Journal Club February 25, Journal Club February 25, 20102010: Kestenbaum et al. : Kestenbaum et al. Defining CSF white blood cell Defining CSF white blood cell count reference values in count reference values in neonates and young infants. neonates and young infants. Pediatrics 2010;125:257-264.Pediatrics 2010;125:257-264.

David H. Rubin, MDDavid H. Rubin, MDChairman and Program Director, PediatricsChairman and Program Director, PediatricsSt Barnabas HospitalSt Barnabas HospitalProfessor of Clinical Pediatrics, Albert Professor of Clinical Pediatrics, Albert Einstein College of MedicineEinstein College of Medicine

OBJECTIVES OF OBJECTIVES OF SEMINARSEMINAR

AimAim

Hypothesis Hypothesis

Methods and statistical Methods and statistical strategiesstrategies

ConclusionConclusion

Competency based Competency based evaluationevaluation

COMPETENCY COMPETENCY BASED OBJECTIVESBASED OBJECTIVES

Medical KnowledgeMedical Knowledge • knowledge about the established knowledge about the established

and evolving biomedical, clinical, and evolving biomedical, clinical, and cognate (epidemiological and and cognate (epidemiological and social-behavioral) sciences and social-behavioral) sciences and their application to patient caretheir application to patient care

COMPETENCY COMPETENCY BASED OBJECTIVESBASED OBJECTIVES

Patient CarePatient Care • family centered patient care family centered patient care

developmentally and age developmentally and age appropriate compassionate and appropriate compassionate and effective for treatment of health effective for treatment of health care problems and promotion of care problems and promotion of healthhealth

COMPETENCY COMPETENCY BASED OBJECTIVESBASED OBJECTIVES

Practice Based LearningPractice Based Learning • investigation and evaluation of investigation and evaluation of

patient care, and the assimilation patient care, and the assimilation of scientific evidenceof scientific evidence

Communication SkillsCommunication Skills • interpersonal and communication interpersonal and communication

skills resulting in effective skills resulting in effective information exchange and learning information exchange and learning with patients, families and with patients, families and professional associatesprofessional associates

COMPETENCY COMPETENCY BASED OBJECTIVESBASED OBJECTIVES

System Based PracticeSystem Based Practice • understanding systems of health understanding systems of health

care organization, financing, and care organization, financing, and delivery, and the relationship of delivery, and the relationship of one’s local practice and these one’s local practice and these larger systemslarger systems

ProfessionalismProfessionalism • carrying out professional carrying out professional

responsibilities, adherence to responsibilities, adherence to ethical principles, and sensitivity ethical principles, and sensitivity to diverse patient populationsto diverse patient populations

INTRODUCTIONINTRODUCTION CSF reference values are extremely CSF reference values are extremely

important – especially for neonates in important – especially for neonates in the 0-28 day and 29-56 day groupsthe 0-28 day and 29-56 day groups

Prospective studies are unethical Prospective studies are unethical • RCT where healthy children 0-60 days of RCT where healthy children 0-60 days of

age are randomized to either LP or no LPage are randomized to either LP or no LP SO…”normal” values are obtained by SO…”normal” values are obtained by

examination of infants who have LPs examination of infants who have LPs because they are illbecause they are ill

INTRODUCTIONINTRODUCTION Prior studies have problemsPrior studies have problems

• Based on children considered “healthy” after initial Based on children considered “healthy” after initial evaluation for CNS infectionevaluation 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 withPast studies have included subjects with• Traumatic LPTraumatic LP• SeizuresSeizures• SepsisSepsis• Congenital infectionsCongenital infections• Low BWLow BW

AIM OF STUDYAIM OF STUDY

Not really stated, but……….Not really stated, but………. Assume: determine the extent of Assume: determine the extent of

normal v abnormal regarding CSF normal v abnormal regarding CSF white cell countswhite cell counts

METHODSMETHODS Cross sectional studyCross sectional study Eligible if LP performed “as part of ED Eligible if LP performed “as part of ED

evaluation between 1/1/2005 and evaluation between 1/1/2005 and 6/30/2007 at CHOP6/30/2007 at CHOP

LP procedure identified byLP procedure identified by• ED order entry records for all infants ED order entry records for all infants

with CSF testingwith 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)

METHODSMETHODS

Exclusion criteria (very important; see page Exclusion criteria (very important; see page 259, Figure 1)259, Figure 1)• Traumatic LPTraumatic LP• SBI (VGE, bacteremia, UTI, osteo, septic arthritis, SBI (VGE, bacteremia, UTI, osteo, septic arthritis,

pneumonia)pneumonia) Those that remained: Those that remained:

• CClassified on basis of enteroviral CSF testing – lassified on basis of enteroviral CSF testing – whether or not it was performed whether or not it was performed andand whether whether test was positive or negativetest was positive or negative

• ““Because viral meningitis can cause CSF Because viral meningitis can cause CSF pleocytosis, patients with pos EV PCR were pleocytosis, patients with pos EV PCR were excluded”excluded”

Primary analysis combined preterm and term Primary analysis combined preterm and term infants (?justified)infants (?justified)

METHODSMETHODS Data Collection: abstraction from Data Collection: abstraction from

medical records; ?verificationmedical records; ?verification WHO did the abstraction – 1 or WHO did the abstraction – 1 or

more authors?more authors? Data analysisData analysis

• Continuous variables – mean, median, Continuous variables – mean, median, interquartile range, 90interquartile range, 90thth ,95 ,95thth %-ile %-ile

• Comparison with Wilcoxon rank sum Comparison with Wilcoxon rank sum testtest

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.

RESULTSRESULTS 1064 infants identified for the study; 1064 infants identified for the study;

380 (36%) met inclusion criteria – see 380 (36%) met inclusion criteria – see Fig 1 page 259.Fig 1 page 259.

Infants 0-28 days had median CSF Infants 0-28 days had median CSF WBC of 3/WBC of 3/L with a 95L with a 95thth %ile value of %ile value of 19/19/LL

Infants 29-56 days had median CSF Infants 29-56 days had median CSF WBC of 2/WBC of 2/L with a 95L with a 95thth %ile value of %ile value of 9/9/LL• P<.001 for difference (Table 2, page 260)P<.001 for difference (Table 2, page 260)

RESULTSRESULTS

Within the 2 age groups, comparison Within the 2 age groups, comparison was made betweenwas made between• Patients who Patients who tested negativetested negative for EV for EV

PCR compared with patients who PCR compared with patients who did did not have EV PCR testingnot have EV PCR testing

• In younger group (0-28days) group with In younger group (0-28days) group with negative EV PCR had median CSF WBC of negative EV PCR had median CSF WBC of 4/4/L – significantly higher than those who L – significantly higher than those who did not have testing (see Table 3, p 260).did not have testing (see Table 3, p 260).

• Older group NSOlder group NS

RESULTSRESULTS

Comparison regarding CSF WBC Comparison regarding CSF WBC counts with and without fever were counts with and without fever were NSNS

Preterm infants Preterm infants • NO effect on 0-28 or 29-56 day old NO effect on 0-28 or 29-56 day old

groupsgroups

DISCUSSIONDISCUSSION

““Our study establishes reference Our study establishes reference values for CSF WBC counts in values for CSF WBC counts in neonates and young children…”neonates and young children…”

YES or NO?YES or NO? Limitations cited by authorLimitations cited by author

• #1: Not all infants and neonates had EV #1: Not all infants and neonates had EV testing (see Table 3)testing (see Table 3)

• 0-28 days (n=142): 37/142 had EV testing = 0-28 days (n=142): 37/142 had EV testing = 26%26%

• 29-56 days (n=238): 38/238 had EV testing = 29-56 days (n=238): 38/238 had EV testing = 16%16%

• Total EV testing: 75/380 = 20%Total EV testing: 75/380 = 20%

DISCUSSIONDISCUSSION

#2: Viral testing not performed#2: Viral testing not performed #3: “Certain patients received #3: “Certain patients received

antibiotics before lumbar puncture…”antibiotics before lumbar puncture…” #4: Observational study so that #4: Observational study so that

physicians (who – attendings, residents, physicians (who – attendings, residents, students?) selected who had LP (no students?) selected who had LP (no protocol)protocol)

#5: Single center study may limit #5: Single center study may limit generalizabilitygeneralizability

#6: Preemies included #6: Preemies included ?effect ?effect

DISCUSSIONDISCUSSION

Other issuesOther issues• Chart abstraction – verification?Chart abstraction – verification?• Level of training of “decision maker” Level of training of “decision maker”

not specifiednot specified• Only ½ year of data – why?Only ½ year of data – why?• Median used – why not mean and Median used – why not mean and

SD, confidence intervalsSD, confidence intervals• Figure 2 (page 261) is a migraine Figure 2 (page 261) is a migraine

headacheheadache

DISCUSSIONDISCUSSION Strengths of the studyStrengths of the study

• Interesting question, importantInteresting question, important• What are other methods to examine What are other methods to examine

this issue?this issue?

COMPETENCY COMPETENCY BASED OBJECTIVESBASED OBJECTIVES

Medical KnowledgeMedical Knowledge • knowledge about the established knowledge about the established

and evolving biomedical, clinical, and evolving biomedical, clinical, and cognate (epidemiological and and cognate (epidemiological and social-behavioral) sciences and social-behavioral) sciences and their application to patient caretheir application to patient care

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

COMPETENCY COMPETENCY BASED OBJECTIVESBASED OBJECTIVES

Patient CarePatient Care • family centered patient care family centered patient care

developmentally and age appropriate developmentally and age appropriate compassionate and effective for compassionate and effective for treatment of health care problems treatment of health care problems and promotion of healthand promotion of health

• Presentation and management of disease Presentation and management of disease by ageby age

• Importance of information for family Importance of information for family regarding signs and symptoms of problemregarding signs and symptoms of problem

COMPETENCY COMPETENCY BASED OBJECTIVESBASED OBJECTIVES

Practice Based LearningPractice Based Learning • investigation and evaluation of patient investigation and evaluation of patient

care, and the assimilation of scientific care, and the assimilation of scientific evidenceevidence

• Scientific evaluation of hypothesis, methods, Scientific evaluation of hypothesis, methods, and conclusion of articleand conclusion of article

Communication SkillsCommunication Skills • interpersonal and communication skills interpersonal and communication skills

resulting in effective information resulting in effective information exchange and learning with patients, exchange and learning with patients, families and professional associatesfamilies and professional associates

COMPETENCY COMPETENCY BASED OBJECTIVESBASED OBJECTIVES

System Based PracticeSystem Based Practice • understanding systems of health care understanding systems of health care

organization, financing, and delivery, organization, financing, and delivery, and the relationship of one’s local and the relationship of one’s local practice and these larger systemspractice and these larger systems

• Referral systems, consultation Referral systems, consultation

ProfessionalismProfessionalism • carrying out professional responsibilities, carrying out professional responsibilities,

adherence to ethical principles, and adherence to ethical principles, and sensitivity to diverse patient populationssensitivity to diverse patient populations

• Patient education in diverse culturesPatient education in diverse cultures