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Temporal Trends in Pediatric Invasive Pneumococcal Disease in the Intermountain West (IMW)
C.L. Byington, S. Barlow, C. Hoff, S. Firth, D. Glover, J. Jensen, K. Korgenski, J. Daly, and A.T. Pavia. Department of Pediatrics, University of Utah and Intermountain Health Care, Salt Lake City, UT.

BACKGROUND: We observed a number of cases of invasive pneumococcal disease (IPD) in children from the IMW states (UT, ID, MT,WY and parts of AZ and NV) due to serogroups not included in the 7-valent pneumococcal conjugate vaccine (PCV-7).

OBJECTIVE: Describe temporal trends in pediatric IPD and serogroup distribution in the IMW before (1997-2000) and after (2001-2003) routine immunization with PCV-7. Compare IPD due to PCV-7 and non-PCV-7 serogroups.

METHODS: The Enterprise Data Warehouse (EDW) of Intermountain Health Care (IHC) was queried for all cases of IPD in children 0-215 months from 1997-2003. During the same period, all isolates of S. pneumoniae from children with IPD treated at Primary Children’s Medical Center (PCMC), the only children’s hospital in the IMW, were serogrouped. Temporal trends for IPD and serogroup distribution were analyzed. Medical records of cases at PCMC were reviewed.

RESULTS: The EDW identified 1535 episodes of IPD in children between 1997-2003. IPD declined from a mean of 58 cases/100,000 children (1997-2000) to 41/100,000 (2001-2003) (p=0.0001). The decline in total IPD was due primarily to a decline in IPD in children 0-24 months (123 cases/100,000 to 77 cases/100,000, p=0.0001). Over the 2 time periods, serious or life-threatening disease, treated at PCMC did not change (8.2/100,000 vs. 8.5/100,000, p=0.6). During the study, 243 children with IPD were treated at PCMC. Between 1997-2000, 73% of IPD at PCMC was caused by PCV-7 serogroups compared to 47% in 2001-2003 (p< 0.0001). Children with IPD due to non-PCV-7 serogroups (n=93) were older (52 months vs. 34 months, p= 0.017), less likely to have penicillin-resistance (11% vs. 39%, p< 0.0001) or bacteremia (65% vs. 84%, p=0.0005) and more likely to have parapneumonic empyema (PE) (40% vs. 12%, p< 0.0001) or to be Pacific Islanders (11% vs. 2.6%, p=0.009). Both groups had similar rates of intensive care (45% vs. 42%), surgery (31% vs. 27%), and death (5.4% vs. 4.6%). IPD at PCMC due to serogroups 1, 3, and 15 increased from 9.4% to 22% (p=0.009) and increased in the IHC population from 3/100,000 to 6/100,000. In the post-PCV-7 period, several new serogroups were identified as causes of IPD at PCMC (8, 17, 20, 21, 28, 33, 35, and 46).

CONCLUSIONS: Total IPD declined in the IMW following the introduction of the PCV-7 vaccine, however the decline was more modest than reported in other US sites and there was no decrease in serious or life-threatening IPD. We speculate that this may be due to serogroup replacement, especially with 1, 3, and 15. IPD due to replacement serogroups results in serious disease especially PE and affects older children. Regional pneumococcal surveillance is critical to optimize vaccine selection and timing for children.

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Clinical and Epidemiologic Features of Influenza-Associated Deaths in Children, United States, 2003–2004 Influenza Season

M.E. Greenberg, J.G. Wright, E. Murray, A. Likos, M. Glover, K. Broder, N. Bhat, D. Posey, C. Borkowf, C.G. Whitney, D. Shay, K. Fukuda, T. Uyeki. Centers for Disease Control and Prevention, Atlanta, GA.

BACKGROUND: Influenza is a major cause of morbidity among children, but deaths are thought to be rare. The Advisory Committee on Immunization Practices (ACIP) recommends annual influenza vaccine for children ³6 months of age with high-risk medical conditions and encourages vaccination for all children aged 6-23 months. Because influenza-associated death is not nationally notifiable, the annual number of pediatric deaths has only been estimated through modeling. During the early 2003-04 U.S. influenza season, reported deaths of several children with influenza prompted the Centers for Disease Control and Prevention (CDC) to initiate national surveillance.

OBJECTIVE: To describe clinical and epidemiologic features of influenza-associated deaths in children during the 2003-04 influenza season.

METHODS: CDC investigators collected standardized information from state and local health departments on influenza-associated deaths in children <18 years of age. All had evidence of influenza from at least one antemortem or postmortem laboratory test.

RESULTS: One hundred thirty-five influenza-associated deaths were reported from 38 states. The median age was 3.4 years (range <1 month to 17 years); 48.1% were female. Of 125 children with known health status, 67 (53.6%) were previously healthy, 32 (25.6%) had high-risk conditions, and 36 (28.8%) had other underlying medical conditions. Among children <2 years of age, 48.9% had underlying conditions compared with 54.7% of those aged 2-17 years (p=0.55). Deaths among children <2 years old were more likely than those among older children to have occurred at home or in the emergency department than in hospital (62.2% vs. 37.5%, p=0.01). Of 96 children with known vaccination status, 20 (20.1%) had received one or more influenza vaccine doses in 2003-04; of these only 5 (25%) were vaccinated per the recommended schedule. Most deaths (N=91, 67%) were in children without ACIP-defined risk.

CONCLUSIONS: These data on U.S. deaths in children with influenza suggest that many occurred in those without an indication for influenza vaccine. Current approaches for protecting children from influenza should be reevaluated.

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A Randomized Clinical Trial of Estrogen Supplementation in Adolescent Girls Receiving Depot Medroxyprogesterone Acetate (DMPA)

B. Cromer, R. Lazebnik, E. Rome, M. Stager, A. Bonny, J. Ziegler, R. Harvey, S. Debanne. MetroHealth Medical Center, Cleveland Clinic Foundation, University Hospitals of Cleveland, Case Western Reserve University.

Introduction:  Bone loss has been attributed to ovarian suppression in girls receiving DMPA. Our hypothesis was that treatment with estrogen concurrent with DMPA would prevent bone loss.  We compared bone mineral density (BMD) in adolescent girls using DMPA for 12 months who received monthly injections of either normal saline [placebo (P)] or estradiol cypionate (E).

Methods: Postmenarcheal girls, 12-18 years of age, requesting DMPA for contraception were recruited from four adolescent health clinics in a large, urban area to a double-blind, randomized, controlled clinical trial. Subjects were stratified by recruitment site, race, and gynecologic age and, within each stratum, they were assigned to one of the two groups using blocked randomization techniques. At baseline, 6, and 12 months, data were obtained on tobacco use, calcium intake, physical exercise, and menstrual history; BMD of the lumbar spine and femoral neck was obtained with dual x-ray absorptiometry (DEXA) Model QDR 4500W fan-beam densitometer. Fixed effects modeling techniques were used to compare BMD between the two groups adjusting for baseline BMD values.

Results:  The study sample included 38 in the P group and 39 in the E group.  The mean (±SD) age was 15.6 (±1.4) years, with a mean weight of 66.8kg (± 18.0), representing an average BMI of 24.1 (± 4.8).  Thirty-two percent were non-black and 68% were black.  There were no differences at baseline between the two groups in weight, percent with regular menses, number of cigarettes smoked per month, and physical activity levels. The mean BMD values of the femoral neck at baseline for the P and E groups were .908 (± .133) and.931 (±. 130) and at 12 months were .886 (±. 138) and  .951 (±. 127), respectively.  Mean BMD values of the lumbar spine at baseline for P and E subjects were .993 (±.098) and .995 (±.114) and at 12 months were .970 (±. 097) and 1.02 (±.125), respectively. The P group had significantly lower femoral neck and lumbar spine BMD values at 12 months than the E group (p<.0001).

Conclusion: Our findings suggest that estradiol cypionate is protective of bone in adolescent girls on DMPA. The clinical question that emerges is: Should estrogen supplementation be considered for clinical practice in adolescents receiving DMPA? 

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Clinical Significance of Vesicoureteral Reflux (VUR) and Urinary Antibiotic Prophylaxis (UAP) After First Episode of Acute Pyelonephritis (APN). A Controlled, Randomized, Multicenter Study

Eduardo H. Garin, Fernando Olavarria, Victor Garcia Nieto, Blanca Valenciano, Alfonso Campos. University of South Florida, Tampa, FL; Universidad Austral, Valdivia, Chile; Hospital de Nuestra Senora de la Candelaria, Las Canarias, Spain.

AIMS: To evaluate the role of VUR and UAP on the urinary tract infection (UTI) recurrence rate and the development of renal scars after APN.

METHODS: Patients with APN (confirmed by DMSA renal scan), age 3 mo-18 yr, with or without VUR were randomized to receive or not to receive UAP. Patients were followed every 3 months for at least a year. DMSA scan was repeated at 6 months or if there was recurrence of febrile UTI. Urinalysis and urine culture were obtained at each clinic visit.

RESULTS: Results after 1 year of follow up are shown on table.

There were no statistical differences for UTI recurrence and renal scars among the groups.

CONCLUSIONS: After first year of follow up: 1. Recurrence UTI rate lower than expected. 2. Recurrence of APN after episode of APN is rather low. 3. Recurrence rate was similar regarding presence or absence of VUR, and use of UAP. 4. Neither VUR nor UAP seems to have a role in the development of renal scars.

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Screening Jaundiced Newborns Using Transcutaneous Bilirubin (TcB) Can Reduce the Hospital Re-admission Rate

John R. Petersen, Anthony O. Okorodudu, Amin A. Mohammad, Karen E. Shattuck. Depts of Pathology and Pediatrics, University Texas Medical Branch, Galveston, TX.

Discharge of mothers and their healthy newborns 24 h after birth is associated with increased risk of readmission for hyperbilirubinemia. In April, 2003 we started using BiliChek to measure TcB of jaundiced term newborns. The purposes of this study were to examine the effect of measuring TcB on hospital charges by determining its effect on 1) the rate of hospital re-admission for hyperbilirubinemia, and 2) laboratory bilirubin testing. Methods: We compared the re-admission rates and number of laboratory bilirubins for all babies in our newborn unit from 8/02-3/03 (before TcB) and 5/03-12/03 (after TcB). The month of April, 2003 was considered a transition period, so was not included in the comparison. Hospital charges were computed using the mean length of stay from 1/02 to 9/03, and were $1510 for a healthy newborn, $2400 for a newborn with hyperbilirubinemia, and $2401 for a baby re-admitted for hyperbilirubinemia. Results: As shown in the table (all numbers represent mean+SD), there was no impact on the number of bilirubins sent to the laboratory before and after initiation of TcB. However, after initiation of TcB the number of re-admits decreased by 58% (p = 0.024). Conclusion: Although there was no impact on laboratory bilirubin testing, use of TcB decreased the number of re-admissions for hyperbilirubinemia. Over the 8 month time frame studied, this translated into a total decrease in hospital charges of $17,288.

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Obese Patients with Insulin Resistance Experience a Significant Drop in Plasma Glucose 3–5 Hours After an Oral Glucose Challenge

Daniel L. Preud’Homme, Sonia M. Michail, Adrienne Stolfi, and Adam G. Mezoff. Department of Pediatrics, Wright State University School of Medicine, Dayton, OH.

BACKGROUND: Patients with insulin resistance (IR) have high fasting insulin levels. The HOMA-IR and QUICKI Index have been used to further define insulin resistance. Focus is usually on fasting insulin (FI), fasting glucose (FG) or 2-hr glucose levels obtained from the oral glucose tolerance test (OGTT). Little is known about glucose levels greater than 2 hours after an OGTT in pediatric patients with obesity and IR.

OBJECTIVE: To determine whether obese patients with IR experience a significant drop in plasma glucose 3-5 hours after an OGTT.

METHODS: 5-hr OGTTs from 117 pediatric lipid clinic patients were studied. Patients were divided into 2 groups based on whether a drop in glucose (defined as >10 mg/dl decrease from FG) occurred at 3, 4, or 5 hrs. Age, sex, BMI, FG, FI, HOMA-IR, and QUICKI were compared between the groups with t-tests or Wilcoxon rank-sum tests.

RESULTS: Group A (n=20) had a mean (± SD) drop from FG of 1.1±9.8 mg/dl at 3-5 hrs; in Group B (n=97) the drop was 26.1±9.2. The drop in Group B occurred at 3 hrs in 10%, 4 hrs in 60%, and 5 hrs in 30%. Mean ages for Groups A and B were 11.1±3.8 and 12.6±2.8 years respectively (P=0.047); BMI z-scores were 2.44±0.60 in A and 2.44±0.35 in B (P=0.946). The groups differed significantly in FG, FI, HOMA-IR, and QUICKI (Table).

CONCLUSION: In most children with obesity and IR ingestion of glucose leads to a drop in plasma glucose below fasting levels at 3, 4 or 5 hours after an OGTT. This may indicate another effect of insulin resistance.

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Comparison of Efficacy and Safety of a Trivalent Live, Attenuated, Intranasal Influenza Vaccine (CAIV-T) with Trivalent Inactivated, Intramuscular Influenza Vaccine (TIV) in Children Aged 6 to <72 Months with a History of Respiratory Tract Infections

Shai Ashkenazi, Andre Vertruyen, Javier Aristegui, Nicola Principi, Douglas McKeith, Timo Kremola, Jiri Biolek, Joachim Kühr, Tadeusz Bujnowski, Daniel Desgrand-Champs, Melanie Saville, Bruce Forrest, William Gruber, CAIV-T study group. Schneider Children’s Medical Center of Israel, Wyeth Vaccines Research, NY.

OBJECTIVES: 1) To compare the efficacy of CAIV-T vs. licensed TIV over one season against culture-confirmed, community-acquired influenza in children aged 6 to <72 months of age with a history of recurrent respiratory tract infections; 2) to compare the safety of CAIV-T to TIV, including the incidence of wheezing after vaccination.

DESIGN/METHODS: 2187 children aged 6 to <72 months of age with a history of at least two practitioner-attended respiratory tract infections in the past 12 months were recruited in nine European countries and Israel. Subjects were randomized 1:1 to receive either two intranasal doses of CAIV-T or two doses of TIV prior to the 2002-2003 influenza season. Wheezing illness was captured by diary card (Day 0-10) and during influenza illness surveillance. Active surveillance for protocol-defined influenza illness occurred weekly until May 2003. For each qualifying illness, a nasal swab was obtained for influenza culture.

RESULTS: 24 (2.3%) of CAIV-T vs. 50 (4.8%) of TIV recipients experienced antigenically similar culture-confirmed influenza illness, a 52.7% statistically superior efficacy for CAIV-T (95%CI, 21.6, 72.2). Type B viruses caused most of the influenza illnesses: 12 (1.1%) in CAIV-T vs. 37 (3.6%) in TIV recipients, a 68% greater efficacy for CAIV-T (95% CI, 37.3, 84.8). A/H1 illnesses occurred in 0 CAIV-T vs. 8 (0.8%) TIV recipients (95% CI 42.3, 100). A/H3 illnesses occurred in 12 CAIV-T vs. 6 TIV recipients; this difference was not statistically significant (95% CI, -540.2, 31.5). Safety: No statistically significant differences were observed between CAIV-T and TIV recipients for wheezing (first episode within 10 or 42 days following the 1st or 2nd dose).

CONCLUSIONS: This is the first study directly comparing CAIV-T to TIV in this population. Overall, CAIV-T had 53% superior efficacy to TIV and demonstrated a similar safety profile.

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North American IgA Nephropathy Trial: Evaluation of Alternate-Day Prednisone (QOD-PRED) or Daily Omega-3 Fatty Acids (OM-3 FA) in Children and Young Adults with IgA Nephropathy

Ronald J. Hogg, Nancy Nardelli, Jeannette Lee, Daniel Cattran, Gladys Hirschman, Bruce A Julian. Medical City Hospital, Dallas, TX; Biostatistics Unit, University of Alabama, Birmingham, AL; Division of Nephrology, The Toronto Hospital, Toronto, Ontario, Canada; Division of Kidney, Urologic, and Hematologic Diseases, NIDDK, Bethesda, MD; Division of Nephrology, University of Alabama, Birmingham, AL.

Background: Optimal therapy (Rx) has not been established for patients with IgA Nephropathy (IgAN), which is an important cause of progressive renal failure in children and adults throughout the world.

Objectives: This randomized, placebo-controlled, double blind trial tested if a 2-year course of QOD-PRED (group A), or daily OM-3 FA (group B) is more effective than placebo (group C) in slowing progression of renal disease (defined as change in estimated glomerular filtration rate [GFR]) in young patients with IgAN.

Design/Methods: Entry criteria included 1) Age =40 years; 2) estimated GFR > 50 ml/min/1.73 m2; 3) urine protein/creatinine (UP/C) =0.5; 4) renal biopsy showing IgAN. Ninety-six patients (45% <18 yrs of age) from 37 centers in the USA and Canada fulfilled entry criteria and were randomized to one of 3 arms: Group A: PRED 60mg/m2 QOD x 3 mo; 40mg/m2 QOD x 9 mos; then 30mg/m2 QOD x 12 mo. Group B: OM-3 FA 4g/day x 2 yrs (1.88g EPA, 1.48g DHA) with lower dose in pts with BSA <1m2. Group C: placebo. All pts were followed for at least 12 months post-Rx. Hypertension was treated with enalapril. The primary endpoint was time to failure, defined as a fall in estimated GFR to less than 60% of baseline. An overall significance level of 0.10 was used.

Results: Patients in the 3 Rx arms were comparable at baseline with respect to demographics, serum creatinine, GFR and BP, but group B pts had significantly higher UP/C at entry than group C (P=0.003). Most pts (73%) completed 24 months of Rx. Neither group A nor B showed benefit over group C with respect to time to failure with 14 pt failures overall (2 in group A, 8 in group B, 4 in group C). The primary factor associated with treatment failure was baseline UP/C; with higher levels correlated with failure rate (P=0.005) and time to failure (P=0.009).

Conclusion: In this population of patients with IgAN, UP/C fell significantly over time in both patient groups. However, superiority of QOD-PRED or OM-3 FA over placebo in slowing change in estimated GFR, was not seen.

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Indomethacin for the Prevention of Intraventricular Hemorrhage Is Effective Only in Boys

Laura Ment, Robert Makuch, Karen Schneider, Karol Katz, Charles Duncan, Richard Ehrenkranz, Betty Vohr, William Oh, Walter Allan, Alstair G. Philip. Depts of Peds, Neuro, Neurosurg, EPH, Yale University, New Haven, CT; Dept of Peds, Brown University, Providence, RI; Dept of Peds, Div of Ped Neuro, Maine Medical Ctr, Portland, ME.

BACKGROUND: Indomethacin has been shown to lower the incidence of intraventricular hemorrhage (IVH) in preterm infants. Gender effects of indomethacin have recently been described and we noted during the follow-up phase of our multicenter "Randomized Indomethacin IVH Prevention Trial" that verbal IQ in males was improving.

OBJECTIVE: To determine if indomethacin would have differential effects on male and female preterm neonates with regard to prevention of IVH and improvement in outcome measures.

DESIGN/METHODS: We reanalyzed our multicenter randomized trial by gender and treatment looking at both rate and type of IVH and long term psychometric testing.

RESULTS: In this cohort of 431 infants with birth weight 600-1250g and lack of IVH at 6 hours of life, recruited between 1989 and 1992, indomethacin reduced the incidence of IVH by more than half (9% v. 22%), and eliminated parenchymal hemorrhage in boys, but had no effect in girls (16% IVH v. 14% IVH). Breslow-Day Test for Homogeneity (male vs female) p = 0.013. Indomethacin treatment was also associated with significantly higher verbal testing scores at 3-8 years corrected age in boys but not girls (see Table).

Peabody Picture Vocabulary Test – R by Treatment, Gender and Corrected Age

CONCLUSION: Indomethacin decreases IVH and provides a significant advantage to long term outcome for the historically more vulnerable male very low birth weight preterm infant. (supported by NS 27116)

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Immature Baboons Treated for 28 Days with Early nCPAP Versus LV-PPV with Delayed Extubation to nCPAP Show Physiologic and Pathologic Differences

Merran A. Thomson, Bradley A. Yoder, Vicki T. Winter, Jacqueline J. Coalson. Division of Paedatrics, Hammersmith Hospital, London UK; Depts of Pathology & Pediatrics, UTHSC-SA & SFBR, San Antonio, TX.

BACKGROUND: Retrospective studies suggest preterm infants treated with early nasal continuous positive airway pressure (nCPAP) may have less severe bronchopulmonary dysplasia (BPD) than those infants who were managed initially with low tidal volume positive pressure ventilation (LV-PPV).

OBJECTIVE: To determine if a delay in extubation to nCPAP following 5 days of ventilation with LV-PPV versus 24 hours of LV-PPV would show comparable respiratory physiologic and pathologic outcomes in immature baboons survived to 28 days.

METHODS: Following delivery by cesarean section at 125-days (term=185days), all infants received 2 doses of Curosurf™ and daily caffeine citrate. Weaning from LV-PPV to nCPAP was attempted at either 24 hours age (nCPAP group n=6) or at 5 days age (PPV-nCPAP group n=5). Serial physiological parameters were recorded. Lung histopathology and morphometric measurements were assessed following necropsy at 28 days or earlier.

RESULTS: Days of treatment, and birth and necropsy weights were similar between groups. PPV-nCPAP animals were more difficult to maintain on nCPAP and required additional ventilatory time (p=0.01). PPV-nCPAP animals had significantly higher FiO2 and pCO2 levels and lower a/A ratios at multiple time points during the study. Pressure volume curves at necropsy were significantly worse in the PPV-nCPAP group than the nCPAP group (p<0.05). Surface to volume ratio measurements were significantly better in the nCPAP group (p=0.05), but no difference in internal surface area measurements was present between the two study groups. Qualitative histopathology showed significantly more bronchiolar inflammation and peribronchiolar interstitial thickening in the PPV-nCPAP group.

CONCLUSION: Elective ventilation for only 5 days in premature baboons was associated with a worsening in physiological parameters, more difficulty in weaning to and maintaining nCPAP and an increase in bronchiolar inflammation and alveolar wall thickening when compared to neonates extubated to nCPAP at 24 hours.

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High Frequency nCPAP Provides Adequate Prolonged Support of the Preterm Lamb

D.M. Null, E.A. O’Brien, M.J. Dahl, M. Williams, B. Reyburn, R.H. Lane, K.H. Albertine. Pediatrics, Salt Lake City, UT.

BACKGROUND: In preterm lambs, the use of high frequency nasal continuous positive airway pressure (nCPAP) instead of conventional ventilation (CV) over a 21-day period enhances alveolar septation and significantly affects expression of key genes involved in lung morphogenesis, such as VEGF, Flk-1, glucocorticoid receptor, and p53. Changes in molecular expression are evident at 72 h of continuous support.

OBJECTIVE: Physiologic studies using nCPAP and the preterm lamb have been limited to <12 h (Jobe, Pediatr Res 52:387, 2002), so the physiological effects of 72 h of nCPAP are unknown. Our objective was to supplement our recent histological and molecular findings with the physiologic consequences of 72 h of nCPAP versus CV support.

DESIGN/METHODS: Preterm lambs were delivered at ~132 days of gestation (treated with antenatal steroids and postnatal surfactant). The lambs were managed by either CV (control; n=6) or nCPAP (n=5) for 72 h. At 24, 48 and 72 h of life, we determined the p02, pCO2, pH, A-a gradient, and oxygenation index (OI).

RESULTS: With the exception of pH at 24 h, no significant differences existed in respiratory parameters between the lambs treated with CV or nCPAP (Table). Note that the A-a gradient significantly decreased in the lambs treated with nCPAP from 24 to 72 h.

CONCLUSION: Using high frequency nCPAP, we are able to support preterm lambs over a 72 h period without compromising their respiratory status. Our ability to adequately maintain these lambs allows further study into the molecular mechanisms through which prolonged nCPAP permits enhanced alveolar septation. (HL62875; CHRC)

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Inhaled Nitric Oxide for Preterm Infants with Severe Respiratory Failure

Krisa P. Van Meurs, David K. Stevenson, Richard A. Ehrenkranz, James A. Lemons, W. Kenneth Poole, Rebecca Perritt, Rosemary D. Higgins and Linda L. Wright, for the Neonatal Research Network. NICHD, Bethesda, MD.

BACKGROUND: Preterm infants with severe respiratory failure continue to experience significant morbidity and mortality. Inhaled nitric oxide (iNO) may benefit such infants because it causes selective pulmonary vasodilatation, improves ventilation/perfusion matching, and decreases pulmonary inflammatory response.

OBJECTIVE: To determine if iNO administration to premature infants with severe respiratory failure decreases mortality or bronchopulmonary dysplasia (BPD).

DESIGN/METHODS: Multicenter (n=16), randomized, double-masked, controlled trial in preterm infants with birth weights (BW) of 401 to 1500 grams with respiratory failure >4 hours after surfactant administration. Patients were stratified by BW and oxygenation index (OI) and randomized to receive placebo (oxygen) or iNO at 5 - 10 ppm. Strata 1 had oxygenation index (OI)>10 and Strata 2 had OI>5 followed by OI>7.5, but <10. Infants with a positive response (>10 torr increase in PaO2) were gradually weaned according to a defined protocol. Infants were monitored for signs of toxicity including methemoglobin >4% and nitrogen dioxide >3 ppm. Total exposure to study gas was limited to 14 days. A head ultrasound was required at 28 + 3 days. Medical and neurodevelopmental assessment at 18 to 22 months corrected age is ongoing.

RESULTS: 415 eligible infants were enrolled. Mean gestational age, BW and OI were 26.0 + 2.3, 840 + 265 and 23.4 + 17.1 in the iNO group (n=207) and 26.0 + 2.3, 840 + 259 and 22.5 + 17.3 in the placebo group (n=208), respectively. Baseline characteristics and status at randomization were not statistically different. Mortality was 52.7% in the iNO group vs. 44.2% in the control group (p=0.08). BPD was 58.6% vs. 66.9%, respectively (p=0.19). The trial was stopped 17 patients short of the sample size because of an apparent increase in severe intracranial hemorrhage (ICH) in the iNO group. Detailed analyses of trial data are underway and will be presented.

CONCLUSIONS: iNO, as delivered in this trial, was not associated with decreased mortality or BPD and was associated with an apparent increase in severe ICH in a very high risk group of preterm infants with severe respiratory failure.

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Short-Term Mechanical Ventilation Increases Airway Reactivity in Rat Pups

Sabine C Iben, Marwan A. Jaber, Musa A. Haxhiu, Richard J. Martin, Martha J. Miller. Pediatrics, Division of Neonatology, Rainbow Babies & Children’s Hospital, Cleveland, OH and Physiology & Biophysics, Howard University, Washington, DC.

BACKGROUND: Neonates who develop chronic lung disease are predisposed to later reactive airway disease.

As a model of neonatal lung injury, hyperoxia exposed rat pups have been shown by ourselves and others to develop airway hyperreactivity, however, the role of mechanical ventilation in this setting is unknown.

OBJECTIVES: We sought to use a rat pup model to delineate whether mechanical ventilation in the absence of supplemental oxygen contributes to the development of airway hyperreactivity.

METHODS: 8 day old Sprague- Dawley rat pups were randomized to either ventilation (n=7) or control groups (n=13). The ventilation assigned animals were anesthetized, intubated and ventilated with a tidal volume 10µl/g and a rate of 100/min in room air for an average of 2.7 hours (1.2- 4 hours). After extubation they were returned to their mothers. Control animals received no intervention. On day of life 10 all animals were sedated, paralyzed and ventilated to measure pulmonary function. Total lung resistance (RL) and lung compliance (CL) were measured in response to increasing doses of Methacholine i.v. (0.03- 3µg/g) by head out body plethysmography using BUXCO software. Responses were compared by two- way- ANOVA.

RESULTS: Baseline resistance and compliance did not differ between groups. However, the response to cholinergic stimulation with Methacholine was significantly potentiated by prior exposure to mechanical ventilation (p<0.01).

CONCLUSION: Mechanical ventilation of rat pups in a normoxic environment increases airway reactivity days after the exposure. This represents an important new model to investigate the mechanisms involved in airway hyperreactivity induced by neonatal lung injury.

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Phase I/II Double Blind, Placebo Controlled, Dose Escalation, Safety and Pharmacokinetics Study in Very Low Birth Weight Neonates of BSYX-A110, an Anti-Staphylococcal Monoclonal Antibody for the Prevention of Staphylococcal Bloodstream Infections

Leonard E. Weisman, Helen M. Thackray, Joseph A. Gracia-Prats, Mirjana Nesin, Jimmy Mond, Joseph H. Schneider, Karen E. Johnson, Karen Adams, William G. Kramer, Gerald W. Fischer. Section of Neonatology Baylor College of Medicine, Houston, TX; Division of Neonatology, Weill Medical College, New York, NY; Biosynexus Incorporated, Gaithersburg, MD.

BACKGROUND: Coagulase-negative staphylococcal (CoNS) sepsis is a major cause of morbidity in very low birth weight infants. A human chimeric monoclonal antibody (BSYX-A110) was developed against staphylococcal lipoteichoic acid. When tested in adults, the antibody appeared safe and serum anti-LTA and bacterial killing levels were dose related and highly correlated. OBJECTIVE: This study evaluates the safety, tolerability, and pharmacokinetics of BSYX-A110 in very low birth weight neonates.

DESIGN/METHODS: A Phase I/II randomized, double blind, placebo controlled dose escalation study enrolled very low birth weight infants (700-1300g), 3-7 days old, to receive 2 doses 14 days apart of either BSYX-A110 at 10, 30, 60, or 90 mg/kg or placebo at a 2:1 ratio. Blood and urine were obtained pre- and post-infusion for analysis of safety and pharmacokinetics. Data was gathered on adverse events and cultures of staphylococcal organisms causing sepsis during the study were collected.

RESULTS; 53 subjects received at least one dose of study drug. The average gestational age was 27.58 weeks; average birth weight was 1003g. All SAEs were deemed unrelated or probably not related to drug. Common morbidities and mortality were not different across study groups. No evidence of immunogenicity of BYSX-A110 was detected. A noncompartmental model demonstrated linear pharmacokinetics of BSYX-A110. Mean clearance, volume of distribution, and elimination half-life were independent of dose. Terminal elimination half life was 20.5 +6.8 days. All CoNS causing sepsis during the study were opsonizable by BSYX-A110.

CONCLUSION: Two infusions of BSYX-A110, administered two weeks apart to high-risk neonates appeared safe and tolerable, and linear pharmacokinetics were observed. Evaluation of more frequent doses, at the highest dose levels tested, in neonates at high-risk of CoNS sepsis is warranted.

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Conservative Transfusion Regimens Are Not Associated with Higher Mortality or Morbidity in ELBW Infants—The Premature in Need of Transfusion (PINT) Randomized Controlled Trial

H. Kirpalani , R. Whyte , C. Andersen , E. Asztalos, M. Blajchman, N. Heddle and R. Roberts, for PINT Investigators. McMaster Univ, Hamilton; Dalhousie Univ, Halifax; Mercy H, Australia; and Univ Toronto.

BACKGROUND: ELBW infants (<1000g BW) are repeatedly transfused with packed red blood cells. We conducted a multicentre randomized trial in 10 NICUs in three countries to determine whether transfusion triggered by low vs. high Hb concentrations affects mortality or severe morbidity in ELBW infants.

METHODS: ELBW infants <48 hrs of age, recruited over 24 months, were randomized to an algorithm of low or high Hb triggers adjusted for cardiorespiratory disease and falling with postnatal age (115 to 75 g/l in low and 135 to 85 g/l in high group). Emergency transfusions were permitted for shock, sepsis, and surgery. The primary composite outcome was death or severe morbidity (BPD, ROP or Brain Injury, see table). Predetermined sample size was 424.

RESULTS: We randomized 451 infants. Maternal and infant prognostic factors were similar in both groups. Median (IQR) birth-weight was 770 (670-887) g and gestational age 26 (25-27) weeks. Hb fell with age in both groups. A difference (p<0.0002) in mean Hb occurred in the first week and was maintained at approximately 10g/L until discharge. Time to first transfusion was significantly delayed by a median of two days with the low trigger. 29 subjects (13%) in the low arm did not receive transfusion compared to 14 (6.1%) in the high arm (p<0.01). Mean number of transfusions given was 4.8 in the low group vs 5.5 in the high (p=0.09).

CONCLUSION: Transfusion of ELBW infants to maintain a high hemoglobin in this range confers no major benefit.

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Actual Versus Intended Pulse Oxygen Saturation (SpO2) in Infants <28 Weeks Gestation

James Hagadorn, Anne Furey, T. Hang Nghiem, Skyler Greene, Ekua Abban, Jennifer Cho, Prashant Shrestha, Ami Vora, Christopher Schmid, Patricia Hibberd, Cynthia H. Cole, The AVIOx Study Group. Division of Newborn Medicine and Division of Clinical Care Research, Tufts-New England Med Ctr, Boston, MA.

BACKGROUND: Detailed data are not available regarding the actual versus intended SpO2 in infants born <28 weeks gestation (extremely premature newborns, EPNs) in the neonatal period during routine care.

OBJECTIVES: To document actual SpO2 in EPNs in the first 4 weeks of life during routine care and compare to the level recommended by local policy/guideline.

DESIGN/METHODS: EPNs <96 hours old were enrolled in a prospective multicenter cohort study. Oximetry data were collected every 2 seconds with masked signal-extraction oximeters for 72 hours in each of the first four weeks of life. Data for infants on supplemental O2 were compared to SpO2 range prescribed by local institutional policy.

RESULTS: 14 centers from 3 countries enrolled 78 infants with mean birth weight 863 + 208 g and mean gestational age 26 wk + 1.4 wk. Lower limits of intended SpO2 ranges at study centers varied between 83-92%, upper limits 92-98%. Infants were monitored for median 70 hours in each week. Overall median SpO2 for infants on supplemental O2 during the first 4 weeks was 95% (range of study center medians 91-96%). Of 12 centers with defined policies, 11 maintained median SpO2 within intended range. Proportion of SpO2 values within intended range varied between 16-71% at different study centers. Most noncompliance was above intended range.

CONCLUSIONS: Median SpO2 was compliant with intended range at most study centers in this cohort. However, proportion of SpO2 values in intended range during routine care of EPNs on supplemental O2 varied substantially among study centers. These data will assist quality improvement and education efforts, and will aid planning of randomized trials examining level of oxygenation.

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Neurologic Complications Associated with Influenza A in Children During the 2003–04 Influenza Season in Houston, Texas

Stephen M. Maricich, Jeffery L. Neul, Timothy E. Lotze, Andreea C. Cazacu, Timothy M. Uyeki, Gail J. Demmler, Gary D. Clark. Sections of Neurology and of Infectious Disease, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX; Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA

BACKGROUND: Recently, influenza has been associated with neurologic symptoms and sequelae in Asia, but only sporadic reports have been published in the U.S. in the past 50 years.

OBJECTIVES: To describe the clinical characteristics of and viruses isolated from patients hospitalized at Texas Children’s Hospital who presented with neurologic symptoms associated with influenza A infection during the 2003-04 influenza season and to raise awareness of the neurologic complications of influenza among U.S. children.

METHODS: We reviewed the medical and laboratory records of all children who were hospitalized with neurologic symptoms and who also had evidence of influenza virus infection by rapid antigen testing or viral isolation.

RESULTS: Eight children aged 5 months to 9 years with neurologic complications associated with influenza A were identified. None of the children had received the influenza vaccine. Four presented with seizures, three with mental status changes, and one with mutism. Seven patients had influenza A viral antigen detected in nasal wash samples, 6 had virus isolated in culture from nasal wash specimens and one had virus isolated from CSF. None of the patients had serum metabolic abnormalities or other CSF abnormalities. Three of the patients had brain imaging abnormalities. Five of the patients were treated with antivirals. All 8 of the patients survived, 6 with complete recovery, and two with sequelae (one mild and one severe).

CONCLUSIONS: Neurologic symptoms and sequelae were associated with influenza A virus infection in children during the 2003-2004 influenza season in Texas. This is the largest single-season, single-institution case series ever reported. Influenza should be considered in the differential diagnosis in U.S. children with seizures and mental status changes, especially if they present with respiratory symptoms or during an influenza outbreak.

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Immunogenicity of PENTACEL™ When Administered as a Fourth Dose at 15 to 18 Months of Age

David P. Greenberg, David Scheifele, Fernando Noriega. Aventis Pasteur, PA; Vaccine Evaluation Centre, BC, Canada.

BACKGROUND: Pentacel™ is a pentavalent combination vaccine designed to provide, in a single injection, immunization against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b as currently recommended at 2, 4, 6, and 18 months of age in Canada, where it has been used universally since 1997. The present study was conducted to support the indication of a 4th dose administration of PENTACEL™ at 15 to 18 months of age, as recommended (ACIP, AAP, AAFP) for acellular pertussis vaccines in the US.

OBJECTIVE: To determine if Pentacel™ elicits similar immune responses whether the 4th dose is administered at 15, 16, 17, or 18 months of age.

METHODS: Randomized, multi-center study performed in subjects who had received 3 doses of Pentacel™ (at 2, 4 and 6 months of age) as part of the recommended immunization series in Canada. Subjects were enrolled at their primary care visit at 12 months of age and randomized to receive the 4th dose of Pentacel™ at either 15, 16, 17 or 18 months of age. Geometric mean titers (GMTs) of antibodies were determined one month after the 4th dose.

RESULTS: Pre-immunization antibody levels did not appreciably differ with age (not shown). As presented in the Table, the immune responses elicited by Pentacel™ were similar throughout the age range tested.

CONCLUSIONS: Responses to a 4th dose of Pentacel™ were robust and consistent between 15 and 18 months of age, demonstrating that this is a suitable age range for boosting with this vaccine.

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A Study of a New Zealand Epidemic Strain Meningococcal B Outer Membrane Vesicle Vaccine Targeting P1.7b, 4 Por A Protein in Healthy 16–24 Month Old Toddlers

Sharon H. Wong, Catherine M. Jackson, Diana M. Martin, Jane M. O’Hallahan, Philipp Oster, Joanna M. Stewart, Diana R. Lennon. The University of Auckland, Auckland, New Zealand; Environmental Science & Research (ESR), Wellington, New Zealand; Ministry of Health, Wellington, New Zealand; Chiron Vaccines, Siena, Italy.

BACKGROUND: New Zealand has been experiencing a monoclonal epidemic of Neisseria meningitidis B:4:P1.7b,4 which has resulted in more than 5000 cases and over 200 deaths since 1991. Children younger than 5 years are at highest risk.

OBJECTIVE: To evaluate the safety, reactogenicity and immunogenicity of an outer membrane vesicle (OMV) vaccine specifically developed for the epidemic strain in 16 – 24 month old toddlers.

METHODS: A Phase II observer-blind, randomised, controlled, single centre trial of 332 healthy children aged 16 – 24 months. Subjects were randomised in a 4:1 ratio to receive 25mcg New Zealand candidate vaccine (NZ98/254) or 25mcg Norwegian parent vaccine (H44/76). Vaccines were administered at 0, 6 and 12 weeks. Serum bactericidal assay (SBA) was used to measure immune response to candidate and parent vaccine strains at baseline, six weeks post dose 2, and four weeks following dose 3. Local and systemic reactions were monitored for 7 days after vaccination.

RESULTS: Responders were defined as those with a 4-fold or greater rise in SBA antibody titre to NZ98/254 four weeks after the third dose compared to baseline. This was achieved in 75% (95% CI: 69-80%) of subjects receiving the candidate vaccine as compared with 4% (95% CI: 0-13%) of subjects who received Norwegian strain vaccine.

CONCLUSION: Three doses of New Zealand candidate vaccine (NZ98/254), administered to 16 – 24 month old toddlers, elicit promising bactericidal antibody results against the New Zealand epidemic strain. This study was funded by the New Zealand Ministry of Health and Chiron Vaccines.

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Comparison of Efficacy and Safety of a Trivalent, Live Attenuated, Intranasal Influenza Vaccine (CAIV-T) with Trivalent, Inactivated, Intramuscular Influenza Vaccine (TIV) in Children and Adolescents Aged 6 to <18 Years with Asthma

Douglas Fleming, Pietro Crovari, Ulrich Wahn, Timo Kremola, Yechiel Schlessinger, Alexangros Langussis, Maria Lisiecka, Knut Øymar, Maria Luz Garcia, Ivo GCM Bierens, Alain Krygier, Herculano Costa, Ulrich Heininger, Melanie Saville, Bruce Forrest, William Gruber, CAIV-T study group. Northfield Health Centre, Birmingham, UK; Wyeth Vaccines Research, Pearl River, NY

OBJECTIVES: 1) To compare the efficacy of CAIV-T vs licensed TIV over one season against culture-confirmed, community-acquired influenza in children aged 6 to <18 years of age with asthma; 2) to compare asthma exacerbations after CAIV-T or TIV.

DESIGN/METHODS: 2231 children and adolescents with asthma were recruited from 12 European countries and Israel. Subjects were randomized 1:1 to receive either one intranasal dose of CAIV-T or one intramuscular dose of TIV prior to the 2002-2003 influenza season. Active surveillance for protocol-defined influenza illness and asthma exacerbations occurred weekly until May 2003. For each influenza-like illness, a nasal swab was obtained for influenza culture.

RESULTS: 46 (4.1%) of CAIV-T vs. 70 (6.4%) of TIV recipients experienced antigenically similar culture-confirmed influenza illness, a 34.7% statistically superior efficacy for CAIV-T (95% CI 3.9, 56.0). Type B viruses caused most cases: 34 (3.1%) in CAIV-T vs. 53 (4.8%) in TIV recipients, a 36.3% greater efficacy for CAIV-T (95% CI 0.1, 59.8). A/H1 illnesses occurred in 0 CAIV-T vs. 5 (0.5%) TIV recipients (95% CI -8.4, 100). Twelve (12) A/H3 illnesses occurred in each group. Safety: No statistically significant differences between groups were noted for asthma exacerbations (increased asthma medication use, unscheduled clinic visits, or hospitalizations) within the first 42 days or throughout the study surveillance.

CONCLUSIONS: This is the first study directly comparing CAIV-T to TIV in children with asthma. Overall, CAIV-T had 35% superior efficacy to TIV and demonstrated a similar safety profile.

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Bioequivalence of Breast Milk from Grandmother Re-lactation HIV Prevention Trial

Chandice Y. Covington and Mohamed S. Abdullah. UCLA School of Nursing, Los Angeles & Aga Khan Hospital, Nairobi, Kenya.

BACKGROUND: The majority of pediatric AIDS cases worldwide are attributed to postpartum breast milk transmission of HIV. Yet breastfeeding (BF) remains the primary source of infant nutrition in developing countries, as formula is neither an affordable nor a safe option due to poor sanitation and lack of clean water.

OBJECTIVE: To evaluate if grandmother age women (GM) can re-establish a milk supply bioequivalent to mother’s milk as proof-of-concept for a "surrogate feeding" intervention to circumvent HIV breast milk transmission.

DESIGN/METHODS: This intervention trial evaluated low-technological methods to re-constitute breast milk production in weaned, older women of grandmother age. Participants were volunteer GM women (N=25; ages 35-70 years) who had breast-fed a minimum of one child (range 1-14 births) for at least 6 months (range 1-28 years) and were now weaned for at least 6 months (range 1-20 years). The woman’s daughter (DA) or neighbor of daughter age (N=25), at least 18 years old and BF, was recruited to donate a comparison breast milk sample. Participants were HIV seronegative, not pregnant nor anemic. The GM used a manual breast pump daily for 4-6 times for 10 minute for 6 weeks. Nurses conducted weekly home visits to ascertain appropriate use of the re-lactation protocol. GM breast milk sample levels of protein (total, IgA, lactoferrin), carbohydrates, vitamin A, iron, and fatty acids and plasma samples for prolactin, hemoglobin, vitamin A, and lipids were compared to DA samples and standard values.

RESULTS: Breast milk from surrogate grandmother aged women in Kenya following a 6 week trial of breast pumping establishes an initial milk supply equivalent nutritionally to that expressed by same village BF mothers. GM amounts of breast milk from one pumping ranged from drops to over 100 ml. Final results review the similarities and differences between human milk components from GMs, DAs, and the literature.

CONCLUSION: The anthropologic grandmother hypothesis that elder women outlive their procreation function to care for the next generations progeny is supported at its very basic level of nutrition. A RCT to ascertain preventive effect and potential problems of this intervention is planned to thwart the dramatic contribution of BF to the global AIDS crisis.

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Can High Rates of Influenza Immunization Be Achieved in Healthy Young Children? Results of a Randomized Controlled Trial Using Registry-Based Recall

Allison Kempe, Matthew F Daley, Jennifer Barrow, Nellie Hester, Brenda L. Beaty, Norma Allred, Kellyn Pearson, Lori A Crane, and Stephen Berman. Dept. of Pediatrics, Univ. of CO Health Sciences Center, Children’s Outcomes Research Program, The Children’s Hospital, Denver, CO, National Immunization Program, Centers for Disease Control, Preventive Medicine & Biometrics, Univ. of CO HSC, Denver, CO.

BACKGROUND: During 2003-2004, a well-publicized and severe influenza (flu) season in CO, the ACIP encouraged flu immunization (Iz) in children 6-23 months. ACIP will recommend Iz in this age group in 2004-2005.

OBJECTIVES: 1) To assess the maximum flu Iz rate that can be achieved in healthy children 6-21 months in private practice settings and 2) to evaluate the efficacy of registry-based recall for flu.

METHODS: The study was conducted in 5 private pediatric practices in Denver, CO with a common billing system and Iz registry. Healthy children 6-21 months were selected (N=5200) and randomized to an intervention (I; n=2601) group that received up to 3 recall letters or to a control (C; n=2599) group that received usual care. The primary outcome was receipt of one or more flu Iz as noted either in the Iz registry or in billing data.
RESULTS: Iz rates in the I groups in the 5 practices were 75.9%, 75.2%, 67.3%, 54.9% and 44.0% by 1/31/04. Overall, 62.0% of I vs. 57.7% of C were immunized (4.3% absolute increase, p=0.002), with absolute % increases over C ranging by practice from 1.0% (p=NS, I vs C) to 8.7% (p=0.003, I vs C). However, before the epidemic (publicity beginning 11/15/03) absolute % increases over C ranged from 4.9% to 15.6% and were 9.5% overall (p<0.0001, I vs C). Before 11/15, significant effects of recall were seen both for children 12-21 months (10.2% increase over C, p<0.0001) and 6-11 months (8.1% increase over C, p=<0.001), but by 1/31 significant effects of recall were seen only in the older age group (5.9% increase over C, p<0.001).

CONCLUSIONS: During an epidemic flu year, private practices were able to immunize the majority of children 6-21 months in a timely manner. Although media coverage regarding the epidemic blunted the effect of registry-based recall, it was still effective in raising rates before the epidemic hit, especially for children 1 to 2 years of age.

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Adolescent Patients’ Response to Internet Health Information in Examination Rooms During Wait Times

Sophia Yen, Xuan-Mai Nguyen, John Hsih. Elizabeth M. OzerDivision of Adolescent Medicine, Department of Pediatrics UC San Francisco, San Francisco, CA and UC Berkeley, Berkeley, CA.

Background: Patient visits to academic centers can entail being seen by a medical student, resident, and/or fellow and an attending physician. Because of this, patients spend Time In Examination Rooms (TIER) waiting while their information is presented to supervising physicians. How this time is spent and how the patient perceives the time and visit have not been previously studied. While studies of computer use in waiting rooms exist, there has never been a study of providing computer education in the examination room.

Objectives: To explore if patient access to health websites improves satisfaction with waiting TIER and visits.

Design/Methods: For 3 months, all patients that attended an academic adolescent clinic were randomized to 1) rooms without computers [control group] or 2) rooms with computers with internet access to restricted health websites [intervention group]. After the visit, patients filled out a questionnaire to assess wait time, satisfaction with wait time, how the wait time was spent, and the impact of computer use, if applicable.

Results: Patient-reported waiting TIER averaged 18 minutes. 42% of all patients reported that they "just sat" while waiting (52% of controls, 32% of the intervention p<.02). The intervention group scored higher in agreement with "I did an interesting activity" during TIER waiting (p<.01). Two-thirds of the patients in the intervention group used the computers. Patients reported an average of 12 minutes computer use. In a sub-analysis comparing the controls to those that received computers and used them, those that used computers scored higher in agreement with statements that during TIER waiting they did an interesting activity, learned something, and made good use of their time (p<.001, .01, .05, respectively). Of those that used the computers, 87% reported the computer was somewhat or very interesting, 87% "learned something," 60% that computers made the visit much better, 9% that the computers made no difference , and 87% that they very much wanted to continue having computers in rooms.

Conclusion: Patients were more satisfied with wait time and their visit when their exam rooms had computers with access to internet health sites. Clinics may want to consider providing patients access to health websites during wait TIER, and future studies may consider applying a health-focused intervention during TIER.

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Multicenter Trial of Mycophenolate Mofetil (MMF) in Children with Steroid Dependent (SD) or Frequent Relapsing (FR) Nephrotic Syndrome (NS). Report of the Southwest Pediatric Nephrology Study Group

Ronald Hogg, Lisa Fitzgibbons, Joy Bruick, Martin Bunke, Bettina Ault, Noosha Baqi, Howard Trachtman, Rita Swinford. Clinical Research, Medical City Hospital, Dallas, Texas; Roche Laboratories, Nutley, NJ; University of Tennessee, Memphis, TN; SUNY Brooklyn, Brooklyn, NY; Schneider Children’s Hospital, New Hyde Park, NY; University of Texas - Houston, Houston, TX.

BACKGROUND: Children with SD or FRNS often have serious steroid side effects (S/E). Alternative therapy with agents such as cyclosporine A (CsA) may also cause S/E with the major long-term concern with CsA being progressive nephrotoxicity. Preliminary data indicate that MMF may be a safer alternative for such patients.

OBJECTIVES: To determine if MMF can maintain children with SDNS or FRNS in persistent remission of their NS without steroids, and whether this can be maintained after MMF is stopped.

DESIGN/METHODS: A liquid formulation of MMF (200mg/ml) was evaluated in 33 children with FRNS or SDNS (81% FR; 19% SD) in 14 centers. All pts were in remission at the time of entry. They received MMF 600mg/m2 BID for 24 weeks, then a tapering dose for 4 weeks. Alternate day prednisone was also given during the first 16 weeks. Treatment failure was defined as a relapse of NS. Features of the patients at the time of entry: Age: 6.8±2.7 years; Range: 2-15 years; 56% Male; 50% White; 25% African American; 25% Other. Number of relapses pre-entry: 4.3 ±2.3 per year. All patients had normal renal function (based on estimated glomerular filtration rate). Renal biopsies were not required for entry into the study.

RESULTS: Twenty-four of the 32 pts (75%) stayed in remission throughout MMF therapy. 7 of these pts have stayed in remission during the entire post-MMF period (mean 18.5 months; range 11-28 months), whereas 17 relapsed after stopping MMF. Thirteen of these 17 pts were re-started on MMF by their primary physician post-study: 5 have subsequently stayed in remission, 6 have had infrequent relapses and 2 have had frequent relapses.

CONCLUSIONS: MMF is an effective agent for maintaining remission in NS patients who receive treatment for at least 6 months and can effectively decrease the adverse events that occur with prednisone in such patients. Our results indicate that MMF may provide an alternative to CsA in children with SDNS or FRNS.

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Cerebral Cortex Thickness in 14-Year-Old Adolescents with Very Low Birth Weight (VLBW) Measured by an Automated MRI-Based Method

M. Martinussen, A.M. Dale, B. Fischl, O. Haraldseth, H. Larsson, J. Skranes, T. Vik, A.-M. Brubakk. Nuclear Magnetic Resonance Center, Massachusetts General Hospital, Harvard Medical School; MIT Artificial Intelligence Laboratory, MIT, Boston, MA; Dept. of Circulation and Medical Imaging; Dept. of Public Health and General Practice; Dept. of Laboratory Medicine, Children’s and Women’s Health, Faculty of Medicine, Norwegian University of Science and Technology, Norway.

Changes in cerebral cortex development in VLBW children may be closely related to perinatal injury and have serious consequences for later behavioral, motor and cognitive development. Aim: The aim of this study was to measure cerebral cortical thickness over the total surface of the brain in VLBW adolescents compared to controls using a new automated MRI based method. Methods: High resolution MR images were obtained in 42 VLBW (<1500gm birth weight) and 58 controls (birth weight appropriate for gestational age at term) at 14 year of age in a population based follow up study. A novel method of automated surface reconstruction yielded measurements of the cortical thickness for each subject’s entire brain and computed cross-subject statistics based on the cortical anatomy. Performing t-tests between the VLBW and controls generated statistical thickness difference maps. Results are presented in figure 1, right hemisphere and figure 2, left hemisphere. The surface reconstruction demonstrates the mean thickness differences of the cortex as statistical maps of control vs. VLBW group. The color scale shows the range of sig., yellow thinner, blue thicker. In both hemispheres, VLBW had focal thinning in the regions of the parietal, the temporal and occipital lobes compared to controls, VLBW had focal thickening in the prefrontal and in the occipital area compared to controls (p<0.0001). This findings of focal changes of cortical thickness in adolescents born VLBW offers an unique opportunity to investigate the relationship between cognitive, visual and motor abilities and psychiatric problems and changes in cortical anatomy.

Figure 1                        Figure 2

               p<0.0001                      p<0.0001

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Changes in Lung Impedance Following Derecruitment During High Frequency Ventilation

Gerhard K. Wolf , Huibert R. van Genderingen , John Thompson , Kenneth Watson , John H. Arnold. Children’s Hospital Boston, USA; Vrije Universiteit Medical Center, Amsterdam, The Netherlands.

BACKGROUND: Monitoring regional recruitment is of great interest in managing acute lung injury with high frequency oscillation ventilation (HFOV). Electric Impedance Tomography (EIT) is an imaging tool to assess regional changes in lung volume at the bedside. Local impedance changes have been correlated with changes in lung density in CT in both animals and humans.

OBJECTIVE: To determine regional lung impedance changes in children with acute lung injury (ALI) on HFOV during a standardized suctioning maneuver (derecruitment) followed by standardized rerecruitment.

DESIGN/METHODS: Regional and global impedance changes in three pediatric patients with ALI ventilated with the Sensormedics 3100A were recorded with 16 circumferential electrodes around the patient’s chest. EIT data were collected using the Goettingen MF II System. Derecruitment of the lung was monitored during a suctioning maneuver. Prior to suctioning, the expired volume was collected and correlated to the impedance change during this maneuver.

RESULTS: We were able to show global and regional lung impedance changes (DZ) during derecruitment, with a difference along the gravitational axis. Disconnection from the ventilator resulted in a DZ of –46. The impedance change was more pronounced in the ventral areas (DZ = –38) than in the dorsal areas (DZ = –8). Impedance in dorsal areas returned to supranormal levels, which suggests efficient recruitment of atelectatic lung regions.

CONCLUSION: Our data demonstrate that regional impedance changes can be monitored with EIT during HFOV in children at the bedside.

Left: Derecruitment is more pronounced in ventral than in dorsal lung regions, as shown by the magnitude of impedance change.

Right: Functional EIT image of the lung

LB27

Assessing Bone Age in Children with Delayed Development Using Ultrasound

Z. Zadik, T. Bistritzer, T. Schwartz, L. Tsoref, I. Yaniv. Pediatric Endocrine Unit, Kaplan Medical Center, Rehovot, Israel. Pediatric Endocrine Unit, Assaf Harofeh Medical Center, Zerifin, Israel. Sunlight Medical Ltd., Tel-Aviv, Israel

BACKGROUND: Skeletal maturity determination, frequently called bone age (BA), has an important role in pediatrics and pediatric endocrinology, especially when evaluating growth and endocrine disorders. In previous studies (1, 2) we introduced a new modality that uses ultrasound of the wrist for BA evaluation and validated its accuracy and correlation to the standard X-ray reading on a general population of pediatric-endocrinology outpatient clinic patients. The aim of this study was to assess the accuracy and correlation of the new system with the Greulich and Pyle (GP) method (3) in children studied for growth retardation.

METHODS: Forty-seven children (32 boys and 15 girls), 11.0 ±2.9 years (range 5.5-17), height SD -1.6±0.7 SD (range –3.31 to 0.28 SD) who were referred to endocrine clinic for growth retardation and bone age retardation were studied. Bone age retardation was defined as a bone age younger than the chronological age by at least 2 years, as determined by the GP method. The radiographs were interpreted by two pediatric endocrinologists. GP readings were compared with measurements obtained with the BonAge device, an apparatus using ultrasound technology. Accuracy was calculated as the absolute average difference from the X-ray results.

RESULTS: The general accuracy for boys and girls together was 1.2 (±0.80) years. When calculated separately, accuracy was 1.3 (±0.8) and 0.9 (±0.7) years for boys and girls respectively. The r2 (r is the Pearson correlation coefficient) between the two methods was 0.88 and 0.89 for boys and girls respectively.

CONCLUSION: The BonAge ultrasound device was found to be a reliable tool for determining BA. Results were highly correlated with X-ray readings using the GP method in growth-retarded children. This automated system for BA readings may be convenient for use at doctors’ offices and in pediatric clinics for diagnosis of growth disorders.

References

1. Z. Zadik et al., 42nd meeting of ESPE Ljubljana, Slovenia, (Sep. 2003) P2-188. 2. Z. Zadik et al., Europaediatrics 2003, Prague, Czech Republic, (Oct. 19-22, 2003). 3. Greulich WW, Pyle SI, Radiographic atlas of skeletal development of the hand and wrist, 2nd ed. Stanford California, Stanford University Press, 1959.

LB28 

Two-Year Neurodevelopmental Outcomes of Premature Infants Treated with Inhaled Nitric Oxide: Longitudinal Follow Up of a Prospective, Randomized Controlled Trial

Karen K. Mestan, Grace Lee, Janell Fuller, Susan Troyke, Kurt E. Hecox, Sunila O’Connor, Dezheng Huo and Michael D. Schreiber. Pediatrics, Occupational Therapy, and Health Studies, University of Chicago, Chicago, IL.

BACKGROUND: In a randomized, placebo-controlled trial of 207 premature infants with RDS, we previously reported inhaled nitric oxide (iNO) decreased the incidence of severe CLD and death (Schreiber, NEJM, 2003). Although the study also suggested that iNO decreased severe IVH/PVL, long-term neurodevelopment may better delineate the effects of iNO on future neurologic outcomes.

OBJECTIVE: To investigate the long-term neurodevelopmental outcomes of premature infants treated with iNO.

DESIGN/METHODS: Infants from the original study (BW 983±378 g, GA 27.0±2.7 wks) were followed longitudinally (mean age 27.7±8.0 mos). Patients were assessed using the Bayley Scales of Infant Development (MDI and PDI) and by neurologic examination by a pediatric neurologist. Examiners were unaware of treatment assignment. A neurodevelopmental disability was defined as having either 1) a diagnosis of cerebral palsy and/or 2) bilateral blindness or hearing loss. A neurodevelopmental delay was defined as 1) not having a disability and 2) at least one Bayley score < 70. Patients with neither a disability nor delay were categorized as normal.

RESULTS: 139 of the 168 surviving patients (83% follow up rate) were examined. Birthweight and gestational age were similar between groups. Patients treated with iNO had significantly lower odds of having abnormal neurodevelopment than placebo (odds ratio 0.41, 95% confidence interval: 0.20-0.83).

CONCLUSION: The incidence of abnormal neurodevelopmental outcomes (i.e., disability and delay) was significantly decreased in premature infants treated in the newborn period with iNO. These findings further support the potential beneficial effects of iNO in premature infants.