Loretta M. Kopelman, PhD Department of Medical Humanities Brody School of Medicine
East Carolina University Greenville, NC 27858-4354
Timothy F. Murphy, PhD Department of Medical Education University of Illinois College of Medicine Chicago, IL 60612-7309
REFERENCES
1. Ross L. The need for consistency in 407 reviews [letter].Pediatrics.2004; 114:901
2. Kopelman LM, Murphy TF. Ethical concerns about federal approval of risky pediatric studies.Pediatrics.2004;113:1783–1789
3. National Institutes of Health, Human Growth Hormone Protocol Review Committee.Report of the NIH Human Growth Hormone Protocol Review Committee. Bethesda, MD: National Institutes of Health; 1992. 4. US Department of Health and Human Services, Office of Human
Re-search Protection. November 3, 2000. Re: Human ReRe-search Subject Pro-tections Under Multiple ProjectAssurance (MPA). Available at: http:// ohrp.osophs.dhhs.gov/detrm㛭letrs/nov00a.pdf. Accessed July 12, 2004 5. Institute of Medicine, Committee on Clinical Research Involving
Chil-dren.The Ethical Conduct of Clinical Research Involving Children. Washing-ton DC: National Academies Press; 2004
DOI: 10.1542/peds.2004-1274
Management of Hyperbilirubinemia in
Newborns: Measuring Performance Using a
Benchmarking Model
To the Editor.—
We thank Dr Mehl1for his appreciation of the graphic depiction
of the Henry Ford Health System (HFHS) guideline for manage-ment of hyperbilirubinemia of the newborn. We agree with him that it is more lenient in its recommendations for use of photo-therapy than the 1994 guideline of the American Academy of Pediatrics (AAP),2but it does address issues not addressed by the
AAP guideline such as newborns of⬍37 weeks’ gestation and the role of home care nurses in postdischarge neonatal care. The guideline was indeed developed prior to the 1994 AAP practice guideline. As an internally developed guideline, it is not subject to the same constraint as the 1994 AAP guideline: that it should adhere strictly to published scientific evidence. Instead, this inter-nal guideline is tailored to the particular practice circumstances faced by HFHS practitioners and extends to issues supported only by expert opinion. For example, the 1994 AAP guideline did not address newborns of⬍37 weeks’ gestation, because there was so little evidence then about this specific high-risk group, whereas the HFHS guideline does address this risk group.
We disagree with Dr Mehl that the HFHS guideline did not address the issue of lower birth weights or of hemolysis. As we reported on page 1266 of our article3and in the Appendix, the
HFHS guideline recommends, “Follow more closely and intervene at lower levels for newborns of 36 to 37 weeks’ gestation or⬍2250 to 2700 g of birth weight (unless small for gestational age).” Also, the text that appears on the back of the HFHS guideline card, shown in the Appendix, gives recommendations concerning work-up and use of phototherapy in cases of hemolysis.3We also
do not understand 2 other of Dr Mehl’s comments. There is no recommendation on the pocket card concerning umbilical cord bilirubin. The card text states clearly that the yellow zone means double phototherapy, and the orange zone is double or triple phototherapy with hydration if the infant is feeding poorly.
Dr Mehl goes on to comment on the 1994 AAP guideline. We cannot address these comments, because we do not represent the AAP guideline subcommittee.
The primary purpose of our article was to promote benchmark-ing, not to promulgate a guideline. Benchmarking is a quality-improvement tool for self-analysis by comparing one’s own re-sults and practices to another’s. We sought to establish that the outcomes achieved by the HFHS could reasonably be used in this
style of quality improvement. Another health care organization or practice group seeking to improve its own outcomes could try out elements of the HFHS approach that might best suit their circum-stances. We agree with the hope expressed by Dr Mehl that pediatric health care providers eventually may exceed the current results of the HFHS in the prevention of hyperbilirubinemia. That is also a goal at HFHS.
R. Heather Palmer, MB, BCh, SM, FAAP Center for Quality of Care Research and Education Harvard School of Public Health
Boston, MA 02115
Sudhakar Ezhuthachan, MD, DCH, FAAP Christine Newman, MS, RNC, CNNP Henry Ford Health System
Detroit, MI 48202
M. Jeffrey Maisels, MD, FAAP William Beaumont Hospital Royal Oak, MI 48073
Marcia A. Testa, MPH, PhD Department of Biostatistics Harvard School of Public Health Boston, MA 02115
REFERENCES
1. Mehl AL. Intervention recommendations for neonatal hyperbiliru-binemia [letter].Pediatrics. 2004;114:322–323
2. American Academy of Pediatrics, Provisional Committee for Quality Improvement. Practice parameter: management of hyperbilirubinemia in the healthy term newborn.Pediatrics.1994;94:558 –565
3. Chou SC, Palmer RH, Ezhuthachan S, et al. Management of hyperbiliru-binemia in newborns: measuring performance by using a benchmarking model.Pediatrics.2003;112:1264 –1273
DOI: 10.1542/peds.2004-0610
Hyperbilirubinemia Benchmarking
To the Editor.—
We agree with our colleagues from the Northern California Kaiser Permanente Medical Care Program (NC-KPMCP)1 that
observational studies such as ours at the Henry Ford Health System (HFHS)2and theirs3,4are subject to competing
explana-tions for findings. None of these studies were randomized, dou-ble-blind, controlled studies. In fact, a benchmarking model is intended to promote discussion of competing explanations. The model is used to ask: If a peer organization seems to have better outcomes, could this be due to a difference in practices, or is it spurious? Also, if the former could be true, what are our peers doing differently, and could we improve our outcomes by adopt-ing their practices? If practice differences seem plausible as an explanation of outcome differences, then one may try adopting the practices of the benchmark organization and then reexamine one’s results. Similar to most quality-improvement activities, bench-marking uses a dialog among peers and an iterative approach to clarify relationships between practices and outcomes. We appre-ciate that Newman et al are interested in promoting such dialog. Our colleagues from NC-KPMCP first question our definitions of hyperbilirubinemia and severe hyperbilirubinemia. They argue that pediatric health care providers cannot influence the low levels of hyperbilirubinemia that we selected, because they are below those at which the American Academy of Pediatrics (AAP) 1994 guideline recommends phototherapy.5Apparently, they see
pho-totherapy as the only means to arrest increasing hyperbiliru-binemia. However, Maisels and Kring6 and several other
au-thors7–11have drawn attention to breastfeeding with inadequate
intake as an important contributory cause for severe hyperbiliru-binemia and the possibility of preventing hyperbiliruhyperbiliru-binemia by supportive management during the establishment of breastfeed-ing. From the beginning of our study we were aware that the HFHS guideline for management of hyperbilirubinemia was
nient in its recommendations for phototherapy while it strongly emphasized early screening for hyperbilirubinemia and manage-ment of breastfeeding with inadequate intake. We therefore chose definitions of outcome that could be responsive to these guideline recommendations. Methodologic considerations also favored choosing these definitions. Outcomes such as total serum bilirubin (TSB)ⱖ25 mg/dL occur too rarely to permit modeling in a data set with several explanatory variables and just over 5000 cases.
Newman et al comment that the level of exclusive breastfeed-ing at HFHS is less than at NC-KPMCP. NC-KPMCP reported 66% exclusive and 11% partial breastfeeding, whereas we reported 30% exclusive and 25% partial breastfeeding.2,4This imbalance is not
surprising, because the NC-KPMCP population is 53% white and 19% black, whereas the HFHS population is 67% black and 14% white,2,4and black mothers have often been reported as less likely
to breastfeed. That is why we adjusted for race, breastfeeding, and other risk factors in comparing outcomes. However, we suspect that comparisons between our 2 studies using the feeding vari-ables are complicated by methodologic differences. For our article, the variables describing feeding practices came from the nursing discharge logs and reflected the mother’s expressed intention about feeding at the time of her discharge. Because these data were regularly used to chart progress for the HFHS participation in the Baby-Friendly Hospital initiative, nurses were aware of the importance of recording these data accurately by 3 categories: exclusive breastfeeding, partial breastfeeding, and exclusive for-mula feeding. In the NC-KPMCP article,4it seems that data
cate-gorizing breastfeeding may have been collected in part by retro-spective record review and in part by interview of the mothers 2 to 3 years after the birth event. If patterns of feeding classified as exclusive breastfeeding at NC-KPMCP were classified as partial breastfeeding at HFHS, we could expect to see the differences in patterns of feeding described above.
We agree with Newman et al that promoting breastfeeding might increase the risk for hyperbilirubinemia. However, with excellent lactation help, this may not occur.7The HFHS had a
vigorous program for promoting breastfeeding but also, as our article reports, had a vigorous program for overcoming difficulties in establishing breastfeeding. There are tantalizing glimpses of the competing explanation of breastfeeding with inadequate intake in the article by Newman et al.4At the time of readmission, all 66 cases
readmitted for phototherapy had lost an average of 6.7% of birth weight, and 10 of 66 had lost⬎12% of birth weight. Also, those newborns who became severely hyperbilirubinemic were more likely to receive early follow-up as recommended by the AAP guideline,5
“primarily because of an almost 20% greater unscheduled outpatient visit rate in the 72 hours following an initial stay of less than 48 hours.”4Could mothers who encountered difficulties in
breastfeed-ing have sought these unscheduled visits?
There are 2 other features of the HFHS guideline that could have influenced the outcomes we observed. First, the HFHS guideline emphasizes closer attention to newborns of gestational age of 36 to 37 weeks or with a birth weight of 2250 to 2700 g, including intervention with phototherapy at lower age-specific TSB levels than for more mature newborns. The 1994 AAP guide-line did not address newborns of⬍37 completed weeks of gesta-tion.12Newman et al speculate that pediatricians in their study did
not select 36- to 37-week-old newborns for more intensive fol-low-up and testing than more mature newborns.3
Second, as we reported, the HFHS practices universal screening with transcutaneous bilirubin (TcB) measurement, with a TSB drawn at a specific trigger value of TcB. Based on these screening results and other risk factors, discharge is delayed for higher-risk newborns or proceeds with a home care nurse referral that may include a specific request for a TSB to be drawn but always permits the home care nurse to draw a TSB. Our article provided evidence that HFHS successfully focuses attention on risk factors: at least 1 postdischarge TSB was drawn for 9 of the 13 newborns of 35 to 36 weeks’ gestation who were white and fully or partially breastfed (ie, high risk).
Newman et al propose as a competing explanation for the differences in outcomes between HFHS and NC-KPMCP that it results from case mix. Specifically, as we reported in Table 3,2we
adjusted for the main effect of each case mix variable 1 at a time and not simultaneously. We did this because we used the tabu-lated data directly from the Newman et al article, which did not contain cross-tabulations, and also because our models were lim-ited by the number of cases in the sample. The example Newman
et al cite in their letter is that “the difference in the rate of hyperbilirubinemia between white newborns from the NC-KPMCP (1.7%) and HFHS (1.2%) reported in Table 3 of the Chou et al article can be explained by the greater proportion of exclusive breastfeeding in the NC-KPMCP (66% vs 30%).”1This statement
implies that if controlling for race yields a relative risk (RR) of 0.5 and controlling for breastfeeding also yields an RR of 0.5, then the total risk reduction if the 2 variables were entered simultaneously would somehow reverse this direction substantially toward 1 (no difference). However, this type of reversal would require an ex-tremely strong breastfeeding-by-race interaction. That is, the im-pact of race would essentially have to alter the relationship be-tween breastfeeding and outcomes so that it would become protective or less risky for one category of race as compared with another. This is the only way that one could maintain an RR of 0.5 for both factors individually but when entered simultaneously produce an RR close to 1. We observed no such interaction effects in our multivariate analyses,2Newman et al report no such
inter-action effects in their multivariate analyses,3,4and we know of no
reports of such interaction effects in the literature to date. If one assumes a constant marginal risk over each level of race and breastfeeding within the HFHS and NC-KPMCP groups, the RR for the between-group effects should be similar whether control-ling for each individually or simultaneously.
We do not find the Newman et al competing explanation of case mix plausible for any of the risk factors, in part because of the differences in classifying breastfeeding described above. In addi-tion, the main effects for all risk factors were strong and consis-tently favored better outcomes at the HFHS. That is, for each risk group and for each level of risk within each risk group, the HFHS newborns had less hyperbilirubinemia than newborns at NC-KPMCP. In the example Newman et al select, race and feeding, these main effects are the strongest.
The second competing explanation offered by Newman et al is that interlaboratory variability in measurements of TSB could explain the differences in hyperbilirubinemia between the HFHS and NC-KPMCP. Laboratory standardization is a problem for benchmarking and also for management of newborns, since a sequence of TSBs done to guide clinical decisions may be done in different laboratories.13In November 2001, we sponsored a
meet-ing of our Makmeet-ing Advances Against Jaundice in Newborn Care (MAJIC) Consortium with a representative of the College of American Pathologists (CAP) to discuss the problem. In January 2002, CAP began to include within its laboratory standardization program an improved proficiency testing sample for neonatal bilirubin of 19.5 mg/dL human serum. The CAP program tests both accuracy and interlaboratory variation. Accuracy evaluates how well a given laboratory’s result on the proficiency test sample matches the result obtained in a CAP reference laboratory. Inter-laboratory coefficients of variation test how well all participating laboratories agree on their results for the proficiency test sample. Accurate laboratories vary little from one another, because their results cluster closely around those of the reference laboratory. In their original study, Newman et al reported that 6 of their 11 hospitals were CAP-accredited, which suggests that they are more accurate than the average laboratory. The HFHS laboratory is also CAP-accredited and also likely to be more accurate than the average laboratory. Thus, we think it unlikely that interlaboratory variation explains the 3-fold differences in percentage of new-borns experiencing severe hyperbilirubinemia between the NC-KPMCP and HFHS populations. However, any hospital engaging in benchmarking regarding hyperbilirubinemia should certainly explore this issue as one of the competing explanations for differ-ences from the benchmark.
Differences in practice remain among the competing explana-tions for differences in the incidence of hyperbilirubinemia. In-deed, Newman et al reported interhospital differences in the in-cidence of hyperbilirubinemia that were not explained by biological risk factors and which they speculate were caused by differences in practices.3Thus, we see a clear agenda ahead. Why
not improve our capacity for benchmarking while at the same time exploring adoption of apparently better practices in the pursuit of improvement? We could disseminate more standardized methods for documenting feeding practices. The CAP and AAP could collaborate to improve laboratory standardization for neonatal TSB levels. Meanwhile, pediatric care providers could improve their screening for newborns at high risk, provide close follow-up to those at risk, and improve management of breastfeeding with
LETTERS TO THE EDITOR 903
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www.aappublications.org/news
inadequate intake. We hope that dialog, exploratory analysis, and benchmarking for quality improvement will flourish!
R. Heather Palmer, MB, BCh, SM, FAAP Center for Quality of Care Research and Education Harvard School of Public Health
Boston, MA 02115
Sudhakar Ezhuthachan, MD, DCH, FAAP Christine Newman, MS, RNC, CNNP Henry Ford Health System
Detroit, MI 48202
M. Jeffrey Maisels, MD, FAAP William Beaumont Hospital Royal Oak, MI 48073
Marcia A. Testa, MPH, PhD Department of Biostatistics Harvard School of Public Health Boston, MA 02115
REFERENCES
1. Newman TB, Liljestrand PJ, Escobar GJ. Hyperbilirubinemia bench-marking [letter].Pediatrics.2004;114:323
2. Chou SC, Palmer RH, Ezhuthachan S, et al. Management of hyperbil-irubinemia in newborns: measuring performance by using a bench-marking model.Pediatrics.2003;112:1264 –1273
3. Newman TB, Escobar GJ, Gonzales VM, Armstrong MA, Gardner MN, Folck BF. Frequency of neonatal bilirubin testing and hyperbiliru-binemia in a large health maintenance organization.Pediatrics.1999;104: 1198 –1203
4. Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and pre-vention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization.Arch Pediatr Adolesc Med.2000;154:1140 –1147 5. American Academy of Pediatrics, Provisional Committee for Quality Improvement. Practice parameter: management of hyperbilirubinemia in the healthy term newborn.Pediatrics.1994;94:558 –565
6. Maisels MJ, Kring E. Length of stay, jaundice, and hospital readmission. Pediatrics.1998;101:995–998
7. Bertini G, Dani C, Tronchin M, Rubaltelli FF. Is breastfeeding really favoring early neonatal jaundice?Pediatrics. 2001;107(3). Available at: www.pediatrics.org/cgi/content/full/107/3/e41
8. Harris MC, Bernbaum JC, Polin JR, Zimmerman R, Polin RA. Develop-mental follow-up of breastfed term and near-term infants with marked hyperbilirubinemia.Pediatrics.2001;107:1075–1080
9. Bhutani VK, Johnson LH. Urgent need for accurate and precise bilirubin measurements in the United States to prevent kernicterus.Clin Chem. 2004;50:477– 480
10. Fevery J. Fasting hyperbilirubinemia: unraveling the mechanism in-volved.Gastroenterology.1997;113:1798 –1800
11. Neifert M. The optimization of breast-feeding in the perinatal period. Clin Perinatol.1998;25:303–326
12. AAP Subcommittee on Neonatal Hyperbilirubinemia. Neonatal jaun-dice and kernicterus.Pediatrics.2001;108:763–765
13. Palmer RH, Clanton M, Ezhuthachan S, et al. Applying the “ten simple rules” of the Institute of Medicine to management of hyperbiliru-binemia in newborns.Pediatrics.2003;112:1388 –1393
DOI: 10.1542/peds.2004-0611
Yes, Steroids Are Safe in Infants With
Asthma-Like Symptoms
To the Editor.—
Thank you for the opportunity of replying to the letter by Hoekstra et al,1which addresses some aspects of the design of our
study published recently inPediatrics.2
First, we need to reiterate from the article that the study is a safety study with efficacy data as secondary outcomes. We previ-ously published articles on the efficacy of inhaled corticosteroids in infants and young children.3–5A study designed and
suffi-ciently powered to include both safety and efficacy as primary outcomes is beyond our ability. We made no attempt to separate
the population according to trigger but recruited patients with a documented history of recurrent cough or wheeze, because we consider the safety of steroids to be independent of the trigger of the symptoms.
Second, patients were not excluded from the study if they fell outside the 5th to 95th percentiles for height and/or weight. Only those patients who fell outside these limits at baseline were ex-cluded. In total, 122 patients were discontinued from the study and were detailed in Table 1.2However, all data were included in
the analysis up to the time of withdrawal as long as subjects had at least 1 data point on treatment.
Third, the subanalysis of the effect of steroid-naive patients was already presented (Table 3) and discussed in the article.
Fourth, this was a randomized, controlled, open trial (ie, not double-dummy), as discussed extensively in the article. Clearly, this cautions interpretation of safety as well as efficacy data. Still, we believe that we have provided the best available evidence on the safety of FP200 based on repeated slit-lamp examination in 358 toddlers and growth measurements in 524 toddlers 1 to 3 years of age followed prospectively in a randomized, controlled trial for 1 year. This database is very reassuring and suggests that the choice of steroid treatment should not be based on fear of side effects.
Hans Bisgaard, MD
COPSAC Clinical Research Unit Department of Pediatrics Copenhagen University Hospital DK-2900 Copenhagen, Denmark
David Allen, MD
Departments of Pediatrics and Pediatric Endocrinology
University of Wisconsin Children’s Hospital Madison, WI 53792
J. Milanowski, MD
Department of Pulmonary Medicine Medical School of Lublin
8 Jaczewskiego, 20-950, Lublin, Poland
I. Kalev, MD
Medical University Paediatric Hospital of Pulmonary Disease and Respiratory Allergy
Sofia 1431, Bulgaria
Lisa Willits, BSc Biomedical Data Sciences GlaxoSmithKline
Middlesex UB6 0HE, United Kingdom
Patricia Davies, PhD European Clinical Operations GlaxoSmithKline
Middlesex UB6 0HE, United Kingdom
REFERENCES
1. Hoekstra MO, Kapitein B, van der Ent CK, Arets HGM. Are inhaled corticosteroids safe and effective in infants with asthma-like symptoms? [letter].Pediatrics.2004;114:325
2. Bisgaard H, Allen D, Milanowski J, Kalev I, Willits L, Davies P. Twelve-month safety and efficacy of inhaled fluticasone propionate in children aged 1 to 3 years with recurrent wheezing.Pediatrics.2004;113(2). Avail-able at: www.pediatrics.org/cgi/content/full/113/2/e87
3. Bisgaard H, Munck SL, Nielsen JP, Petersen W, Ohlsson SV. Inhaled budesonide for treatment of recurrent wheezing in early childhood. Lancet.1990;336:649 – 651
4. Nielsen KG, Bisgaard H. The effect of inhaled budesonide on symptoms, lung function, and cold air and methacholine responsiveness in 2- to 5-year-old asthmatic children.Am J Respir Crit Care Med.2000;162(4 pt 1):1500 –1506
5. Bisgaard H, Gillies J, Groenewald M, Maden C. The effect of inhaled fluticasone propionate in the treatment of young asthmatic children: a dose comparison study.Am J Respir Crit Care Med.1999;160:126 –131
DOI: 10.1542/peds.2004-0767
DOI: 10.1542/peds.2004-0611
2004;114;902
Pediatrics
and Marcia A. Testa
R. Heather Palmer, Sudhakar Ezhuthachan, Christine Newman, M. Jeffrey Maisels
Hyperbilirubinemia Benchmarking
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Hyperbilirubinemia Benchmarking
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