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

OBJECTIVES OF SEMINAR  Aim  Hypothesis  Methods and statistical strategies  Conclusion  Competency based evaluation

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 careknowledge about the established and evolving biomedical, clinical, and cognate (epidemiological and social- behavioral) sciences and their application to patient care

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 healthfamily centered patient care developmentally and age appropriate compassionate and effective for treatment of health care problems and promotion of health

COMPETENCY BASED OBJECTIVES  Practice Based Learning investigation and evaluation of patient care, and the assimilation of scientific evidenceinvestigation 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 associatesinterpersonal and communication skills resulting in effective information exchange and learning with patients, families and professional associates

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 systemsunderstanding 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 populationscarrying out professional responsibilities, adherence to ethical principles, and sensitivity to diverse patient populations

INTRODUCTION  CSF reference values are extremely important – especially for neonates in the 0-28 day and day groups  Prospective studies are unethical RCT where healthy children 0-60 days of age are randomized to either LP or no LPRCT 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

INTRODUCTION  Prior studies have problems Based on children considered “healthy” after initial evaluation for CNS infectionBased on children considered “healthy” after initial evaluation for CNS infection No uniform exclusion criteriaNo uniform exclusion criteria PCR not previously availablePCR not previously available Small numbers, poor powerSmall numbers, poor power  Past studies have included subjects with Traumatic LPTraumatic LP SeizuresSeizures SepsisSepsis Congenital infectionsCongenital infections Low BWLow BW

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

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 testingED order entry records for all infants with CSF testing Clinical virology lab testing recordsClinical virology lab testing records (Had to have both to be eligible)(Had to have both to be eligible)

METHODS  Exclusion criteria (very important; see page 259, Figure 1) Traumatic LPTraumatic LP SBI (VGE, bacteremia, UTI, osteo, septic arthritis, pneumonia)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 negativeClassified 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”“Because viral meningitis can cause CSF pleocytosis, patients with pos EV PCR were excluded”  Primary analysis combined preterm and term infants (?justified)

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

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.

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 95 th %ile value of 19/  L  Infants days had median CSF WBC of 2/  L with a 95 th %ile value of 9/  L P<.001 for difference (Table 2, page 260)P<.001 for difference (Table 2, page 260)

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 testingPatients 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). 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 Older group NS

RESULTS  Comparison regarding CSF WBC counts with and without fever were NS  Preterm infants NO effect on 0-28 or day old groupsNO effect on 0-28 or day old groups

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)#1: Not all infants and neonates had EV testing (see Table 3) 0-28 days (n=142): 37/142 had EV testing = 26% 0-28 days (n=142): 37/142 had EV testing = 26% days (n=238): 38/238 had EV testing = 16% days (n=238): 38/238 had EV testing = 16% Total EV testing: 75/380 = 20% Total EV testing: 75/380 = 20%

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

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

DISCUSSION  Strengths of the study Interesting question, importantInteresting question, important What are other methods to examine this issue?What are other methods to examine this issue?

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 careknowledge 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? What are normal values of CSF WBC by age?

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 healthfamily 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 Presentation and management of disease by age Importance of information for family regarding signs and symptoms of problem Importance of information for family regarding signs and symptoms of problem

COMPETENCY BASED OBJECTIVES  Practice Based Learning investigation and evaluation of patient care, and the assimilation of scientific evidenceinvestigation and evaluation of patient care, and the assimilation of scientific evidence Scientific evaluation of hypothesis, methods, and conclusion of article 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 associatesinterpersonal and communication skills resulting in effective information exchange and learning with patients, families and professional associates

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 systemsunderstanding systems of health care organization, financing, and delivery, and the relationship of one’s local practice and these larger systems Referral systems, consultation Referral systems, consultation  Professionalism carrying out professional responsibilities, adherence to ethical principles, and sensitivity to diverse patient populationscarrying out professional responsibilities, adherence to ethical principles, and sensitivity to diverse patient populations Patient education in diverse cultures Patient education in diverse cultures