Value of Point-of-care Ketones in Assessing Dehydration and Acidosis in Children With Gastroenteritis

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1 ORIGINAL RESEARCH CONTRIBUTION Value of Point-of-care Ketones in Assessing Dehydration and Acidosis in Children With Gastroenteritis Jason A. Levy, MD, Mark Waltzman, MD, Michael C. Monuteaux, ScD, and Richard G. Bachur, MD Abstract Objectives: Children with gastroenteritis often develop dehydration with metabolic acidosis. Serum ketones are frequently elevated in this population. The goal was to determine the relationship between initial serum ketone concentration and both the degree of dehydration and the magnitude of acidosis. Methods: This was a secondary analysis of a prospective trial of crystalloid administration for rapid rehydration. Children 6 months to 6 years of age with gastroenteritis and dehydration were enrolled. A point-of-care serum ketone (beta-hydroxybutyrate) concentration was obtained at the time of study enrollment. The relationship between initial serum ketone concentration and a prospectively assigned and previously validated clinical dehydration score, and serum bicarbonate concentration, was analyzed. Results: A total of 188 patients were enrolled. The median serum ketone concentration was elevated at 3.1 mmol/l (interquartile range [IQR] = 1.2 to 4.6 mmol/l), and the median dehydration score was consistent with moderate dehydration. A significant positive relationship was found between serum ketone concentration and the clinical dehydration score (Spearman s rho = 0.22, p = 0.003). Patients with moderate dehydration had a higher median serum ketone concentration than those with mild dehydration (3.6 mmol/l vs. 1.4 mmol/l, p = 0.007). Additionally, the serum ketone concentration was inversely correlated with serum bicarbonate concentration (q = 0.26, p < 0.001). Conclusions: Children with gastroenteritis and dehydration have elevated serum ketone concentrations that correlate with both degree of dehydration and magnitude of metabolic acidosis. Point-of-care serum ketone measurement may be a useful tool to inform management decisions at the point of triage or in the initial evaluation of children with gastroenteritis and dehydration. ACADEMIC EMERGENCY MEDICINE 2013; 20: by the Society for Academic Emergency Medicine Acute gastroenteritis is one of the most common reasons for emergency department (ED) visits and accounts for approximately 10% of all pediatric admissions, most commonly due to dehydration. 1 4 The degree of dehydration, however, may be difficult to judge precisely, and numerous research investigations have attempted to quantify the level of volume depletion with both clinical and laboratory parameters. 5 In a previous study we found that children with gastroenteritis and dehydration have elevated serum ketones. 6 Metabolic acidosis from ketonemia may contribute to ongoing nausea, vomiting, and malaise. With appropriate rapid rehydration, we demonstrated that these ketones could be lowered significantly. Furthermore, many children with moderate to severe dehydration have low serum bicarbonate with an anion gap acidosis. 7 9 Previous data have suggested that serum bicarbonate is the most accurate laboratory parameter in the assessment of degree of dehydration 5,10,11 and may be useful in determining which patients will tolerate oral rehydration therapy 9 or need prolonged intravenous (IV) fluids and observation. 7 No other previous studies have demonstrated elevated serum ketone concentrations in this population or correlated serum ketones with clinical parameters of dehydration or magnitude of acidosis in children with gastroenteritis. We sought to assess the relationship between serum ketone concentration and the degree of dehydration as From the Division of Emergency Medicine, Boston Children s Hospital, Harvard Medical School, Boston, MA. Received April 3, 2013; revisions received June 11 and June 28, 2013; accepted June 29, The study was partially funded by a private industry grant from Abbott Laboratories. The authors have no other financial relationships relevant to this article and no conflicts of interest to disclose. Supervising Editor: Lawrence M. Lewis, MD. Address for correspondence and reprints: Jason Levy, MD; jason.levy@childrens.harvard.edu. ISSN by the Society for Academic Emergency Medicine 1146 PII ISSN doi: /acem.12256

2 ACADEMIC EMERGENCY MEDICINE November 2013, Vol. 20, No measured by a previously validated clinical dehydration score, 12 as well as the relationship between serum ketone and serum bicarbonate concentrations. We hypothesized that serum ketones would correlate with both the severity of dehydration and the degree of acidosis. If true, then point-of-care ketone measurement might provide an opportunity to aid in the initial assessment of dehydration or help guide triage decisions. METHODS Study Design This was a secondary analysis of a registered (Clinical- Trials.gov #NCT ) prospective, double-blind, randomized controlled clinical trial investigating the use of an IV dextrose bolus for children with symptoms of gastroenteritis and dehydration requiring IV fluids. 6 The study was approved by the hospital institutional review board. Written informed consent was obtained from parents or guardians. Study Setting and Population Participants were enrolled from November 2007 to December 2010 at an urban, academic, tertiary care hospital with approximately 60,000 ED visits per year. Eligible children included those aged 6 months to 6 years who had symptoms of gastroenteritis and who were felt to require IV fluids for dehydration as determined by the treating attending physician. A convenience sample of children was identified when a study enroller (research assistant or study investigator) was available. Subjects were excluded if they had histories of chronic illness or disorder of glucose metabolism, had symptoms for more than 7 days, received IV fluids in the previous 12 hours, or were suspected to have comorbid conditions such as pneumonia, urinary tract infection, or appendicitis. Study Protocol As part of the original study protocol, each patient was required to have an IV catheter placed for fluid administration. At the time of catheter placement, point-of-care serum glucose and ketone concentrations were obtained and recorded by the study enroller (Precision Xtra blood glucose and ketone monitoring system; Abbott Laboratories, Libertyville, IL). The ketone measured by this bedside monitoring system (and thus defined for this study) was beta-hydroxybutyrate only. All medical team members and caretakers were blinded to bedside measurements unless the serum glucose was less than 40 mg/dl or greater than 200 mg/dl, at which point the patient was removed from the study protocol. Prior to fluid administration, the treating physician completed a standardized data form that included 10 clinical parameters related to dehydration including assessment of decreased urine output, tired general appearance, elevated heart rate, abnormal respirations, delayed capillary refill time, dry mucous membranes, absence of tears, sunken eyes, abnormal skin turgor, and poor peripheral perfusion or pulses; this information was used to calculate a dehydration score (one point for each) based on previously published data. 12 As previously reported and defined for this analysis, dehydration was stratified as mild (score = 0 to 2), moderate (score = 3 to 6), or severe (score = 7 to 10). The treating attending physician also assigned a general appearance score using a five-point scale (with 1 = obtunded to 5 = alert and active). Data Analysis The main outcomes were the correlations between initial point-of-care serum ketone concentration, and both the dehydration score and the degree of metabolic acidosis as measured by serum bicarbonate concentration. We also analyzed the correlation between serum bicarbonate and the dehydration score. We then compared the correlation coefficients to determine which parameter was more strongly associated with the dehydration score, serum ketones, or serum bicarbonate. Additional analyses compared serum ketones to 1) serum glucose, 2) the prospectively assigned appearance score, and 3) duration of symptoms. Demographic data are reported as frequencies, with medians and interquartile ranges (IQRs) for ordered nonnormal data and means with standard deviations (SDs) for continuous normally distributed data. We compared median ketone concentrations between groups stratified by dehydration score using the nonparametric equality-of-medians test. To assess relationships between continuous variables, we used the Spearman correlation. We generated scatter plots with best-fitting regression lines and corresponding 95% confidence intervals to depict the relationship between ketone concentration and bicarbonate and glucose concentrations. RESULTS Study enrollers identified and approached 231 eligible patients, 32 of whom declined participation. Five patients were withdrawn after consent because of either inability to obtain IV access (n = 4) or a change in diagnosis from gastroenteritis (n = 1) at the time of consent. Six patients were excluded as part of the study protocol because of initial serum glucose concentrations less than 40 mg/dl. A total of 188 subjects were enrolled. Five children were ultimately found to have diagnoses other than gastroenteritis: two patients with urinary tract infection, two patients with pneumonia, and one patient with glomerulonephritis and acute renal failure. Data from these patients were included in all analyses. Characteristics of study subjects and serum ketone concentrations are shown in Table 1. The median serum ketone concentration was 3.1 mmol/l (IQR = 1.2 to 4.6 mmol/l), where normal is <0.2 mmol/l. The median dehydration score was 4 (IQR = 3 to 5; range = 0 to 7), consistent with moderate dehydration as defined above. Seventy-two percent of children were acidotic with serum bicarbonates less than or equal to 20 mmol/l. Of enrolled patients, 26 of 173 (15%) were hypoglycemic (glucose < 60 mg/dl) on their initial point-of-care glucose measurements. We found a significant positive relationship between serum ketone concentration and the prospectively assigned dehydration score (Spearman s q = 0.22, p = 0.003). For each interval increase in serum ketone

3 1148 Levy et al. SERUM KETONES IN DEHYDRATION AND METABOLIC ACIDOSIS Table 1 Baseline Characteristics of Study Subjects Characteristic (n = 188) Results Age (yr), median (IQR) 2.3 ( ) Dehydration score, median (IQR) 4 (3 5) Score > 2 (%) 79 Beta-hydroxybutyrate concentration 3.1 ( ) (mmol/l), median (IQR) Duration of symptoms (days), median (IQR) 2.5 (2 3) <1 (%) (%) 27 3 (%) 50 General appearance score, median (IQR) 3 (3 4) Laboratory measurements (n = 173) Glucose (mg/dl), mean (SD) 78 (18.5) Glucose < 60 mg/dl (%) 15 Bicarbonate (mmol/l), mean (SD) 18 (3.6) Bicarbonate 20 mmol/l (%) 72 IQR = interquartile range. concentration, there was a greater percentage of children with at least moderate dehydration, as shown in Figure 1. Additionally, patients with moderate dehydration had a higher median serum ketone concentration than those with mild dehydration (3.6 mmol/l vs. 1.4 mmol/l, p = 0.007) by the clinical dehydration score. Serum ketone concentration was inversely correlated with serum bicarbonate concentration (q = 0.26, p < 0.001; see Figure 2). We found a significant positive relationship between serum bicarbonate concentration and dehydration score (Spearman s q = 0.19, p= 0.011). When compared, the correlation between ketones and dehydration score was significantly stronger than the correlation between bicarbonate and dehydration score (Wald v 2 (1) = 5.51, p = 0.019). For the additional analyses, we found that serum ketone concentration was significantly correlated with both general appearance score (q = 0.26, p < 0.001) and serum glucose concentration (q = 0.74, p < 0.001). As ketone concentration rose, subjects had lower general appearance scores (i.e., were less active/alert) and lower serum glucose concentrations (Figure 3). In comparing subjects with respect to length of symptoms, there was a significant difference in ketone concentrations between patients with symptom duration of less than 1 day versus 1 to 2 days (median = 1.3 mmol/l vs. 3.8 mmol/l, respectively; p = 0.001) and between patients with symptom duration of less than 1 day versus longer than 3 days (median = 1.3 mmol/l vs. 4.0 mmol/l, respectively; p < 0.001), but not between patients with symptom duration of 1 to 2 days versus longer than 3 days (median = 3.8 mmol/l vs. 4.0 mmol/ L, respectively; p = 0.736; Figure 4). DISCUSSION We found a statistically significant relationship between serum ketone concentration and the degree of dehydration as evidenced both by a clinical dehydration score and by serum bicarbonate concentration. To our knowledge, we are the first to report an elevated serum ketone concentration in children with gastroenteritis and to show a correlation between serum ketones and historical, physical examination, and laboratory findings associated with dehydration. While clinical examination should remain the mainstay of evaluating children with dehydration, our findings suggest that point-of-care serum ketone measurement might provide an opportunity to aid in the assessment of level of dehydration and thereby help guide management in select children. Because clinical assessment is still inexact and bedside ketone concentration is available immediately, point-of-care testing for ketones may provide the most benefit by augmenting triage decisions currently based on historical and physical examination findings alone or in settings where a clinician with considerable pediatric experience is not present to assess dehydration more precisely. Children with acute gastroenteritis and dehydration are often found to have low serum bicarbonate concen- Percent Moderately Dehydrated by Score n=21 n=72 n=27 n=32 n= > 4 Serum Ketone Concentration (mmol/l) Figure 1. Percentage of patients who were at least moderately dehydrated by clinical dehydration score stratified by serum ketone concentration.

4 ACADEMIC EMERGENCY MEDICINE November 2013, Vol. 20, No Figure 2. Relationship between serum ketone concentration and serum bicarbonate concentration. Figure 3. Relationship between serum ketone concentration and serum glucose concentration. malnutrition, severe dehydration, and greater than 14 days of diarrheal illness. We suspect that children living in industrialized nations would have a different pathophysiologic process for development of acidosis in dehydration. Young children have more limited reserves of stored glycogen than adults, and those with gastroenteritis often refuse any oral intake due to nausea. As glycogen stores become depleted, fat metabolism ensues leading to ketoacid production, thereby contributing to metabolic acidosis. We are the first to show a monotonic relationship between serum ketone and bicarbonate concentrations and contend that ketoacidosis contributes some portion to the metabolic acidosis in dehydrated patients with gastroenteritis. Additionally, we found that children with greater than 1 day of symptoms were more likely to be ketotic and that those with elevated ketones were more likely to be moderately dehydrated. These results lend further evidence that there needs to be adequate time required to deplete glycogen stores before free fatty acids can accumulate. Finally, we also found a relationship between serum ketone concentration and both glucose concentration and length of symptoms. As ketone concentrations rose, serum glucose concentrations declined, and there was no patient with a glucose concentration of less than 70 mg/dl who had a normal ketone concentration. These findings are consistent with the hypothesis that glycogen stores are depleted over time, leading to fat metabolism and ketoacid production. Additionally, in previously published data 6 we demonstrated that children who received boluses of 5% dextrose in normal saline had greater reductions in serum ketones when compared to those who received normal saline boluses without dextrose, lending evidence that providing IV dextrose can arrest or reduce this fatty acid production in children with metabolic acidosis. LIMITATIONS Figure 4. Relationship between serum ketone concentration and length of symptoms. trations and anion gap acidosis. 5 9,11,13 Studies around serum bicarbonate have shown that it may be useful to assess degree of dehydration, 8,11 it can predict success of oral rehydration therapy, 9 and it can determine patient disposition. 7 Only one study, however, has addressed the source of the metabolic acidosis. Weizman et al. 14 found that children with anion gap acidosis had significant elevations in serum lactate secondary to decreased perfusion of tissues. The population studied, however, consisted of nomadic Bedouins with severe This was a secondary analysis of a convenience sample of patients enrolled for a randomized clinical trial. Subjects were already deemed to require IV rehydration as part of the primary study protocol. Consequently, we are only able to assess the relationship between serum ketones and laboratory or clinical variables in this chosen group of patients who were already considered dehydrated by the treating clinicians. How serum ketone concentration may correlate with degree of dehydration and metabolic acidosis in children presenting along the full spectrum of dehydration requires further study. Although we showed a relationship between elevated ketones and low serum bicarbonate, we cannot determine the proportion of acidosis secondary to ketones versus other anions such as lactate. Lactic acid generation, however, normally occurs from anaerobic metabolism secondary to poor tissue perfusion and usually requires significant hypovolemia, hypoxemia, anemia, hypotension, or sepsis-like syndromes; children with mild to moderate dehydration likely do not fall into this category. Additionally, our experience suggests that patients with prolonged or profound diarrhea but without dehydration may still have low serum bicarbonate associated with nonanion gap acidosis. We would not expect a correlation between

5 1150 Levy et al. SERUM KETONES IN DEHYDRATION AND METABOLIC ACIDOSIS serum ketone concentration and dehydration level or serum bicarbonate concentration in this population. Finally, because this was a secondary analysis of a prospective, double-blind trial, subjects were randomized to one of two study treatments and therefore outcomes subsequent to fluid administration could not be assessed. CONCLUSIONS Children with gastroenteritis requiring intravenous rehydration had elevated serum beta-hydroxybutyrate concentrations that correlated with both degree of dehydration and magnitude of metabolic acidosis. Our findings suggest that point-of-care serum ketone measurement may be a useful tool to inform management decisions at the point of triage or in the initial evaluation of children with gastroenteritis and dehydration. References 1. McConnochie KM, Conners GP, Lu E, Wilson C. How commonly are children hospitalized for dehydration eligible for care in alternative settings? Arch Pediatr Adolesc Med. 1999; 153: Glass RI, Lew JF, Gangarosa RE, LeBaron CW, Ho MS. Estimates of morbidity and mortality rates for diarrheal diseases in American children. J Pediatr. 1991; 118:S American Academy of Pediatrics. Practice Parameter: The management of acute gastroenteritis in young children. American Academy of Pediatrics, Provisional Committee on Quality Improvement, Subcommittee on Acute Gastroenteritis. Pediatrics 1996; 97: King CK, Glass R, Bresee JS, Duggan C. Managing acute gastroenteritis among children, oral rehydration, maintenance, and nutritional therapy. MMWR Recomm Rep. 2003; 52: Steiner MJ, DeWalt DA, Byerley JS. Is this child dehydrated? JAMA. 2004; 291: Levy JA, Bachur RG, Monuteaux MC, Waltzman M. Intravenous dextrose for children with gastroenteritis and dehydration: a double-blind randomized controlled trial. Ann Emerg Med. 2012; 61: Wathen JE, MacKenzie T, Bothner JP. Usefulness of the serum electrolyte panel in the management of pediatric dehydration treated with intravenously administered fluids. Pediatrics. 2004; 114: Yilmaz K, Karabocuoglu M, Citak A, Uzel N. Evaluation of laboratory tests in dehydrated children with acute gastroenteritis. J Paediatr Child Health. 2002; 38: Reid SR, Bonadio WA. Outpatient rapid intravenous rehydration to correct dehydration and resolve vomiting in children with acute gastroenteritis. Ann Emerg Med. 1996; 28: Mackenzie A, Shann F, Barnes G. Clinical signs of dehydration in children. Lancet. 1989; 2: Vega RM, Avner JR. A prospective study of the usefulness of clinical and laboratory parameters for predicting percentage of dehydration in children. Pediatr Emerg Care. 1997; 13: Gorelick MH, Shaw KN, Murphy KO. Validity and reliability of clinical signs in the diagnosis of dehydration in children. Pediatrics. 1997; 99:E Madati PJ, Bachur R. Development of an emergency department triage tool to predict acidosis among children with gastroenteritis. Pediatr Emerg Care. 2008; 24: Weizman Z, Houri S. Ben-Ezer Gradus D. Type of acidosis and clinical outcome in infantile gastroenteritis. J Pediatr Gastroenterol Nutr. 1992; 14: