Diabetic Ketoacidosis in Adolescents and Children: A Prospective Study of Blood versus Urine Ketones in Monitoring Therapeutic Response.

BACKGROUND: diabetic ketoacidosis (DKA) is a potentially lethal complication of diabetes mellitus (DM). There is no study in Indonesia that compares the much-preferred capillary beta hydroxybutirate (ß-OHB) measurement to urine acetoacetate in monitoring therapeutic response of DKA in adolescents. METHODS: a prospective study of 37 adolescents and children with DKA in Cipto Mangunkusumo Hospital was done between June 2006 and March 2011. The patients were followed until the time of DKA resolution. Hourly measurement of random blood glucose, capillary ß-OHB concentration, and urine ketones were done, while blood gas analysis and electrolyte were measured every four hours. RESULTS: median time to resolution was 21 (9-52) hours. Compared to urine ketones, capillary ß-OHB concentration showed stronger correlation with pH (r= -0,52, p= 0,003 vs r= -0,49, p= 0,005) and bicarbonate level (r=-0,60, p=0.000 vs r= -0.48, p=0.007) during the median time of DKA resolution. All capillary ß-OHB measurement yielded negative results at median time of DKA resolution, while urine ketones were still detected up to 9 hours after resolution. CONCLUSION: blood ketone concentration showed better correlation with pH and bicarbonate level, as a tool to monitor therapeutic response in DKA in adolescent, compared to traditional urine ketones test in adolescents.

Old and new approaches to the interpretation of acid-base metabolism, starting from historical data applied to diabetic acidosis.

The approach to acid-base chemistry in medicine includes several methods. Currently, the two most popular procedures are derived from Stewart's studies and from the bicarbonate/BE-based classical formulation. Another method, unfortunately little known, follows the Kildeberg theory applied to acid-base titration. By using the data produced by Dana Atchley in 1933, regarding electrolytes and blood gas analysis applied to diabetes, we compared the three aforementioned methods, in order to highlight their strengths and their weaknesses. The results obtained, by reprocessing the data of Atchley, have shown that Kildeberg's approach, unlike the other two methods, is consistent, rational and complete for describing the organ-physiological behavior of the hydrogen ion turnover in human organism. In contrast, the data obtained using the Stewart approach and the bicarbonate-based classical formulation are misleading and fail to specify which organs or systems are involved in causing or maintaining the diabetic acidosis. Stewart's approach, despite being considered 'quantitative', does not propose in any way the concept of 'an amount of acid' and becomes even more confusing, because it is not clear how to distinguish between 'strong' and 'weak' ions. As for Stewart's approach, the classical method makes no distinction between hydrogen ions managed by the intermediate metabolism and hydroxyl ions handled by the kidney, but, at least, it is based on the concept of titration (base-excess) and indirectly defines the concept of 'an amount of acid'. In conclusion, only Kildeberg's approach offers a complete understanding of the causes and remedies against any type of acid-base disturbance.

Utility of ketone measurement in the prevention, diagnosis and management of diabetic ketoacidosis.

Ketone measurement is advocated for the diagnosis of diabetic ketoacidosis and assessment of its severity. Assessing the evidence base for ketone measurement in clinical practice is challenging because multiple methods are available but there is a lack of consensus about which is preferable. Evaluating the utility of ketone measurement is additionally problematic because of variability in the biochemical definition of ketoacidosis internationally and in the proposed thresholds for ketone measures. This has led to conflicting guidance from expert bodies on how ketone measurement should be used in the management of ketoacidosis. The development of point-of-care devices that can reliably measure the capillary blood ketone ß-hydroxybutyrate (BOHB) has widened the spectrum of applications of ketone measurement, but whether the evidence base supporting these applications is robust enough to warrant their incorporation into routine clinical practice remains unclear. The imprecision of capillary blood ketone measures at higher values, the lack of availability of routine laboratory-based assays for BOHB and the continued cost-effectiveness of urine ketone assessment prompt further discussion on the role of capillary blood ketone assessment in ketoacidosis. In the present article, we review the various existing methods of ketone measurement, the precision of capillary blood ketone as compared with other measures, its diagnostic accuracy in predicting ketoacidosis and other clinical applications including prevention, assessment of severity and resolution of ketoacidosis.

Bicarbonate therapy in severe metabolic acidosis.

The utility of bicarbonate administration to patients with severe metabolic acidosis remains controversial. Chronic bicarbonate replacement is obviously indicated for patients who continue to lose bicarbonate in the ambulatory setting, particularly patients with renal tubular acidosis syndromes or diarrhea. In patients with acute lactic acidosis and ketoacidosis, lactate and ketone bodies can be converted back to bicarbonate if the clinical situation improves. For these patients, therapy must be individualized. In general, bicarbonate should be given at an arterial blood pH of < or =7.0. The amount given should be what is calculated to bring the pH up to 7.2. The urge to give bicarbonate to a patient with severe acidemia is apt to be all but irresistible. Intervention should be restrained, however, unless the clinical situation clearly suggests benefit. Here we discuss the pros and cons of bicarbonate therapy for patients with severe metabolic acidosis.

Use of capillary ketones monitoring in treatment of mild ketotic crisis in people with ketosis-prone atypical diabetes.

This study was carried out to assess the potential reduction in duration of intensive diabetic ketoacidosis treatment in adults with ketosis-prone atypical diabetes (KPD) when using capillary versus urinary ketones. In this cross-sectional study, we included 20 people with KPD presented at the National Obesity Center of the Yaoundé Central Hospital with hyperglycemic decompensation (random capillary glucose ≥13 mmol/L) and significant ketosis (ketonuria≥++) requiring intensive insulin treatment. In all subjects, intensive insulin treatment was initiated at 10 UI per hour with simultaneous measurement of capillary beta-hydroxybutyrate and ketonuria every 2 hours until disappearance of ketonuria. Time-to-disappearance of urine ketones was compared with the time-to-normalization of capillary ß-hydroxybutyrate concentrations. Subjects were aged 46±13 years with a median duration of diabetes of 1.5 (IQR: 0-2.5) years. On admission, the mean blood glucose was 22.8±5 mmol/L and capillary ketones level was 2.9±2.7 mmol/L. The median time-to-disappearance of ketonuria was 5 (IQR: 3-8) hours compared with the time-to-normalization of capillary ß-hydroxybutyrate of 4 (IQR: 2-6) hours, p=0.0002. The absolute difference in time-to-normalization of ketonuria versus ketonemia was 2 (IQR: 1-3) hours and the relative time reduction of treatment was 32.5%±18.0%. Our results suggested that the use of capillary ketones versus ketonuria would allow a significant reduction in duration of intensive insulin treatment by one third in people with KPD.

Evaluation of a portable meter to measure ketonemia and comparison with ketonuria for the diagnosis of canine diabetic ketoacidosis.

BACKGROUND: The diagnosis of canine diabetic ketoacidosis (DKA) usually is based on measurement of urinary acetoacetate (ketonuria). In humans, this test is less sensitive and specific than blood 3-beta-hydroxybutyrate (ketonemia) evaluation. HYPOTHESIS: Ketonemia measurement using a portable meter is more accurate than ketonuria determination with a dipstick to diagnose canine DKA. ANIMALS: Seventy-two client-owned diabetic dogs with ketonemia, ketonuria, or both. METHODS: Prospective observational study. Based on blood bicarbonate concentration and anion gap, dogs were divided into 2 groups: patients with DKA (n= 25); patients with diabetic ketosis (n= 47). Sensitivity, specificity, and positive and negative likelihood ratio (LR) at different cut-off points were determined for both ketonemia and ketonuria. Receiver operating characteristic (ROC) analysis was used to assess the accuracy of each diagnostic test to diagnose DKA. RESULTS: With regard to ketonemia, cut-off values of 2.3 and 4.3 mmol/L revealed 100% sensitivity and 100% specificity, respectively, whereas cut-off values of 2.8 and 3.5 mmol/L showed a -LR of 0.05 and a + LR of 13.16, respectively. With regard to ketonuria, a cut-off value of 1+ revealed 92% sensitivity, 40% specificity, and -LR of 0.20, whereas a cut-off value of 3+ revealed 44% sensitivity, 94% specificity, and +LR of 6.89. The areas under the ROC curves for the ketonemia and ketonuria tests were significantly different (0.97 and 0.81, respectively, P= .003). CONCLUSIONS AND CLINICAL IMPORTANCE: Measurement of ketonemia is accurate and more effective than measurement of ketonuria to diagnose canine DKA.

Ketone measurements using dipstick methodology in cats with diabetes mellitus.

OBJECTIVES: To compare the results of urine and plasma ketone dip test in a group of diabetic cats with possible ketosis or ketoacidosis, using laboratory plasma beta-hydroxybutyrate measurements as the gold standard. METHODS: According to clinical examinations, plasma beta-hydroxybutyrate measurements and venous blood gas analysis, 54 cats with diabetes mellitus were classified as non-ketotic (n=3), ketotic (n=40) or ketoacidotic (n=11). Plasma and urine acetoacetate concentrations were determined using urine reagent strips. RESULTS: Although there was a significant positive correlation between blood and urine ketone measurements (r=0.695, P<0.001), the results differed significantly (Z=-3.494, P<0.001). Using the differential positive rates, the best cut-off value to detect cats with ketoacidosis was 1.5 mmol/l for urine and 4 mmol/l for plasma. The sensitivity/specificity was 82/95 per cent for urine and 100/88 per cent for plasma, respectively. CLINICAL SIGNIFICANCE: The urine and plasma ketone dip tests have a different diagnostic accuracy, and results have to be interpreted differently. Because of its high sensitivity, the plasma ketone dip test performs better than the urine ketone dip test to identify cats with impending or established ketoacidosis.

Comparison of capillary blood ketone measurement by electrochemical method and urinary ketone in treatment of diabetic ketosis and ketoacidosis in children.

We aimed to compare the recent practical method of capillary beta-hydroxy butyrate (betaOHB) measurement with the widely used urinary ketone measurement in monitoring metabolic status of the patient during treatment of diabetic ketoacidosis (DKA) and diabetic ketosis (DK). Patients with DKA and DK admitted to the hospital were followed with simultaneous measurements of capillary betaOHB by electrochemical method (Medisense Optium, Abbott), and urinary ketone by semi-quantitative method. Blood gases were measured in 2-4 h intervals. Fourteen patients with DKA/DK (7 males and 7 females, age: 9.2 +/- 4.2 years) were included with 50 simultaneous measurements of capillary and urinary ketone. No correlation was detected between urinary ketone and blood pH (P = 0.06) and HCO3 (P = 0.79), whereas a significant negative correlation was found between capillary betaOHB and blood pH (r = -0.41, P < 0.05) and HCO3 (r = -0.35, P < 0.05). Capillary betaOHB and urinary ketone levels did not correlate at the beginning and 3.3 +/- 1.4 h after treatment, but did correlate in the third samples taken 7.8 +/- 2.0 h after treatment (r = 0.8, P < 0.05). Capillary betaOHB levels show good correlation with the degree of acidosis (pH and HCO3). Capillary betaOHB measurement is more sensitive than urinary ketone measurement in reflecting the patient's metabolic status and improvement during treatment.

Ketonuria in pregnancy--with special reference to calorie-restricted food intake in obese diabetics.

Early morning ketonuria, as judged by Ketostix testing, occurred in 19% of urine samples from insulin-independent diabetic pregnant women eating 1000 calorie diets, in 14% from diabetics on higher calorie diets, and in 7% of urines from nondiabetic pregnant women. Ketostix test was never found to be positive in blood, even when it was 2+ in urine samples, and acetoacetate levels were always below 1 mmol/L. Enzymatic estimations of acetoacetate (AA) and beta-hydroxybutyrate (BB) in urine and plasma samples revealed (1) no significant differences in range or mean between the groups receiving different restricted diets or full diets, the highest value observed for plasma AA being 0.34 mmol/L; (2) that Ketostix became positive at a concentration of AA above 1 mmol/L and that such a value in urine corresponded to plasma levels of between 0.06 and 0.1 mmol/L, i.e., double the normal; and (3) a 50-100-fold increase in urine AA when blood levels exceeded 0.08 mmol/L. Neonates born to diabetic mothers with ketonuria had no fetal distress or asphyxia neonatorum. The lowest Apgar score at 5 min was 8; 80% of neonates had a score of 10. Hence, positive Ketostix tests in urine samples do not indicate toxic levels in the blood, and a 1000 calorie diet for obese pregnant diabetics appears to be safe as regards neonatal outcome.

Bone calcium changes during diabetic ketoacidosis: a comparison with lactic acidosis due to volume depletion.

In this study, we aimed to compare bone calcium system changes from children with diabetic ketoacidosis or acute metabolic acidosis due to dehydration to find out the relative contribution of metabolic acidosis and diabetes-related factors on expected negative calcium balance. We studied a set of non-invasive parameters of bone remodeling in 16 children with diabetic ketoacidosis due to new onset type 1 diabetes and 25 children with acute metabolic acidosis due to dehydration complicating acute gastroenteritis before and after the correction of acidosis. The two groups of subjects were matched for age, sex, pubertal status, and degree of metabolic acidosis and dehydration. A group of 18 age and sex-matched healthy children served as the control group. Plasma ionized calcium levels were increased in both groups, significantly more so in diabetic ketoacidosis. While osteoblastic markers, osteocalcin and alkaline phosphatase, were depressed to a comparable degree in both groups, urinary calcium/creatinine ratio and hydroxyproline excretion were significantly greater in diabetic ketoacidosis. No significant changes in calcitrophic hormone (intact PTH, calcitonin, 25-hydroxy vitamin D3) levels were observed. All study parameters except for serum phosphate levels behaved in parallel in both clinical conditions, and abnormalities disappeared with the correction of acidosis except for IGF-1, which remained low in diabetic subjects. In conclusion, our results suggest that, in diabetic ketoacidosis, the observed severe negative calcium balance occurred through diminished bone formation mediated by metabolic acidosis per se and increased bone mineral dissolution and bone resorption because of severe insulin deficiency and secondarily via metabolic acidosis. Observed changes appear to be independent of calcitrophic hormones.

Urine C-peptide after recovery from diabetic ketoacidosis: an index of insulin dependency.

C-peptide immunoreactivity (CPR) in 24-h urine was assayed in 13 diabetic patients during and after recovery from ketoacidosis. In 10 patients who remained insulin-dependent on discharge and in the subsequent follow-up period, urine CPR was low (18 micrograms/day or less), while in three patients who were ultimately controlled by diet or sulfonylureas, urine CPR was normal (59-92 micrograms/day, normal value 74 +/- 26 micrograms/day). In the latter group, urine CPR in one patient assayed during ketoacidosis was 6 micrograms/day and, in another patient, it was 22 micrograms/day on the 3rd day of the admission. This may imply that in the latter group, B-cell function was decompensated in ketoacidosis, but was restored after recovery. Clinical courses suggested that these patients were not in the remission phase of IDDM, but belonged to NIDDM. Among other groups of diabetic patients, urine CPR in those treated with diet or sulfonylureas was 72 +/- 30 micrograms/day and always higher than 20 micrograms/day. The prevalence of urine CPR less than 20 micrograms/day was more frequent in those with younger onset of diabetes, higher insulin dosage, unstable diabetes, or previous history of ketoacidosis among insulin-treated patients. We suggest that urine CPR less than 20 micrograms/day is an index of insulin dependency, although in a state of extreme decompensation of B-cells such as in ketoacidosis, urine CPR can be decreased low even in NIDDM.

The urine anion gap: the critical clue to resolve a diagnostic dilemma in a patient with ketoacidosis.

Usually, ketoacidosis presents few if any diagnostic or therapeutic problems; in this article, we report a case where ketoacidosis was clinically occult and biochemically obscure. The patient presented with acute pancreatitis associated with a modest antecedent alcohol intake. Metabolic acidosis with a normal anion gap (10 meq/L) was observed together with moderate hyperglycemia and a 2 + (but not 4 +) test for serum ketones. None of the usual causes of metabolic acidosis with a normal anion gap was identified nor was there an obvious explanation for a reduction in unmeasured anion gap (e.g., hypoalbuminemia, dysproteinemia, or the presence of abnormal halides). Despite the initial normal anion gap, ketoacidosis was suspected clinically and this was confirmed by the elevated serum B-hydroxybutyrate of 8 mmol/L. We deduced that the serum unmeasured anions, which should have been increased by at least 8 meq/L, were being underestimated because of the effect of hypertriglyceridemia on the serum chloride determination. When the serum chloride was reestimated by a method not influenced by hyperlipidemia, the value was 102 mmol/L not 112 mmol/L and, when reevaluated, the anion gap was indeed appropriately elevated. In addition, the urine anion gap (Na + K - Cl) was 103 meq/L in the absence of renal disease. This indicated that the expected large quantity of urinary ammonium must have been masked by an even greater quantity of unmeasured anion; in this case proven by direct measurement to be B-hydroxybutyrate. Finally, metabolism of the alcohol ingested, which yields hepatic NADH, could explain, in part, the modest hyperglycemia and the absence of a 4 + test for serum ketones.(ABSTRACT TRUNCATED AT 250 WORDS)

Ketonemia and ketonuria in gestational diabetes mellitus.

BACKGROUND: The use of capillary blood 3-ß-hydroxybutyrate (3HB) is a more precise method than urine ketones measurement for the diagnosis of diabetic ketoacidosis. Fasting ketonuria is common during normal pregnancy, while there is evidence that it is increased among pregnant women with Gestational Diabetes Mellitus (GDM) who are on a diet. 3HB levels have been related to impaired offspring psychomotor development. Reports with concomitant measurement of blood and urine ketones in women with GDM who followed a balanced diet are lacking. OBJECTIVE: To compare the prevalence of fasting ketonemia and ketonuria in women with GDM following the Institute of Medicine diet instructions and assess their possible relation with metabolic parameters and therapeutic interventions. RESEARCH DESIGN AND METHODS: 180 women with GDM were studied. In each patient, in successive visits, capillary blood and urine ketones were simultaneously measured. The total measurements were 378, while the average number of measurements per patient was 2.1. RESULTS: The prevalence of ketonuria was significantly higher than that of ketonemia (x(2)=21.33, p <0.001). Significantly higher mean 3HB levels were observed with respect to ketonuria severity (p=0.001). Bedtime carbohydrate intake was associated with significantly lower 3HB levels (p=0.035). Insulin treatment was associated with significant 3HB levels reduction (p=0.032). Body weight reduction per week between two serial visits was associated with increased 3HB levels (p=0.005). Multiple linear regression analysis showed that weight loss remained the only independent predictor of 3HB levels. CONCLUSIONS: The presence of ketonemia was significantly lower than the presence of ketonuria. Weight loss per week was the only independent factor found to be associated with increased levels of 3HB. The clinical significance of this small increase requires further investigation.

Sulfur amino acid metabolism in juvenile-onset nonketotic and ketotic diabetic patients.

Sulfur amino acid metabolism was studied in non-fasting nonketotic and ketotic juvenile-onset diabetic children and the results were compared to age-matched healthy children on an ordinary diet. An increased excretion of total sulfur and inorganic sulfate was found in diabetic children, probably a result of a decreased protein-serum synthesis and/or increased endogenous protein catabolism, although as a result of hyperglycemia a decreased tubular reabsorption may also have contributed. All diabetics showed a normal excretion of methionine. For cyst(e)ine and taurine an increased excretion was seen in ketotic diabetics, probably also a consequence of an increased endogenous protein degradation. As a sign of the latter, an increased output of 3-methylhistidine was also observed, a confirmation of earlier reports. The increased output of mercaptolactate and mercaptoacetate found in ketotic patients, was probably also a result of enhanced endogenous protein degradation. An increased urinary excretion of N-acetylcysteine was seen in diabetic children, which may reflect an enhanced availability to acetyl coenzyme A.

Ketone interference in estimation of urinary creatinine; effect on creatinine clearance in diabetic ketoacidosis.

Acetoacetate is known to spuriously raise serum creatinine concentration in patients with diabetic ketoacidosis. Its effect on urinary creatinine has not been studied. Since the renal threshold for ketoacids is low, large amounts of acetoacetate may be present in the urine of uncontrolled diabetics. We investigated this interference using three different automated analysers. We found that +3 or +4 reactions with Ketostix, equivalent to greater than 10 - 15 mmol/L of acetoacetate caused significant interference with the Abbott VP and Beckman Astra instruments. This could cause errors in the calculation of creatinine clearance especially when serum creatinine is close to a normal level. We recommend that measurement of creatinine clearance be delayed until better diabetic control is achieved or the creatinine be measured by a method which is free from ketone interference, e.g., by the Dupont aca.

Increased urinary excretion of beta-hydroxyisovaleric acid in ketotic and non-ketotic type II diabetes mellitus.

To evaluate the catabolism of leucine in diabetes mellitus, the urinary excretion of beta-hydroxyisovaleric acid, a by-product of leucine catabolism, in 21 nonproteinuric type II diabetic patients with and without ketosis and 21 control subjects was measured using gas chromatography-mass spectrometry. Urinary beta-hydroxyisovaleric acid and serum leucine concentrations were higher in the 9 ketotic diabetic patients than in the 12 nonketotic diabetic patients (p less than 0.005, p less than 0.01, respectively) or in the control subjects (p less than 0.01, p less than 0.01, respectively). The serum leucine concentrations in the nonketotic diabetic patients and control subjects did not differ significantly (p greater than 0.05), but urinary beta-hydroxyisovaleric acid concentrations were significantly greater in the former (p less than 0.01). These data suggest that in type II diabetic patients the catabolism of leucine is accelerated even in the absence of ketosis and that the urinary beta-hydroxyisovaleric acid concentration is a useful marker of short-term metabolic control in these patients.