured by enzymatic method. Serum electrolytes were measured by Ion Sensitive Electrode (ISE) technique. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for urinary ketone method were calculated against the blood ketone.

Ethical consideration

The study protocol was approved by the ethical review committee of Diabetic Association of Bangladesh. Informed written consent was obtained from all patients.

Statistical analysis

Details medical history was taken and clinical findings of the subjects were recorded in a redesigned case record from. All analysis was done using the Statistical package for social science (SPSS) package for windows. Experimental values were expressed as mean ± SD (standard deviation) or median (range) as appropriate. To compare results between two groups, unpaired Student's t-test and for same groups, paired Student's t-test were performed where appropriate Pearson correlation coefficient were done to show the correlation between different parameters in the same group. Statistical significance was considerable to be indicated by a P ≤ 0.05 in all cases.


   Results Top


Clinical characteristics of the study subjects

The clinical characteristic of the study subjects are given in [Table 1].
Table 1: Clinical characteristics of the study subjects

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The mean (±SD) age of the study subjects was 39 (±15) years. The mean (±SD) BMI of the study subjects was 20.3 (±2.4) kg/m 2 . Among the study subjects, 78 (64%) were male and 44 (36%) were female. The relative frequency of the clinical risk factors present among the study subjects were: infection in 40 (32.8%), omission of insulin or inadequate insulin in 35 (28.7%), initial presentation of diabetes mellitus (DM) in 30 (24.6%), medical illness in 10 (8.2%), and unknown cause in seven (5.7%).

Sensitivity, specificity, and predictive values of urinary ketone for blood ketone

The sensitivity, specificity, and predictive values of urinary ketone for blood ketone are given in [Table 2].
Table 2: The sensitivity, specificity, and predictive values of urinary ketone for blood ketone

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The sensitivity of urinary ketone for blood ketone was 32.6%, specificity 93.7%, PPV 73.68%, and NPV 71.84%.

Comparison of the subjects with and without DKA diagnosed on the basis of ketonuria

The comparison of the subjects with and without DKA diagnosed on the basis of ketonuria is given in [Table 3].
Table 3: Comparison of the subjects with and without DKA diagnosed on the basis of ketonuria

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Subjects with DKA, diagnosed on the basis of criteria that includes ketonuria level had higher median blood b-hydroxybutyrate level {3.7 (1.1-6.0) vs. 0.8 (0.20-5.0) mmol/l, P < 0.001), serum urea median level {46 (28-72) vs. 36 (14-123) mg/dl, P < 0.03}, and serum potassium (5.8 ± 1.4 vs. 4.8 ± 0.6 mmol/l, P < 0.023) compared to subjects without DKA. The DKA subjects had lower serum sodium (134.0 ± 5.6 vs. 138.43 ± 4.28 mmol/l, P < 0.001), total carbon dioxide (26.6 ± 2.0 vs. 29.2 ± 2.1 mmol/l, P < 0.001), and serum osmolality (294.30 ± 10.5 vs. 300.8 ± 8.50 mOsm/kg, P < 0.013) compared to subjects without DKA. Random plasma glucose was higher (26.2 ± 4.5 vs. 23.9 ± 4.1 mmol/l) in DKA subjects but it was nearly significant (P = 0.06). There was no significant difference in HbA 1C , creatinine, and magnesium level between the subjects with and without DKA.

Comparison of the subjects with and without DKA diagnosed on the basis of ketonemia

The comparison of the subjects with and without DKA diagnosed on the basis of ketonemia is given in [Table 4].
Table 4: Comparison of the subjects with and without DKA diagnosed on the basis of ketonemia

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Subjects with DKA, diagnosed on the basis of criteria that include ketonemia had higher beta-hydroxy butyrate median level {3.4 (1.8-6.0) vs. 0.7 (0.20-4.60) mmol/l, P < 0.001), serum urea median level {50 (23-116) vs. 34 (14-123), P < 0.001}, serum creatinine (1.8 ± 0.8 vs. 1.3 ± 0.3 mg/dl, P < 0.02), and serum potassium (5.7 ± 1.2 vs. 4.8 ± 0.5 mmol/l, P < 0.003) compared to subjects without DKA. The DKA subject had lower serum sodium (135.3 ± 4.9 vs. 138.5 ± 4.4 mmol/l, P < 0.005), total carbon dioxide (26.8 ± 1.70 vs. 29.38 ± 2.13 mmol/l, P < 0.02), and serum osmolality (296.0 ± 9.4 vs. 300.9 ± 8.6 mOsm/kg, P < 0.02). There was no significant difference in plasma glucose, HbA 1C , and serum magnesium between subjects with and without DKA.

Pearson correlation of different variables with blood ketone level

The Pearson correlation of different variables with blood ketone level is given in [Table 5].
Table 5: Pearson correlation of different variables with blood ketone level

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Using Pearson correlation, significant correlation was observed between blood ketone level and the following variables: Serum potassium level (r = 0.449, P = 0.001), serum sodium (r = −0.303, P = 0.001), serum magnesium (r = −0.174, P = 0.05), serum total carbon dioxide (r = −0.573, P = 0.001), venous pH (r = −0.659, P = 0.001), and serum osmolality (r = −0.273, P = 0.002) in DKA subjects. There was no correlation between random plasma glucose, HbA 1C , urea and creatinine among these DKA subjects.

Pearson correlation of different variables with plasma glucose level

The Pearson correlation of different variables with plasma glucose level is given in [Table 6].
Table 6: Pearson correlation of different variables with plasma glucose level

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Using Pearson correlation, significant correlation was observed between plasma glucose level and the following variables: HbA 1C (r = 0.370, P = 0.001) and serum sodium level (r = −0.301, P = 0.001) in DKA subjects. There was no correlation between blood ketone, serum urea, serum creatinine, serum potassium, serum magnesium, serum total carbon dioxide, venous pH, and serum osmolality among these DKA subjects.


   Discussion Top


The present study reports the relative frequency of DKA and hyperketonemia such studies were not done earlier on Bangladeshi diabetic subjects. Previous reports have shown that type 1 DM is relatively rare in Bangladesh and thus typical DKA in young subjects is an uncommon clinical experience in our country. This reality is reflected in the present study. Even in a tertiary care center like BIRDEM, where acute patients are referred to from almost all over the country, the prevalence of clinically diagnosed case of DKA in its Emergency Department was nil over a period of June 2004 to December 2005 (total patient registered 45,000). It is surprising that type 2 DM with DKA, which is precipitated by factors like infection, omission of insulin, medical illness and others, was not recorded at all in the emergency department during this period. It may indicate that type 2 DM patients in this country rarely develop ketoacidosis. It may also reflect a dark side of the reality, i.e., a very poor referral and patient transport system for acutely ill patients with consequent death before it reaches BIRDEM.

When the emergency patients were assessed by the urinary ketone criterion (≥3+) 19 of 122 patients (15.6%) could be diagnosed as patients with DKA. Using the same criterion showed 26% of DKA in European population. [11] The data show that the prevalence of DKA is low in our population, even if the urinary ketone criterion is used.

Measurement of ketone bodies in the blood was a central issue in the present study. Hyperketonemia (HK) is defined as β-hydroxybutyrate >1.0 mmol/l and DKA is defined as β-hydroxybutyrate >3.0 mmol/l in blood. [12] Using these criteria, 50% patients showed HK and 13.9% showed DKA in type 2 DM. DKA was reported to be 20% in undefined adult patients in an American population. [13] The lower prevalence in the present study may be due to the fact that all the study subjects belong to type 2 DM. So far, there has been no data reported on prevalence of DKA in either type 1 or type 2 DM in Bangladesh. As mentioned above, the data of this study may not give a true picture of prevalence of HK or DKA in the community; the low prevalence may be just a reflection of poor referral care.

The major precipitating factor of DKA based on ketonemia among the study subjects was various types of infection (32.8%), which is similar to previous reports. [14] The omission of insulin or inadequate insulin of the patients under investigation (28.7%) was the second most common factor; this highlights the importance of home monitoring and education for diabetic subjects as well as the caregivers. It was the initial presentation of DM in 24.6%, i.e., around 1/4 th of the subjects did not have any previous history of diabetes, which highlights the importance of blood ketone testing at presentation of newly diagnosed cases in the emergency room as well as in the Out-Patient Department. It may be possible that subjects with symptoms of DKA are not always referred to this tertiary care center and though investigation is not always performed, thereby potential or impending DKA cases remain unnoticed till the very critical stage.

The development of inexpensive quantitative tests of capillary blood β-hydroxybutyrate levels was recently taken into serious consideration by the unreliability of the urinary ketone tests in their role as DKA diagnosis and management tools. In the present study, the usefulness of blood ketone body measurement against urinary ketone measurement was evaluated in the context of an Emergency Dept in a tertiary care center of Bangladesh. Blood ketone was measured by a rapid technique (reflectance meter), which has been validated with measurement by spectrophotometric techniques. [7] Using blood ketone as the reference method the sensitivity of urinary ketone measurement was found to be very poor (32.6%), although specificity was at an acceptable level (93.7%). In the present study, PPV and NPV reflect the usability of a test in a better way and the values of urinary ketone against blood ketone were 73.7% and 71.8%, respectively. Both the values show that urinary ketone measurements have severe limitations with an error of about 25-30% in diagnosing the cases. It is worth noting that ketosis positivity was more frequently reported with capillary ketonemia than with ketonuria. [15] Therefore, similar to the fact that self-monitoring of blood glucose by fingerstick has replaced urine glucose testing, it is tempting to speculate that fingerstick determinations of β-hydroxybutyrate levels might increase patient compliance with recommendations for ketone testing. A previous study showed that ketone body measurements using a reflectance meter could also enhance the management of DKA. [16] Healthcare professionals should be aware that currently available urine ketone tests are not reliable for diagnosing DKA or in monitoring its treatment. Consequently, the American Diabetes Association (ADA) recommends the use of blood ketone testing methods rather than urine ketone testing for diagnosis and monitoring of DKA. [17]

The DKA subjects, whether diagnosed by urinary ketone or blood ketone criteria, showed significant biochemical derangements in terms serum urea, creatinine, sodium, potassium, magnesium, total carbon dioxide, and osmolality. Some of the abnormalities were severe and required immediate intervention. For individual subjects correlation analysis, rather than difference between DKA and without DKA groups, is of more clinical relevance. Such analysis showed that for electrolytes, blood gas and acid-base status there are highly significant correlation of blood ketone levels with the relevant parameters. No such correlation was found with plasma glucose except that for serum sodium.


   Conclusions Top


Measurement of ketonuria by nitroprusside reaction has considerable limitations with an error of about 25-30% in detecting the ketonemic status of type 2 diabetic patients. The present data also demonstrated that severity of hyperketonemia, but not that of hyperglycemia, reflects better the underlying biochemical derangements in type 2 diabetic patients.

 
   References Top

1.Yan P, Cheah JS, Thai AC, Yeo PP. Current concepts of the pathogenesis and management of diabetic ketoacidosis. Ann Acad Med Singapore 1983;12:596-605.  Back to cited text no. 1
    
2.Levy-Marchel C, Papoz L, de Beaufort C. Clinical and laboratory features of type 1 diabetic children at the time of diagnosis. Diabet Med 1992;9:279-84.  Back to cited text no. 2
    
3.Komulainen J, Lounamaa R, Knip M, Kaprio EA, Akerbloom HK. Ketoacidosis at the diagnosis of type I (Insulin dependent) diabetes mellitus is related to poor residual beta cell function. Childhood Diabetes in Finland study Group. Arch Dis Child 1996;75:410-5.  Back to cited text no. 3
    
4.Eledrisi MS, Alshanti MS, Shah MF, Brolosy B, Jaha N. Overview of the diagnosis and management of diabetic ketoacidosis. Am J Med Sci 2006;331:243-551.  Back to cited text no. 4
    
5.Chiasson JL, Aris-Jilwan N, Bélanger R, Bertrand S, Beauregard H, Ekoé JM, et al. Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state. CMAJ 2003;168:859-66.  Back to cited text no. 5
    
6.Sulay MJ, Malins JM. Acetone in diabetic ketoacidosis. Lancet 1970;2:736-40.  Back to cited text no. 6
    
7.Guerci B, Benichou M, Floriot M, Bohme P, Fougnot S, Franck P, et al. Accuracy of an electrochemical sensor for measuring capillary blood ketones by fingerstick samples during metabolic deterioration after continuous subcutaneous insulin infusion interruption in type 1 diabetic patients. Diabetes Care 2003;26:1137-41.  Back to cited text no. 7
    
8.Byrne HA, Tieszen KL, Hollis S, Dornan TL, New JP. Evaluation of electrochemical sensor for measuring blood ketones. Diabetes Care 2000;23:500-3.  Back to cited text no. 8
    
9.McGarry JD, Woeltje KF, Kuwajima M, Foster DW. Regulation of ketogenesis and the renaissance of carnitine palmitoyl transferase. Diabetes Metab Rev 1989;5:271-84.  Back to cited text no. 9
    
10.Wiggam MI, Okane MJ, Harper R. Treatment of diabetic ketoacidosis using normalization of blood 3-hydroxybutyrate concentration as the end point of emergency management. Diabetes Care 1997;20:1347-52.  Back to cited text no. 10
    
11.Taboulet P, Haas L, Porcher R, Manamani J, Fontaine JP, Feugeas JP, et al. Urinary acetoacetate or capillary beta-hydroxybutyrate for the diagnosis of ketoacidosis in the Emergency Department setting. Eur J Emerg Med 2004;11:251-8.  Back to cited text no. 11
    
12.Mitchell GA, Kassovska-Bratinova S, Boukaftance Y, Robert MF, Wang SP, Ashmarina L, et al. Medical aspects of ketone body metabolism. Clin Invest Med 1995;18:193-216.  Back to cited text no. 12
    
13.Graves EJ, Gillium BS. Detailed diagnosis and procedures: National Discharge Survey, 1995. National Center for Health Statistics. Vital Health Stat 13 (no 133), 1997.  Back to cited text no. 13
    
14.Umpierrez GE, Kelly JP, Navarrete JE, Casals MM, Kitabchi AE. Hyperglycemic crises in urban blacks. Arch Intern Med 1997;157:669-75.  Back to cited text no. 14
    
15.Eager M, Davey Smith G, Stettler C, Diem P. Risk of adverse effects of intensified treatment in insulin-dependent diabetes mellitus: A meta-analysis. Diabet Med 1997;14:919-28.  Back to cited text no. 15
    
16.Umpierrez GE, Watts NB, Phillips LS. Clinical utility of beta-hydroxybutyrate determined by reflectance meter in the management of diabetic ketoacidosis. Diabetes Care 1995;18:137-8.  Back to cited text no. 16
    
17.American Diabetes Association (ADA). Test of glycemia in diabetes. Diabetes Care 2002;25:S97-9.  Back to cited text no. 17
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


This article has been cited by
1 Evaluation of the Accuracy of Capillary Hydroxybutyrate Measurement Compared with Other Measurements in the Diagnosis of Diabetic Ketoacidosis: A Systematic Review
Joanne Brooke,Marlon Stiell,Omorogieva Ojo
International Journal of Environmental Research and Public Health. 2016; 13(9): 837
[Pubmed] | [DOI]



 

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