Cerebrospinal Fluid Glucose and Protein in Disposition and Treatment Decisions

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1 298 BRIEF REPORTS Givens et al. CSF GLUCOSE AND PROTEIN Cerebrospinal Fluid Glucose and Protein in Disposition and Treatment Decisions Routine laboratory analysis performed when bacterial meningitis is suspected includes the measurement of cerebrospinal fluid (CSF) glucose and protein levels. In the setting of bacterial meningitis, CSF protein levels are usually elevated, and a CSF glucose concentration less than two-thirds of the blood glucose concentration is common. 1 7 However, neither finding is diagnostic, and retrospective data suggest that CSF glucose and protein levels add little to initial treatment or disposition determinations Previous studies primarily included adults and were retrospective. We concurrently evaluated whether pediatric emergency physicians (EPs) consider either CSF glucose or protein values in making decisions to initiate antibiotic treatment and/or admit to the hospital patients undergoing lumbar puncture. METHODS Study Design. This study evaluated CSF glucose and protein levels in pediatric patients undergoing lumbar puncture. We also surveyed physicians regarding the value of CSF glucose and protein in clinical decision making. The study was approved by the hospitals institutional review boards. Study Setting and Population. Physicians performing lumbar punctures in the emergency departments (EDs) of four tertiary, university-affiliated children s hospitals between April 1, 1997, and vember 0, 1997, were asked to complete a study form at the time clinical care was provided. Study Protocol. Data collected included: patient age, indication for performing the lumbar puncture (febrile neonate 8 weeks of age, rule out meningitis >8 weeks of age, or other), history of current antibiotic therapy, CSF laboratory results [description of fluid appearance, white blood cell (WBC) count and differential, red blood cell (RBC) count, glucose and protein levels, Gram stain results, and serum glucose value, where obtained], patient disposition (admit or discharge), and whether antibiotics were given. In addition, physicians were asked two questions: As an independent factor, did the CSF glucose or protein result cause you to do anything differently regarding 1) your disposition decision (admit/discharge)? and 2) your treatment decision (antibiotics/no antibiotics)? Physicians who responded yes to either query were asked to describe in what way these values affected their decisions. Meningitis was defined as either positive CSF bacterial culture, positive Gram stain for bacteria, or pleocytosis (CSF WBC 5 cells) in the absence of a traumatic lumbar puncture. Children 60 days of age or less were classified as neonates. Classification of reported CSF glucose and protein values as normal or abnormal was done using institution-specific laboratory norms (Table 1), since physicians at those institutions made disposition and treatment decisions based on their local laboratory reference standards. Data Analysis. Categorical data were analyzed using the Pearson chi-square test, using SPSS (SPSS, Inc., Chicago, IL) and Stat-Exact 4 (Cytel Software Corporation, Cambridge, MA). Fisher s exact test was used where appropriate. RESULTS Data from 751 cases of patients undergoing lumbar puncture were reviewed. Seventy-three cases were excluded because physicians had failed to answer the two study questions; 46 because no CSF glucose or protein level had been obtained (e.g., traumatic tap with only enough CSF obtained for culture). The remaining 62 cases formed the study group. Table 2 details characteristics of the study sample. The mean age of the patients was 18.1 months (range days 17 years). Neonates comprised 58% of the study population; accordingly, the median patient age was 1.8 months. Eighty-nine (14%) patients had been pretreated with antibiotics prior to undergoing lumbar puncture: 58 with oral antibiotics, 27 with a parenteral antibiotic such as ceftriaxone, and 4 in whom the route was unspecified. Three hundred twenty-four (5%) of 616 CSF protein results reported were normal by local laboratory standards. Because three of the hospitals use a CSF glucose norm based on comparison with a contemporaneous serum glucose, many reported CSF glucose values were uninterpretable. Of the 52 interpretable CSF glucose values, 229 (65%) were normal for the reporting institution s standards. When CSF glucose values were reclassified as normal or abnormal using a standard reference (The Harriet Lane Handbook ), 601 (95%) were normal, while 12 (2%) were too high and 18 (%) were too low. Conclusions from subsequent data analyses were not altered whether either method of classification was used. Physicians answered that yes, the CSF glucose and/or protein values had an influence on their disposition decisions in 16 cases (2.5%, TABLE 1. rmal Values for Cerebrospinal Fluid (CSF) Glucose and Protein by Participating Institution Study Site CSF Glucose CSF Protein Site 1 2/ serum glucose 0 1 month: mg/dl 1 month 16 years: mg/dl >16 years: mg/dl Site 2 2/ serum glucose 0 1 month: mg/dl 1 2 months: mg/dl >2 months: mg/dl Site mg/dl mg/dl Site 4 2/ serum glucose mg/dl

2 ACADEMIC EMERGENCY MEDICINE March 2000, Volume 7, Number 299 TABLE 2. Demographic Information for 62 Study Patients Site (n) Age, months Mean Median Neonates rmal Glucose* rmal Protein* Pretreated Meningitis Site 1 (126) (64%) 7 (24%) 92 (7%) 10 (8%) 22 (17%) Site 2 (114) (40%) 14 (29%) 80 (71%) 19 (17%) 19 (17%) Site (241) (5%) 200 (8%) 108 (45%) 46 (19%) 29 (12%) Site 4 (151) (7%) 8 (24%) 44 (29%) 14 (10%) 27 (18%) TOTAL (62) (58%) 229 (65%) 24 (5%) 89 (14%) 97 (15%) *rmals based on local institutional standards; % based on evaluable cases. 95% CI = 1.5% to 4.1%) and on their treatment decisions in 1 cases (2.1%, 95% CI = 1.1% to.5%). Pretreatment with antibiotics and whether CSF glucose and protein values were abnormal did not impact physicians disposition or treatment decisions. Patients for whom physicians indicated that the CSF glucose and protein values had influenced their disposition decisions were less likely to be admitted to the hospital (1% vs 7%, 2 = 14.64, p = 0.001) than were patients for whom they had no influence on disposition. Patients for whom physicians indicated that the CSF glucose and protein values had influenced their treatment decisions were less likely to be neonates (15% vs 58%, 2 = 10.1, p = 0.006), less likely to be admitted to the hospital (54% vs 7%, 2 = 40.57, p < 0.001), and less likely to receive antibiotic treatment (46% vs 85%, 2 = 19.0, p < 0.001) than were those for whom they did not influence treatment. There were 97 cases of meningitis (15.%). Patients with meningitis were more likely to have been pretreated with antibiotics (24% vs 1%, 2 = 8.09, p = 0.005) and older (41% neonates vs 61%, 2 = 12.55, p < 0.001) than were patients without meningitis. Whether CSF glucose and protein values were abnormal had no significant influence on disposition or treatment decisions in patients with meningitis, compared with patients without evidence of meningitis. DISCUSSION Physicians decisions to hospitalize and/or initiate treatment with antibiotics in patients undergoing lumbar puncture are often made clinically, before laboratory data are available. This is particularly true in neonates, where management decisions are often protocol-driven. Nevertheless, laboratory tests, including CSF glucose and protein levels, are obtained in an attempt to refine diagnosis. Although no single laboratory value can be examined in isolation from the whole, some pieces of the clinical puzzle carry more weight in clinical decisions than others. While they may be helpful in cases where more specific indicators of bacterial meningitis (e.g., culture) are unreliable, or in cases where patients may be at risk of unusual organisms (e.g., tuberculous meningitis), the CSF glucose and protein seldom add clinically meaningful information to a total CSF WBC count with differential and Gram stain. Previous literature on the utility of CSF glucose and protein values in the diagnosis of bacterial meningitis suggests that neither value is reliable Lindquist and colleagues prospectively determined the sensitivity, specificity, and predictive values for the WBC count, glucose, protein, lactate, and C-reactive protein levels in the CSFs of 710 children and adults who underwent lumbar puncture for suspected central nervous system infection. They commented that in the prediction of bacterial meningitis, a CSF/blood glucose ratio of <0.5 (more rigorous than our institutions standards) has a sufficiently low specificity (84%) and sufficiently high false-positive rate (75%) to make this discriminatory limit inappropriate for use in clinical practice. 8 This is evident in our data as well. At the three hospitals with a CSF glucose norm of more than two-thirds the serum glucose value, 71 76% of interpretable results were abnormal, yet the prevalence of meningitis was only 17 18%, a high false-positive rate. Similarly, while CSF protein levels were elevated in most patients with bacterial meningitis, the sensitivity was low at a reliable discriminatory level. A total protein cutoff value of 50 mg/dl had a sensitivity of 88% and a specificity of 60%, while raising the cutoff to 100 mg/ dl found a sensitivity of 69% and a specificity of 90%. The authors concluded that CSF/blood glucose ratio and determination of CSF glucose, total protein and WBC are unreliable tools for the diagnosis of bacterial meningitis. 8 Bonsu and Harper retrospectively reviewed 6,18 consecutive cases of patients undergoing CSF analysis, excluding those with CSF RBC counts >1,000/mm. In cases with <100 WBC/mm, the CSF glucose, protein, or % neutrophil ratio provided no added utility in diagnosing acute bacterial meningitis. However, for CSF WBC counts 100/ mm, a decrease in the cutoff value for CSF glucose from 40 to 20 mg/dl increased the likelihood ratio of bacterial meningitis from 4.7 to 28, and a rise in the protein level from 50 to 200 mg/dl increased the likelihood ratio from.8 to In the subset of cases with CSF WBC counts 100/mm in our study, physicians were no more likely to consider the CSF glucose and/or protein than in cases with lower WBC counts. While older patients usually have other signs and symptoms suggestive of meningitis, the indication for lumbar puncture in the neonatal age group is often alone. Despite the fact that the expected rate of positive CSF findings is lower, hospitalization and initiation of antibiotics are rather dogmatic in the subset of patients less than 60 days of age. While this would tend to skew answers toward the no response, it nonetheless underscores the point that CSF glucose and protein add little and should not be ordered routinely. For each of the 20 yes cases

3 TABLE. Patients for Whom Physicians Were Influenced by Cerebrospinal Fluid (CSF) Glucose and/or Protein Values in Treatment and/or Disposition Decisions* Patient Age Pretreated? Indication for LP Patient 1 41 days Yes (?drug) Neonate with 286 (21 P, 79 M) Patient 2 16 yr HA, ataxia 1 Patient 54 days Yes (ceftriaxone) Neonate with CSF Laboratory Results WBCs/mm Glucose (Differential) RBCs/mm (mg/dl) 6 (10 P, 90 M) Patient 4 15 mo R/o HSV 1 ( differential) Patient 5 0 days Neonate with 10 Patient 6 8 yr R/o meningitis 18 (76 P, 24 M) Patient 7 6 yr R/o meningitis 2 Patient 8 52 days Neonate with Patient 9 48 days Neonate with Patient days Yes (cefprozil) Neonate with 1 (100 M) Patient 11 5 mo Yes (TMP- SMX) Patient yr Yes (TMP- SMX) R/o meningitis 1 HIV 1 HA Patient 1 8 days Neonate with 2 (1 P, 99 M) Patient 14 9 yr R/o meningitis 20 (7 P, 9 M) Protein (mg/dl) Admit? Antibiotics Did Values Influence: Disposition? Yes Yes Yes ( admit for antibiotics ) , Yes Yes Yes ( pretreated, h/o apnea ) Yes Therapy? Yes ( r/o bacteremia ) NA ( already had antibiotics ) Yes Yes Yes ( admit 2 low glucose ) 0 80/96 4 Yes Yes ( no antibiotics 2 looks viral ) Yes Yes Yes Yes answer Yes 2 57/ /7 26 Yes 1 59/ Yes Patient 15???? Neonate with /94 6 Yes Patient days Yes (ceftriaxone) R/o meningitis /8 67 Yes Yes Yes ( added van- (91 P, 9 M) comycin ) Patient 17 4 days Neonate with 20 Yes ( presumed (1 P, 69 M) meningitis ) 12 44/76 80 Yes Yes Yes ( high protein with upper WNL WBC ) 00 BRIEF REPORTS Givens et al. CSF GLUCOSE AND PROTEIN

4 ACADEMIC EMERGENCY MEDICINE March 2000, Volume 7, Number Yes Yes Yes Patient 18 4 mo R/o meningitis 2 2 WNL WNL Yes Yes ( would send fungal culture if protein high ) ( differential) Patient yr R/o encephalitis Yes ( clinical picture abnormal CBC ) 58, Yes Yes Yes ( protein too high, even with blood ) Patient 20 4 yr R/o meningitis 00 (92 P, 8 M) *TMP-SMX = trimethoprim-sulfamethoxazole; LP = lumbar puncture; HA = headache; R/o = rule out; HSV = herpes simplex virus; HIV = human immunodeficiency virus; WBCs = white blood cells; P = polymorphonuclear neutrophils; M = monocytes; RBCs = red blood cells; WNL = within normal limits; h/o = history of; 2 = secondary to; CBC = complete blood count. (Table ), we prompted physicians to indicate in what way the laboratory findings influenced their decisionmaking process. We discovered that abnormal values had little influence on physician behavior; more often physicians cited normal CSF glucose and protein values as reasons not to admit and/or treat patients. In our series, there were three categories in which the CSF glucose and/or protein values were helpful to pediatric EPs: 1) patients >8 weeks of age with a CSF pleocytosis, in which a decision whether to treat with antibiotics is at issue ( cases); 2) patients pretreated with antibiotics (4 cases); and ) patients at risk for infection with unusual organisms due to immunosuppression (1 case). In many cases we found the reasons given by the physicians were incongruous with their actions: they either misunderstood the study questions or had a knowledge deficit regarding CSF glucose and protein analysis in lumbar puncture. For instance, patient 1 is a 41-day-old infant, pretreated with antibiotics, who had 286 WBCs in the CSF, yet the physician indicated that the CSF glucose (normal at their institution) and protein (normal) levels influenced him to admit and to treat the patient. One must wonder whether abnormal values would have influenced the physician to discharge the patient or to withhold antibiotic therapy. Further query was impossible without injecting bias into the analysis, but it appears that even in those cases where physicians use the results, they sometimes do so inappropriately. LIMITATIONS AND FUTURE QUESTIONS We made no attempt to evaluate whether CSF glucose and protein values obtained at the onset of hospitalization and therapy influenced subsequent caregivers decisions regarding changes in length of antibiotic therapy, initiation of antiviral treatment, or length of hospitalization. It is possible that other physicians (e.g., infectious disease specialists) may take the initial CSF glucose and protein values into account in certain clinical situations. There are data showing that while antibiotic pretreatment may decrease positive CSF bacterial culture and Gram stain recovery rates, it does not significantly influence other CSF parameters (WBC, glucose, or protein), 16,17 making these values potentially useful in pretreated patients. Similarly, though CSF protein levels are generally elevated in traumatic lumbar puncture specimens, the CSF glucose is unchanged by the presence of blood and may provide etiologic clues to diagnosis Future studies examining how often physicians use CSF glucose and protein level data in these instances are needed. Some limitations of our study stem from the survey method of data collection. It is unclear whether physicians understood the study questions as they were posed, as illustrated above. Further, there is an inherent self-reporting bias when physicians complete the survey after they have made clinical decisions. An alternative approach would have surveyed physicians regarding disposition and treatment prior to knowing the CSF glucose and protein results, then made the results available and asked them whether the results had changed their initial decisions. To ensure physician blinding to selected laboratory results would have required the immediate presence of a study investigator at all times at all four hospitals. In an effort to gather data from as many cases as possible, we decided to forgo this option. Another limitation is the possibility of case selection bias. In an effort to control for this, the principal investigator (TGG) cross-referenced the completed study forms from his institution against a list generated by the hospital laboratory of all CSF specimens originating in the ED during the study period. All of the missing patient charts were reviewed retrospectively. When compared, the study patients and the missing patients were found to be similar demographically and in regard to all study parameters. While this review was not done at all four participating hospitals, we assume that similar proportions of patients were enrolled at all four institutions, and that selection bias was minimal. Selection bias is also possible due to seasonal issues, as patients were enrolled between the months of

5 02 BRIEF REPORTS Givens et al. CSF GLUCOSE AND PROTEIN April and vember only. Since viral disease is more prevalent in older patients during this portion of the year, physician disposition and treatment decisions may depend more or less on the CSF WBC number and type as their primary determinants, and CSF glucose and protein values may or may not carry lesser importance. Because we classified patients with CSF pleocytosis but not necessarily a positive bacterial culture or Gram stain as having meningitis, we are unable to discriminate between bacterial and viral or other types of meningitis in this group. Although we did not perform routine follow-up on patients after the ED visit, we are not aware of any cases from our four hospitals during the study period in which a patient was not treated and subsequently grew a bacterial pathogen from the CSF. We also used local laboratory reference standards, rather than universally published standards, for CSF glucose and protein norms. This was to give the physicians the benefit of the doubt in assessing whether patients at their institutions met criteria for abnormal or normal laboratory values. If we had applied a single standard for all cases, the number of laboratory values classified as abnormal or uninterpretable for analysis would have increased, although this would have had no significant impact on physicians disposition or treatment decisions. Of note was the large number of CSF glucose values that lacked concomitant serum glucose values for comparison. In many instances either physicians are unaware that the local standard for CSF glucose interpretation requires a serum glucose for comparison, or they choose not to use this ratio as their standard. This common practice lends further weight to our contention that pediatric EPs do not consider CSF glucose and protein values in disposition or treatment decisions. Further investigation is needed to determine whether the CSF glucose and protein can be eliminated from the evaluation of suspected meningitis without missing cases. CONCLUSIONS In the pediatric ED, CSF glucose and protein levels seldom influence physicians decisions regarding disposition or therapy. They may be of use in evaluating patients undergoing lumbar puncture for suspected bacterial meningitis when the patient has been pretreated with antibiotics, is at risk for infection with unusual agents (e.g., immunosuppressed), is older (aged > 8 weeks), or has a CSF pleocytosis, and a decision whether to treat with antibiotics is at issue. TIMOTHY G. GIV- ENS, MD (tggive01@gwise.louisville. edu), and RONALD I. PAUL, MD, University of Louisville, Lousiville, KY; JOAN P. BOTHNER, MD, University of Colorado, Denver, CO; WIL- LIAM E. HARDWICK JR., MD, University of Alabama, Birmingham, AL; and CHRISTINE M. WALSH- KELLY, MD, Medical College of Wisconsin, Milwaukee, WI Presented at the Annual Meeting, Southern Section, American Federation for Medical Research/Southern Society for Clinical Investigation, New Orleans, LA, February The authors acknowledge L. Jane Goldsmith, PhD, for her assistance in sample size calculation and confidence interval analysis. Key words. cerebrospinal fluid; meningitis; emergency department; treatment; disposition. References 1. Arvin AM. Clinical use of the microbiology laboratory. In: Behrman RA (ed). Nelson s Textbook of Pediatrics, ed 15. Philadelphia: W. B. Saunders, 1996, pp Prober CG. Infections of the central nervous system. In: Behrman RA (ed). Nelson s Textbook of Pediatrics, ed 15. Philadelphia: W. B. Saunders, 1996, pp Barone MA. Johns Hopkins Hospital: The Harriet Lane Handbook, ed 15. St. Louis: Mosby Year Book, 1996, p McCracken GH. Current management of bacterial meningitis in infants and children. Pediatr Infect Dis J. 1992; 11: Bonadio WA. The cerebrospinal fluid: physiologic aspects and alterations associated with bacterial meningitis. Pediatr Infect Dis J. 1992; 11: Kooiker JC. Spinal puncture and cerebrospinal fluid examination. In: Roberts JR, Hedges JR (eds). Clinical Procedures in Emergency Medicine, ed 2. Philadelphia: W. B. Saunders, 1991, pp Klein JO, Feigin RD, McCracken GH. Report of the Task Force on Diagnosis and Management of Meningitis. Pediatrics. 1986; 78(5 Suppl):s959 s Lindquist L, Linne T, Hansson L-O, et al. Value of cerebrospinal fluid analysis in the differential diagnosis of meningitis: a study in 710 patients with suspected central nervous system infection. Eur J Clin Microbiol Infect Dis. 1988; 7: Bonsu BK, Harper MB. Do the cerebrospinal fluid differential count, protein and glucose give additional information in patients with low-level pleocytosis? [abstract]. McLean, VA: Ambulatory Pediatric Association Program and Abstracts, Karandanis D, Schulman JA. Recent survey of infectious meningitis in adults: review of laboratory findings in bacterial, tuberculous, and aseptic meningitis. South Med J. 1976; 69: Geiseler PJ, Nelson KE, Levin S, et al. Community-acquired purulent meningitis: a review of 1,16 cases during the antibiotic era Rev Infect Dis. 1980; 2: Briem H. Comparison between cerebrospinal fluid concentrations of glucose, total protein, chloride, lactate, and total amino acids for the differential diagnosis of patients with meningitis. Scand J Infect Dis. 198; 15: Powers WJ. Cerebrospinal fluid to serum glucose ratios in diabetes mellitus and bacterial meningitis. Am J Med. 1981; 71: Donald PR, Malan C, van der Walt A. Simultaneous determination of cerebrospinal fluid glucose and blood glucose concentrations in the diagnosis of bacterial meningitis. J Pediatr. 198; 10: Rodewold LE, Woolin KA, Szilagyi PG, et al. Relevance of common tests of cerebrospinal fluid in screening for bacterial meningitis. J Pediatr 1991; 119: Rothrock SG, Green SM, Wren J, et al. Pediatric bacterial meningitis: is prior antibiotic therapy associated with altered clinical presentation? Ann Emerg Med. 1992; 21: Scott SM. Initial approach to the child who presents with infections of the central nervous system. Semin Pediatr Infect Dis. 1996; 7(1): Mehl AL. Interpretation of traumatic lumbar puncture. Clin Pediatr. 1986; 25: Bonadio WA. Interpreting the traumatic lumbar puncture. Contemp Pediatr. 1989; 11:2 2.

Critical Review Form Clinical Prediction or Decision Rule

Critical Review Form Clinical Prediction or Decision Rule Development and Validation of a Multivariable Predictive Model to Distinguish Bacterial from Aseptic Meningitis in Children, Pediatrics 2002; 110: