David H. Rubin, MD Chairman and Program Director, Pediatrics St Barnabas Hospital

1. Journal Club February 25, 2010: Kestenbaum et al. Defining CSF white blood cell count reference values in neonates and young infants. Pediatrics 2010;125:257-264. David H. Rubin, MD Chairman and Program Director, Pediatrics St Barnabas Hospital Professor of Clinical Pediatrics, Albert Einstein College of Medicine

2. OBJECTIVES OF SEMINAR • Aim • Hypothesis • Methods and statistical strategies • Conclusion • Competency based evaluation

3. COMPETENCY BASED OBJECTIVES • Medical Knowledge • knowledge about the established and evolving biomedical, clinical, and cognate (epidemiological and social-behavioral) sciences and their application to patient care

4. COMPETENCY BASED OBJECTIVES • Patient Care • family centered patient care developmentally and age appropriate compassionate and effective for treatment of health care problems and promotion of health

5. COMPETENCY BASED OBJECTIVES • Practice Based Learning • investigation and evaluation of patient care, and the assimilation of scientific evidence • Communication Skills • interpersonal and communication skills resulting in effective information exchange and learning with patients, families and professional associates

6. COMPETENCY BASED OBJECTIVES • System Based Practice • understanding systems of health care organization, financing, and delivery, and the relationship of one’s local practice and these larger systems • Professionalism • carrying out professional responsibilities, adherence to ethical principles, and sensitivity to diverse patient populations

7. INTRODUCTION • CSF reference values are extremely important – especially for neonates in the 0-28 day and 29-56 day groups • Prospective studies are unethical • RCT where healthy children 0-60 days of age are randomized to either LP or no LP • SO…”normal” values are obtained by examination of infants who have LPs because they are ill

8. INTRODUCTION • Prior studies have problems • Based on children considered “healthy” after initial evaluation for CNS infection • No uniform exclusion criteria • PCR not previously available • Small numbers, poor power • Past studies have included subjects with • Traumatic LP • Seizures • Sepsis • Congenital infections • Low BW

9. AIM OF STUDY • Not really stated, but………. • Assume: determine the extent of normal v abnormal regarding CSF white cell counts

10. METHODS • Cross sectional study • Eligible if LP performed “as part of ED evaluation between 1/1/2005 and 6/30/2007 at CHOP • LP procedure identified by • ED order entry records for all infants with CSF testing • Clinical virology lab testing records • (Had to have both to be eligible)

11. METHODS • Exclusion criteria (very important; see page 259, Figure 1) • Traumatic LP • SBI (VGE, bacteremia, UTI, osteo, septic arthritis, pneumonia) • Those that remained: • Classified on basis of enteroviral CSF testing – whether or not it was performed and whether test was positive or negative • “Because viral meningitis can cause CSF pleocytosis, patients with pos EV PCR were excluded” • Primary analysis combined preterm and term infants (?justified)

12. METHODS • Data Collection: abstraction from medical records; ?verification • WHO did the abstraction – 1 or more authors? • Data analysis • Continuous variables – mean, median, interquartile range, 90th ,95th %-ile • Comparison with Wilcoxon rank sum test

13. WILCOXON RANK SUM TEST • Like the t-test for correlated samples, the Wilcoxon signed-ranks test applies to two-sample designs involving repeated measures, matched pairs, or "before" and "after" measures. • Beginning with a set of paired values of Xa and Xb, this page will take the absolute difference |Xa—Xb| for each pair; • Omit from consideration those cases where |Xa—Xb|=0; • Rank the remaining absolute differences, from smallest to largest, employing tied ranks where appropriate; • Assign to each such rank a "+" sign when Xa—Xb>0 and a "—" sign when Xa—Xb<0; • Calculate the value of W for the Wilcoxon test, which in the present version of the procedure is equal to the sum of the signed ranks.

14. RESULTS • 1064 infants identified for the study; 380 (36%) met inclusion criteria – see Fig 1 page 259. • Infants 0-28 days had median CSF WBC of 3/L with a 95th %ile value of 19/L • Infants 29-56 days had median CSF WBC of 2/L with a 95th %ile value of 9/L • P<.001 for difference (Table 2, page 260)

15. RESULTS • Within the 2 age groups, comparison was made between • Patients who tested negative for EV PCR compared with patients who did not have EV PCR testing • In younger group (0-28days) group with negative EV PCR had median CSF WBC of 4/L – significantly higher than those who did not have testing (see Table 3, p 260). • Older group NS

16. RESULTS • Comparison regarding CSF WBC counts with and without fever were NS • Preterm infants • NO effect on 0-28 or 29-56 day old groups

17. DISCUSSION • “Our study establishes reference values for CSF WBC counts in neonates and young children…” • YES or NO? • Limitations cited by author • #1: Not all infants and neonates had EV testing (see Table 3) • 0-28 days (n=142): 37/142 had EV testing = 26% • 29-56 days (n=238): 38/238 had EV testing = 16% • Total EV testing: 75/380 = 20%

18. DISCUSSION • #2: Viral testing not performed • #3: “Certain patients received antibiotics before lumbar puncture…” • #4: Observational study so that physicians (who – attendings, residents, students?) selected who had LP (no protocol) • #5: Single center study may limit generalizability • #6: Preemies included  ?effect

19. DISCUSSION • Other issues • Chart abstraction – verification? • Level of training of “decision maker” not specified • Only ½ year of data – why? • Median used – why not mean and SD, confidence intervals • Figure 2 (page 261) is a migraine headache

20. DISCUSSION • Strengths of the study • Interesting question, important • What are other methods to examine this issue?

21. COMPETENCY BASED OBJECTIVES • Medical Knowledge • knowledge about the established and evolving biomedical, clinical, and cognate (epidemiological and social-behavioral) sciences and their application to patient care • What are normal values of CSF WBC by age?

22. COMPETENCY BASED OBJECTIVES • Patient Care • family centered patient care developmentally and age appropriate compassionate and effective for treatment of health care problems and promotion of health • Presentation and management of disease by age • Importance of information for family regarding signs and symptoms of problem

23. COMPETENCY BASED OBJECTIVES • Practice Based Learning • investigation and evaluation of patient care, and the assimilation of scientific evidence • Scientific evaluation of hypothesis, methods, and conclusion of article • Communication Skills • interpersonal and communication skills resulting in effective information exchange and learning with patients, families and professional associates

24. COMPETENCY BASED OBJECTIVES • System Based Practice • understanding systems of health care organization, financing, and delivery, and the relationship of one’s local practice and these larger systems • Referral systems, consultation • Professionalism • carrying out professional responsibilities, adherence to ethical principles, and sensitivity to diverse patient populations • Patient education in diverse cultures