Rapid Feeding Volume Advancements: Uncertainty About the Effect on Necrotizing Enterocolitis Incidence: In Reply

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Letters to the Editor

Letters to the Editor reflect the viewpoints of the writers and do not represent the official position of the journal or of the American Academy of Pediatrics. Letters on any topic, including the contents ofPediatrics,are welcome from all members of the profession. For instructions on submitting Letters to the Editor, please see the Instructions for Authors in this issue or visit the journal’s Web site.

Rapid Feeding Volume Advancements:

Uncertainty About the Effect on Necrotizing

Enterocolitis Incidence

To the Editor.—

In a recent issue ofPediatrics, Caple et al1_{reported on a}

ran-domized, controlled trial of slow versus rapid feeding volume advancements in appropriate-for-gestational-age infants between 1000 and 2000 g at birth. The authors presented findings that are in good agreement with prior studies on the same subject.2

Un-fortunately, long-term outcome measures have not been assessed thus far. Shortening the period of intravenous nutrition may de-crease the rate of neonatal nosocomial bacteremia,3_{and neonatal}

infection is known to carry an increased risk of mortality, growth delay, and poor neurodevelopmental prognosis.4,5_{The potential}

of improving the outcome by a simple modification in feeding strategy, therefore, is tempting. However, the possible benefit must outweigh any associated adverse effects. We cannot agree with the suggestion that speeding up enteral feeding advance-ments would be a safe practice. As yet, the effect of rapid feeding volume advancements on necrotizing enterocolitis (NEC) is not elucidated. Similar to late-onset sepsis, necrotizing enterocolitis is associated with an increased risk of poor growth and neurodevel-opmental delay.6,7_{Although the present study did not reveal an}

increased incidence of NEC in the intervention group (absence of evidence), an increased risk, up to 10-fold, may exist (no evidence of absence). Indeed, the 95% confidence interval around the rela-tive risk crosses the line of no effect and the limit(s) of equiva-lence.8_{This uncertainty should be fully acknowledged. Finally, we}

do not know whether sepsis and NEC are equivalent surrogate outcome measures. Therefore, future trials should preferably take survival and neurodevelopmental outcome as primary end points.

Pieter L. J. Degraeuwe, MD, PhD Carlos E. Blanco, MD, PhD

Department of Pediatrics University Hospital Maastricht Maastricht 6202 AZ, Netherlands

REFERENCES

1. Caple J, Armentrout D, Huseby V, et al. Randomized, controlled trial of slow versus rapid feeding volume advancement in preterm infants.

Pediatrics.2004;114:1597–1600

2. Kennedy KA, Tyson JE, Chamnanvanikij S. Early versus delayed initia-tion of progressive enteral feedings for parenterally fed low birth weight or preterm infants.Cochrane Database Syst Rev.2000;(2):CD001970 3. Kilbride HW, Powers R, Wirtschafter DD, et al. Evaluation and

devel-opment of potentially better practices to prevent neonatal nosocomial bacteremia.Pediatrics.2003;111(4 pt 2). Available at: www.pediatrics. org/cgi/content/full/111/4/SE1/e504

4. Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Net-work.Pediatrics.2002;110(2 pt 1):285–291

5. Stoll BJ, Hansen NI, Adams-Chapman I, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neo-natal infection.JAMA.2004;292:2357–2365

6. Sonntag J, Grimmer I, Scholz T, et al. Growth and neurodevelopmental outcome of very low birthweight infants with necrotizing enterocolitis.

Acta Paediatr.2000;89:528 –532

7. Salhab WA, Perlman JM, Silver L, et al. Necrotizing enterocolitis and neurodevelopmental outcome in extremely low birth weight infants

⬍1000 g.J Perinatol.2004;24:534 –540

8. Alderson P. Absence of evidence is not evidence of absence.BMJ.2004; 328:476 – 477

doi:10.1542/peds.2004-2824

In Reply.—

We appreciate the comments of Degraeuwe and Blanco. In their letter these authors conclude that our findings are in good agree-ment with those of the only 2 other randomized trials of this subject, summarized by Kennedy and Tyson in a recent systematic review.1_{None of the 3 studies reviewed by Kennedy and Tyson}

reported a significant increase in the incidence of necrotizing enterocolitis (NEC). Furthermore, the relative risk for NEC re-ported in this review is remarkably close to a position of equipoise (relative risk: 0.97; 95% confidence interval: 0.50 –1.87). Although we agree with Degraeuwe and Blanco that this evidence is not definitive proof of safety, we did not recommend adopting the practice of more rapid advancement of feedings. Moreover, using the same rationale, one should question the validity of advancing feedings at a slower pace, which is equally unproven. Thus, we concluded our article with a call for a large, multicenter, prospec-tive trial with a sample size large enough to answer this question more definitively.

Although the suggestion that additional trials of feeding meth-ods should use survival and neurodevelopmental outcomes as primary end points is laudable, conducting such trials would be very difficult, especially considering the low occurrence of death, severe complications such as NEC, and neurodevelopmental ab-normalities in premature infants such as those included in our study (1000 –2000 g). For instance, to demonstrate that the inci-dence of NEC observed in our study group (4%) is significantly higher than that of the control group (2.5%) with an␣of .05 and ␤of .20, we would have needed to enroll⬃2193 infants per group. We firmly believe that sepsis and NEC are not equivalent surrogate outcome measures and did not comment on the former complication in our study. Nonetheless, we agree with Degraeuwe and Blanco in recognizing the impact of infection on neonatal outcome.2

Judith Caple, RNC, MSN, NNP Debra Armentrout, RNC, MSN, NNP Valerie Huseby, RNC, MSN, NNP Brenda Halbardier, RNC, MSN, NNP Jose Garcia, MD

John W. Sparks, MD Fernando R. Moya, MD

Department of Pediatrics

University of Texas–Houston Medical School Houston, TX 77030

REFERENCES

1. Kennedy KA, Tyson JE. Rapid versus slow rate of advancement of feedings for promoting growth and preventing necrotizing enterocolitis in parenterally fed low-birth-weight infants [Cochrane review]. In: The Cochrane Library. Oxford, United Kingdom: Update Software; 2005: In press

2. Stoll BJ, Hansen NI, Adams-Chapman I, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neo-natal infection.JAMA.2004;292:2357–2365

doi:10.1542/peds.2005-0255

Optimal Timing and Dosing Intervals of

Palivizumab in Premature Neonates: Still Some

Work to Do

To the Editor.—

We read with great interest the Pediatrics article published by Wu et al,1_{which showed that very premature infants had}

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sustained optimal protective levels of palivizumab (⬎40␮g/mL) serum concentrations only after the second dose, and up to 77% of the infants tested had no protective concentrations be-fore the second dose. Because the ability of premature neonates to achieve efficient protection against respiratory syncytial virus (RSV) infection relies on serum palivizumab concentrations, one should suspect a considerable rate of inefficacy of palivizumab (in its currently recommended schedule) in preventing RSV infec-tions in the first month of administration and, similarly, a con-siderable rate of uncertainty of protection in the subsequent months, particularly in the days preceding the new administra-tion.

The authors correctly claim that “[a]dditional studies are needed to establish the optimal timing of the initial dose and optimal dosing interval of palivizumab in this most vulnerable population”; thus, we briefly describe our experience that shows the clinical impact of the data provided by Wu et al and the opportunity for reconsidering some issues with the current pro-phylactic schedule.

In our 2 third-level units, which attends to a mean of 9000 births per year, we treated 389 infants at risk with palivizumab in the last 4 epidemic seasons. Infants were enrolled following the recom-mendations of the Italian Society of Pediatrics,2,3_fully

implement-ing in Italy the American Academy of Pediatrics guidelines4_;

palivizumab, 15 mg/kg per dose intramuscularly, was adminis-tered every 28 days in the months from October to April. Com-pliance to recruitment was very high (96.8%), and 91.1% of the infants completed the scheduled course (5– 6 monthly administra-tions). The overall incidence of RSV-related hospitalizations was very low (9 infants [2.3%]). It is notable that all episodes occurred between the 19th and 23rd days after the previous administration: 5 of them occurred after the second dose, and 4 occurred after the third dose, always during the epidemic peak. No fatal event occurred.

Our experience underlines the fact that, despite achieving high compliance rates, the efficacy of palivizumab administered by following the currently recommended schedule is not satisfactory (all RSV-positive admissions in our series occurred when palivi-zumab serum concentrations, according to the study of Wu et al, had probably dropped under the optimal range) and probably could be improved by modifying the schedule (increasing the doses in the first and second courses and/or shortening the intervals between courses during the epidemic peak). In our opin-ion, efforts to improve the efficacy of palivizumab should be increased, not only to improve compliance but also to prevent failures related to less-than-optimal timing and dosing, which are frustrating after the hard work that was needed to achieve optimal compliance.

Paolo Manzoni, MD Ugo Sala, MD Giovanna Gomirato

Neonatology and Hospital NICU S. Anna Hospital

Azienda Ospedaliera OIRM-S. Anna University of Turin

10136 Turin, Italy

Alessandra Coscia, MD Claudio Fabris

Cattedra di Neonatologia University of Turin 10136 Turin, Italy

REFERENCES

1. Wu S-Y, Bonaparte J, Pyati S. Palivizumab use in very premature infants in the neonatal intensive care unit.Pediatrics.2004;114(5). Available at: www.pediatrics.org/cgi/content/full/114/5/e554

2. American Academy of Pediatrics, Committee on Infectious Diseases and Committee of Fetus and Newborn. Prevention of respiratory syncytial virus infections: indications for the use of palivizumab and update on the use of RSV-IGIV.Pediatrics.1998;102:1211–1216

3. Meissner HC, Long SS; American Academy of Pediatrics, Committee on Infectious Diseases and Committee on Fetus and Newborn. Revised indications for the use of palivizumab and respiratory syncytial virus

immune globulin intravenous for the prevention of respiratory syncytial virus infections.Pediatrics.2003;112:1447–1452

4. Societa` Italiana di Neonatologia. Raccomandazioni per la prevenzione della malattia da virus respiratorio sinciziale (RSV). Riv Ital Pediatr.

2000;26:379 –381

doi:10.1542/peds.2004-2865

In Reply.—

We appreciate the comments of Manzoni et al regarding our article related to palivizumab use in very premature infants in the neonatal intensive care unit.1_{Manzoni et al report respiratory}

syncytial virus (RSV)-related hospitalizations in 2.3% of high-risk infants treated with palivizumab in Italy despite rigorous adher-ence to the current American Academy of Pediatrics guidelines for palivizumab use. Their findings are comparable with reports of RSV-related hospitalizations in high-risk infants treated with palivizumab in the United States and other countries.2–5

It is interesting that Manzoni et al observed that all RSV-related hospitalizations in their high-risk infants occurred only after the 19th day of palivizumab administration. Based on the findings of our study, we suspect that RSV infection in some of these infants might have been associated with suboptimal palivizumab concen-trations. Although 71% of very premature infants (born at⬍30 weeks’ gestation) in our study attained optimal palivizumab con-centrations (midpoint concon-centrations of⬎40␮g/ml) 2 weeks after the first dose, only 23% were able to sustain optimal concentra-tions until the second dose or 4 weeks after the first dose (trough concentrations). However, these premature infants were able to attain sustained optimal protective serum concentrations after the second dose of palivizumab. Furthermore, serum concentrations rose with repeated dosing in our study infants; midpoint and trough palivizumab concentrations before the third dose were significantly higher than those before the second dose. Saez-Llorens et al6_{have reported that the percentage of infants with}

trough concentrations of ⬎40␮g/mL increased after each of 5 monthly injections (66%, 86%, 91%, and 95%, respectively).

Although the overall rates of RSV-related hospitalization are low, we agree with Manzoni et al that RSV prophylaxis in high-risk infants should be addressed further to prevent failures in this vulnerable group. For instance, we suspect that a majority of very premature infants, who receive the first dose of palivizumab just before discharge from the hospital (as is the common practice), probably remain susceptible to infection in the weeks after dis-charge and preceding the next injection. We suggest that early initiation of prophylaxis in the NICU to accommodate a second dose before discharge in all such infants may ensure better RSV protection at discharge. The optimal age of initiation of RSV prophylaxis for very premature infants in the NICU during the RSV season and the interval between doses in this most vulnerable population should be closely reviewed.

Shou-Yien Wu, MD Joel Bonaparte, MD Suma Pyati, MD

Division of Neonatology Department of Pediatrics

John H. Stroger, Jr. Hospital of Cook County Chicago, IL 60612

Rosalind Franklin University of Medicine and Science Chicago Medical School

North Chicago, IL 60064

REFERENCES

1. Wu S-Y, Bonaparte J, Pyati S. Palivizumab use in very premature infants in the neonatal intensive care unit.Pediatrics.2004;114(5). Available at: www.pediatrics.org/cgi/content/full/114/5/e554

2. Sorrentino M, Powers T. Effectiveness of palivizumab: evaluation of outcomes from the 1998 to 1999 respiratory syncytial virus season. The Palivizumab Outcomes Study Group. Pediatr Infect Dis J. 2000;19: 1068 –1071

3. Lacaze-Masmonteil T, Roze JC, Fauroux B; French Pediatricians’ Group of Sunagis Patients’ Name-Based Programs. Incidence of respiratory syncytial virus-related hospitalizations in high-risk children: Follow-up

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of a national cohort of infants treated with palivizumab as RSV prophy-laxis.Pediatr Pulmonol.2002;34:181–188

4. Oh PI, Lanctjt KL, Yoon A, et al. Palivizumab prophylaxis for respiratory syncytial virus in Canada: utilization and outcomes.Pediatr Infect Dis J.

2002;21:512–518

5. Henckek E, Luthander J, Berggren E, et al. Palivizumab prophylaxis and hospitalization for respiratory syncytial virus disease in the Stockholm infant population, 1999 through 2002.Pediatr Infect Dis J.2004;23:27–31 6. Saez-Llorens X, Castano E, Null D, et al. Safety and pharmacokinetics

of an intramuscular humanized monoclonal antibody to respiratory syn-cytial virus in premature infants and infants with bronchopulmonary dysplasia. The MEDI-493 Study Group. Pediatr Infect Dis J. 1998;17: 787–791

doi:10.1542/peds.2005-0224

Improvement of Glucose Homeostasis After

Weight Loss in Obese Children

To the Editor.—

We read with great interest thePediatrics article by Reinehr et al.1 _{The authors provided important information about the}

changes in insulin sensitivity in obese children and adolescents according to degree of weight loss,1_{showing that a decrease of}

at least 0.5 of SD score BMI (mean:⫺0.67;⬃30% of those who were overweight) is required to observe a significant improvement in insulin sensitivity (⬃65% increase). No data concerning obese subjects with impaired glucose tolerance (IGT) were provided.

Given that type 2 diabetes in children, once considered rare, has become increasingly common in association with obesity2

and IGT represents the frequently missed link between insulin resistance and type 2 diabetes, it might be useful to study the effect of weight loss on glucose metabolism in children with IGT.

Fifteen severely obese children and adolescents with IGT were included in the study (mean age: 12.2⫾2 years; meanzscore BMI at baseline: 4.9⫾1.3). IGT was defined as a serum glucose level of ⱖ140 mg/dL and⬍200 mg/dL after a 2-hour oral glucose-toler-ance test according to American Diabetes Association guidelines. The subjects were submitted to a nutritionally balanced hypoca-loric diet (60% of the recommended dietary energy allowances for age and gender). The oral glucose-tolerance test was repeated after 6 months. Glucose tolerance appeared normalized in 14 children (8 girls), which showed a statistically significant reduction of their

z score BMI (mean:⫺1.6⫾0.6; range: ⫺2.1 to⫺1.2) (Table 1). Insulin resistance, calculated by using the homeostasis model assessment, improved and plasma insulin levels decreased (Table 1).

The patient who still showed IGT after the follow-up was a 10.5-year-old boy. Despite the reduction of hiszscore BMI from 4.35 to 2.7, he was not able to restore normal glucose tolerance.

When insulin resistance increases, insulin secretion must in-crease for glucose tolerance to remain normal. Deterioration in glucose tolerance occurs when a compensatory increase in insulin secretion is incomplete.3_{Adiposity reduction, which restores}

in-sulin sensitivity, prevents the impairment of pancreatic islet cell function.

Our observation, which suggests that the reduction of⬃30% of excess weight is enough to reverse IGT in severely obese children and adolescents, adds data that are consistent with and integrate those reported by Reinehr et al.1_{To lose weight when IGT has}

manifested represents the last opportunity for an obese child to normalize the glucose homeostasis before the appearance of type

2 diabetes with its associated irreversible deterioration in␤-cell function.3,4

Nicola Santoro, MD Michele Di Nardo, MD Alessandra Amato, MD Laura Perrone, MD

Emanuele Miraglia del Giudice, MD

Seconda Universita` di Napoli Department of Pediatrics Via L. De Crecchio no. 4 80138 Napoli, Italy

REFERENCES

1. Reinehr T, Kiess W, Kapellen T, Andler W. Insulin sensitivity among obese children and adolescents, according to degree of weight loss.

Pediatrics.2004;114:1569 –1573

2. Sokol RJ. The chronic disease of childhood obesity: the sleeping giant has awakened [commentary].J Pediatr.2000;136:711–713

3. Gungor N, Arslanian S. Progressive beta cell failure in type 2 diabetes mellitus of youth.J Pediatr.2004;144:656 – 659

4. Rosenbaum M, Nonas C, Horlick M, et al. Beta-cell function and insulin sensitivity in early adolescence: association with body fatness and family history of type 2 diabetes mellitus. J Clin Endocrinol Metab. 2004;89: 5469 –5476

doi:10.1542/peds.2005-0139

In Reply.—

We are grateful to Santoro et al for their comments and for sharing their data with us. We totally agree with their general concept and conclusion. However, it is difficult to compare our data1_{with theirs. Santoro et al used other BMI percentiles (which}

were not defined) to define the degree of overweight than we did, because the mean SD score (SDS) BMI at baseline was 5.0 in their study. In our study, consisting of obese and extremely obese children, the median SDS BMI was 2.2. Overweight is defined by an SDS BMI of⬎1.3, obesity is defined by an SDS BMI of⬎1.9, and extreme obesity is defined by an SDS BMI of⬎2.3 in the percen-tiles underlying our study.2_{Furthermore, if the LMS method is not}

used to calculate SDS BMI, the effect of weight reduction could be overestimated in the study of Santoro et al compared with our study, because BMI percentiles are not distributed normally. Therefore, only relative changes and not absolute changes of SDS BMI can be compared between the data of Santoro et al and our data.

The clinical data of Santoro et al demonstrate that a reduction of⬃30% of overweight leads to a clinically relevant improvement in insulin sensitivity in obese children with impaired glucose tolerance, in concordance with our study in obese children.1_A

reduction of⬎30% overweight (median decrease SDS BMI: 0.88; baseline median SDS BMI; 2.74) (see Table 1) is also associated with a relevant improvement of insulin sensitivity in overweight children with type 2 diabetes mellitus.3_{Diagnosis of type 2}

dia-betes mellitus was established in these white children by the criteria of the American Diabetes Association4_{: fasting plasma}

glucose of⬎126 mg/dL (7.0 mmol/L) and/or⬎200 mg/dL (11.1 mmol/L) after 2 hours in the oral glucose-tolerance test by re-peated testing on different days. Autoantibodies were negative in all patients. The degree of overweight (SDS BMI) was calculated on the basis of the German percentiles and the LMS method.2_The

insulin-resistance index (calculated by using the homeostasis

TABLE 1. Baseline and Follow-up Features of the Subjects Who Reversed Their IGT

Baseline Follow-up ⌬ F P

2-h glucose, mg/dL 148.5⫾7.3 115.5⫾13.2 ⫺33⫾15.5 6.8 ⬍.001

SD score BMI 5.0⫾1.9 3.4⫾1.2 ⫺1.6⫾1.0 3.3 .01

Insulin, mU/L 37.7⫾23.6 27.8⫾8.7 ⫺9.9⫾3.2 1.2 .2

IR-HOMA 7.9⫾4.9 5.9⫾3.2 ⫺2.0⫾4.2 1.2 .2

All the variables were log transformed and compared at baseline and follow-up by using the general linear model. When insulin and insulin resistance (calculated by using the homeostasis model assessment关IR-HOMA兴) were compared, gender, age, and pubertal stage were used as covariates. All data are shown as geometric means and deviation scores.

LETTERS TO THE EDITOR 1441

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DOI: 10.1542/peds.2005-0255

2005;115;1439

Pediatrics

John W. Sparks and Fernando R. Moya

Judith Caple, Debra Armentrout, Valerie Huseby, Brenda Halbardier, Jose Garcia,

Necrotizing Enterocolitis Incidence: In Reply