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Timing of Initial Surfactant Treatment for Infants 23 to 29 Weeks’ Gestation: Is Routine Practice Evidence Based?

Jeffrey D. Horbar, MD^*,, Joseph H. Carpenter, MS, Jeffrey Buzas, PhD, Roger F. Soll, MD^*,, Gautham Suresh, MD^*, Michael B. Bracken, PhD^||, Laura C. Leviton, PhD^¶, Paul E. Plsek, MS#^#, John C. Sinclair, MD^**, for the members of the Vermont Oxford Network

^* Department of Pediatrics, University of Vermont College of Medicine, Burlington, Vermont
Vermont Oxford Network, Burlington, Vermont
Department of Mathematics and Statistics, University of Vermont, Burlington, Vermont
^|| Center for Perinatal, Pediatric and Environmental Epidemiology, Yale University, New Haven, Connecticut
^¶ Robert Wood Johnson Foundation, Princeton, New Jersey
^# Directed Creativity, Atlanta, Georgia
^** Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
Center for Clinical Research and Evidence-Based Medicine, University of Texas Medical School, Houston, Texas

	ABSTRACT

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Objective. To describe the timing of initial surfactant treatment for high-risk preterm infants in routine practice and compare these findings with evidence from randomized trials and published guidelines.

Methods. Data from the Vermont Oxford Network Database for infants who were born from 1998 to 2000 and had birth weights 401 to 1500 g and gestational ages of 23 to 29 weeks were analyzed to determine the time after birth at which the initial dose of surfactant was administered. Multivariate models adjusting for clustering of cases within hospitals identified factors associated with surfactant administration and its timing. Evidence on surfactant timing from systematic reviews of randomized trials and from published guidelines was reviewed.

Results. A total of 47 608 eligible infants were cared for at 341 hospitals in North America that participated in the Vermont Oxford Network Database from 1998 to 2000. Seventy-nine percent of infants received surfactant treatment (77.6% in 1998, 79.4% in 1999, and 79.6% in 2000). Factors that increased the likelihood of surfactant treatment were outborn birth, lower gestational age, lower 1-minute Apgar score, male gender, white race, cesarean delivery, multiple birth, or birth later in the study period. The first dose of surfactant was administered at a median time after birth of 50 minutes (60 minutes in 1998, 51 minutes in 1999, and 42 minutes in 2000). Over the 3-year study period, inborn infants received their initial dose of surfactant earlier than outborn infants (median time: 43 minutes vs 79 minutes). Other factors associated with earlier administration of the initial surfactant dose were gestational age, lower 1-minute Apgar score, cesarean delivery, antenatal steroid treatment, multiple birth, and small size for gestational age. In 2000, 27% of infants received surfactant in the delivery room. There was wide variation among hospitals in the proportion of infants who received surfactant treatment in the delivery room (interquartile range: 0%–75%), in the median time of the initial surfactant dose (interquartile range: 20-90 minutes), and in the proportion of infants who received the first dose >2 hours after birth (interquartile range: 7%–34%). Six systematic reviews of randomized trials of surfactant timing were identified. No national guidelines addressing the timing of surfactant therapy were found.

Conclusion. Although the time after birth at which the first dose of surfactant is administered to infants 23 to 29 weeks’ gestation decreased from 1998 to 2000, in 2000 many infants still received delayed treatment, and delivery room surfactant administration was not routinely practiced at most units. We conclude that there is a gap between evidence from randomized controlled trials that supports prophylactic or early surfactant administration and what is actually done in routine practice at many units.

Key Words: surfactant • very low birth weight • Vermont Oxford Network • evidence • respiratory distress syndrome • preterm delivery

Abbreviations: RDS, respiratory distress syndrome • NICU, neonatal intensive care unit • VON, Vermont Oxford Network • CI, confidence interval • RR, relative risk

Nearly 50 years after the discovery that infants with respiratory distress syndrome (RDS) are deficient in pulmonary surfactant and more than a decade after the introduction of exogenous surfactants for routine clinical use in neonates, questions remain concerning the optimal treatment strategy. There are 2 basic approaches to therapy. Surfactant may be administered soon after birth as prophylaxis to infants who are at risk for developing RDS or later as rescue treatment to infants who have developed signs of respiratory distress. Multiple randomized controlled trials have demonstrated that both of these approaches to surfactant therapy are safe and effective,¹ yet controversy remains over how to select infants for prophylactic treatment and how soon after birth to initiate therapy. Many neonatal units lack standardized protocols for surfactant treatment. As a result, there is likely to be considerable variation in surfactant treatment practices both within and among neonatal intensive care units (NICUs), but data on these practices are not currently available.

In this article, we describe the timing of initial surfactant treatment for high-risk preterm infants and identify factors associated with variations in timing of initial treatment. The report includes data for infants who were of 23 to 29 weeks’ gestation and were born from 1998 to 2000 and cared for at the 341 NICUs in the United States that participated in the Vermont Oxford Network (VON). These analyses provide a detailed description of current surfactant treatment practices and allow us to evaluate how the available evidence has been translated into routine practice.

	METHODS

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Vermont Oxford Network
The VON is a voluntary collaboration of health professionals whose mission is to improve the quality and safety of medical care for newborn infants and their families through a coordinated program of research, education, and quality improvement.² In support of this mission, VON maintains a database for infants 401 to 1500 g. Members adhere to uniform definitions included in VON's Database Manual of Operations.³ Infants with birth weights 401 to 1500 g are eligible for inclusion in the database if they were born at a VON center or were transferred to it within 28 days of birth. In addition to submitting data on eligible infants, each member hospital completes an annual hospital survey, which provides information on the types of services available.⁴

Study Sample
This report is based on an analysis of data for infants who were born from 1998 to 2000 with gestational ages from 23 and 29 weeks and birth weights from 401 to 1500 g. Infants with lethal or life-threatening birth defects were excluded. All US and Canadian VON hospitals that participated in the VON database in any of those years were included in the analyses. Infants who were transferred from a VON hospital to another VON hospital within 28 days of life were included only at the second VON hospital to avoid data redundancy and to ensure that data were as complete as possible.

Surfactant Outcome Measures
Whether infants received surfactant at any time and the age in hours and minutes at first dose were collected in the database for infants who were born from January 1, 1998, to December 31, 2000. The VON began collecting data on whether infants received surfactant in the delivery room for infants who were born in 2000. In addition to these 3 measures, we constructed a dichotomous variable for infants who received surfactant to evaluate whether their first dose was after 2 hours of age. Data on the number of doses or type of surfactant administered were not collected.

Evidence Review
A search for systematic reviews and published guidelines was conducted to ascertain what evidence was available to support specific surfactant treatment strategies. Searches were made of the Cochrane Library and Medline (key words: surfactant, pulmonary surfactant; limits: guidelines, meta-analysis). Two systematic reviews published in the Cochrane Library address the issue of timing of treatment.^5,6 Four meta-analyses published in peer-reviewed journals addressed issues of treatment strategy including timing of treatment.^7–10 The 4 non-Cochrane reviews were limited either by initial design (a review of only 1 surfactant product or dosing regime) or incomplete literature review. We therefore based our summary of the randomized trials evidence on the Cochrane reviews that included all trials identified in any of the other reviews. Two published guidelines were identified.^11,12

Statistical Methods
Multivariate models were created to explore the relationship between infant and hospital characteristics and the administration and timing of surfactant treatment during the period 1998 to 2000. All standard errors and significance tests reflect adjustment for clustering of infants within hospitals.¹³

Dichotomous outcome measures (surfactant at any time, surfactant in the delivery room, and surfactant after 2 hours) were modeled using logistic regression. Intrahospital correlation was accounted for using generalized estimating equations. The exchangeable correlation structure was assumed in all logistic models, unless there was a problem with convergence, in which case the independent correlation structure was used. A linear model including infant and hospital characteristics was used to model time to first dose of surfactant, with random effects for hospital. To minimize outlier effects, the natural log of time to first dose was used as the dependent measure in this model.

Infant-level covariates in all models included gestational age in completed weeks, small for gestational age (yes or no for birth weight <10th percentile for infants’ gestational age and gender and maternal race and multifetal gestation), birth location (inborn or outborn), Apgar score at 1 minute after birth, multiple birth (yes or no), mode of delivery (cesarean section or vaginal), antenatal steroids (yes or no), gender, and maternal race or ethnicity (black, Hispanic, white, or other). For the surfactant measures available during the entire study period (all except delivery room surfactant), we included month of birth (1-36) to test for a time trend. For improving the model fit, gestational age was modeled as a categorical variable.

Hospital characteristics specified in all models were geographic region, teaching hospital (yes or no), annual volume of eligible infants with birth weights between 401 and 1500 g (<50, 50) and level of service (type A, B, or C). Level of service was assigned on the basis of the VON Annual Membership Survey. Type A hospitals are those that have restrictions on providing assisted ventilation or that provide only minor surgery. Type B hospitals perform major surgery but not cardiac surgery and have no restrictions on assisted ventilation. Type C hospitals perform major surgery, including cardiac surgery, and have no restrictions on assisted ventilation. Statistical analyses were performed using SAS statistical software version 8.2 (SAS Institute, Cary, NC).

	RESULTS

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A total of 341 hospitals in the United States and Canada contributed to the VON Database during the period 1998 to 2000. Of these hospitals, 252 participated during all 3 years, 49 during 2 of the years, and 40 for only 1 of the years. The median average annual number of infants contributed by an individual hospital was 43 with an interquartile range of from 24 to 71 infants. Characteristics of participating hospitals are shown in Table 1.

Multivariate logistic models that explored the relation between surfactant administration with infant and hospital characteristics showed that infants were more likely to receive surfactant when they were born later in the study period or were outborn, had lower gestational age, had lower 1-minute Apgar score, were male, were white, were delivered by cesarean section, or were 1 of multiple births (P < .001 for all) or were treated at hospitals that were members of the Council on Teaching Hospitals (P < .02). The likelihood of surfactant treatment increased from 1998 to 2000 (P < .01). No treatment differences were observed in type A, B, or C hospitals or in lower versus higher volume hospitals, after adjusting for other predictors.

The median time after birth at which the initial dose of surfactant was administered to infants who were of 23 to 29 weeks’ gestation and received surfactant is shown by gestational age and year in Fig 1. Overall, the median time after birth at which the initial dose of surfactant is given remains relatively constant from 23 to 25 weeks’ gestation and then increases steadily up to 29 weeks. Importantly, there is a decrease in the median time of the initial dose from 1998 to 2000 in every gestational age category. At 23 weeks, the median time decreased from 41 minutes in 1998 to 30 minutes in 2000; at 29 weeks, the median time decreased from 95 minutes in 1998 to 67 minutes in 2000.

View larger version (40K): [in this window] [in a new window]   Fig 1. Median time (minutes) at administration of the first dose of surfactant by gestational age and year of birth for infants who were 23 to 29 weeks’ gestation and received surfactant (VON 1998-2000).

View larger version (24K): [in this window] [in a new window]   Fig 2. Median time (minutes) at administration of the first dose of surfactant by location of birth (inborn, outborn) and year of birth for infants who were 23 to 29 weeks’ gestation and received surfactant (VON 1998-2000).

The VON collected information on delivery room administration of surfactant for the first time in the year 2000. For that reason, we focus on the timing of initial surfactant treatment for infants who were born in that year. In these analyses, the denominator is all infants rather than infants who received surfactant to identify overall differences in prophylactic treatment practices among centers.

Overall, 26.6% of infants who were 23 to 29 weeks’ gestation and born in 2000 were treated with surfactant in the delivery room. The values of the mean hospital percentages and quartiles for infants who received surfactant at the 323 hospitals that participated in 2000 are shown by location of birth and gestational age in Table 3. There is wide variation among hospitals in the proportion of infants who receive surfactant treatment in the delivery room. For example, although overall 38% of all inborn infants of 24 weeks’ gestation received surfactant in the delivery room in 2000, the interquartile range among hospitals was from 0% to 75%. This indicates that in 25% of hospitals, no 24-week inborn infants received surfactant in the delivery room, whereas at the 25% of hospitals with the highest rates, >75% of 24-week inborn infants received surfactant in the delivery room. There is less variation in treatment practice for outborn infants at 28 or 29 weeks’ gestation when no infants received delivery room surfactant at 75% of hospitals.

View larger version (17K): [in this window] [in a new window]   Fig 3. Cumulative percentage of all infants who were 23 to 29 weeks’ gestation and received the first dose of surfactant at specific time intervals after birth. The vertical bars represent the interquartile ranges for the percentages at the 341 participating units (VON 1998-2000).

Because all infants who are intubated in the delivery room are potentially eligible to receive surfactant in the delivery room, it is of interest to determine what proportion of these infants actually received surfactant in the delivery room and what proportion were treated with surfactant at a later time. These data are shown by gestational age in Fig 4, in which the total height of the vertical bar represents the proportion of infants who were intubated in the delivery room. The proportion of infants who were intubated in the delivery room increases from 78% at 23 weeks to 93% at 24 weeks and 92% at 25 weeks and then decreases with advancing gestational age. Although a high proportion of infants who are intubated in the delivery room ultimately are treated with surfactant, <36% of the infants who are intubated in the delivery room receive surfactant in the delivery room.

View larger version (30K): [in this window] [in a new window]   Fig 4. Administration and timing of surfactant treatment for infants who were 23 to 29 weeks’ gestation and intubated in the delivery room. The total height of the stacked bar at each gestational age represents the percentage of infants at that gestational age who were intubated in the delivery room. Each bar is divided into 3 categories: infants who received the first dose of surfactant in the delivery room (black), infants who received the first dose of surfactant after leaving the delivery room (dark gray), and infants who never received surfactant (light gray) (VON, 1998-2000).

	DISCUSSION

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It is instructive to consider these findings in light of available evidence regarding administration and timing of surfactant therapy. Substantial evidence demonstrates that surfactant therapy is beneficial for high-risk preterm infants,¹ and our data show that for infants of 23 to 29 weeks’ gestation, surfactant therapy is widely used. Furthermore, there is a strong rationale to support the preference for prophylactic over rescue surfactant administration. Prophylactic administration of surfactant offers the theoretical advantage of replacing surfactant before the onset of respiratory disease, decreasing the need for ventilator support and avoiding secondary barotrauma that may result from even short periods of assisted ventilation.^14,15 In animal models, surfactant is distributed more homogeneously when given immediately after birth into lungs that are still fluid filled.¹⁶ Eight randomized, controlled trials that evaluated the benefits of prophylactic surfactant therapy compared with treatment of infants with established RDS were included in the systematic reviews of the Cochrane Collaboration.⁵ In these trials, infants who were at high risk of developing RDS were randomized to either intubation in the delivery room and administration of natural surfactant extract or to natural surfactant extract treatment of established RDS (surfactant treatment for infants on assisted ventilation with clinical signs of RDS). In these trials, prophylactic surfactant was administered within 10 minutes of birth, whereas rescue treatment was administered at mean times ranging from 90 minutes to >7 hours based on each individual study’s prespecified criteria for the threshold severity of respiratory distress. Meta-analysis of the 8 trials demonstrates that prophylactic administration of natural surfactant extract leads to a significant reduction in the risk of pneumothorax (typical relative risk: 0.62; 95% confidence interval [CI]: 0.42-0.89; typical risk reduction: –2%, 95% CI –4% to –1%) and a significant reduction in the risk of mortality (typical relative risk: 0.61; 95% CI: 0.48-0.77; typical risk reduction: –5%; 95% CI: –7% to –2%).² Because of the greater risk of RDS and mortality with decreasing gestational age, the benefits of prophylactic surfactant administration are most pronounced in infants of <30 weeks’ gestation.

Four randomized, controlled trials that compared early surfactant administration within 2 hours of birth with delayed therapy are included in the systematic review of the Cochrane Collaboration.⁶ Early surfactant administration leads to decreased risks of pneumothorax (typical relative risk [RR]: 0.70; 95% CI: 0.59-0.82), pulmonary interstitial emphysema (typical RR: 0.63; 95% CI: 0.43-0.93), neonatal mortality (typical RR: 0.87; 95% CI: 0.77-0.99), and chronic lung disease (typical RR: 0.70; 95% CI: 0.55-0.88).

Guidelines from the Canadian Pediatric Society and the American Academy of Pediatrics were available during the time period covered by this study.^11,12 Although these guidelines suggest the need for institutionally approved protocols to govern surfactant administration, they did not include specific recommendations regarding the timing of the first dose.

Are the practices that we observed at 341 North American neonatal units in this study consistent with this evidence? Prophylactic surfactant therapy was not widely practiced in 2000 by either of the 2 measures available to us: administration of the first dose of surfactant within 15 minutes of birth and administration of surfactant in the delivery room. Fewer than 30% of infants received the first dose of surfactant within 15 minutes of birth. At many units, no infants were treated within this time frame, and no infants received treatment in the delivery room. Furthermore, the first dose of surfactant is often delayed beyond 2 hours after birth. At >25% of neonatal units in our study, >30% of the infants who were treated with surfactant received the first dose >2 hours after birth. Thus, current surfactant treatment practices at many units are inconsistent with the evidence favoring prophylactic and early surfactant treatment. Although delivery room treatment is 1 strategy for achieving prophylactic therapy, in those units where the NICU is directly adjacent to the delivery room, it may be possible to achieve treatment in the NICU within a few minutes.

A concern about interpreting the evidence from randomized trials is that these trials were conducted at a time when the use of antenatal corticosteroid therapy was much lower than it is today.¹⁷ Therefore, potential benefits of prophylactic and early surfactant treatment in the current practice environment may be less than that reported in the original trials. Nonetheless, infants who go on to develop RDS are still likely to benefit from earlier rather than delayed therapy. It is interesting to note that we observed that infants who were delivered by cesarean section and those whose mothers received antenatal corticosteroids were more likely to receive the first dose of surfactant sooner after birth. This suggests that the decision to provide early surfactant treatment is more common in cases in which an antenatal decision has been made to provide full obstetric intervention.

Location of birth was a major determinant of the timing of the first dose of surfactant. As expected, the first dose of surfactant was delayed considerably for outborn as compared with inborn infants. Outborn infants have a higher risk for mortality and morbidity than inborn infants.¹⁸ Surfactant treatment before transport or more rapidly after arrival at the referral center are potential opportunities for improving the outcomes of outborn infants.

Evidence from randomized, controlled trials, as summarized in the Cochrane systematic reviews, demonstrates that prophylactic or early surfactant as compared with delayed rescue surfactant treatment results in improved outcomes for high-risk preterm infants.^5,6 However, the trials have not provided a definitive answer to the question, "How early is early enough?" because no trial has yet compared prophylactic therapy with early rescue therapy administered at 20 or 60 minutes after birth. This uncertainty may account for some of the marked variation in practice that we observed.

Another factor that may contribute to the variation in practice is the recent interest in using nasal continuous positive airway pressure shortly after delivery to avoid endotracheal intubation, surfactant administration, and mechanical ventilation. Observational studies have reported that this approach may decrease the incidence of chronic lung disease and the need for mechanical ventilation as well as surfactant use.^19–21 The efficacy of this approach has not yet been tested in randomized, controlled trials.²²

Our data indicate considerable opportunity for improvement. The high proportion of infants who receive delayed treatment at some NICUs suggests that there are in fact unintended delays in surfactant treatment that are amenable to change. Furthermore, delays in treating outborn infants suggest that substantial opportunities for improvement exist in this population.

We recommend that each NICU create a multidisciplinary team to review the available evidence and to assess their own unit’s practices. This exercise will involve reviewing the administration and timing of surfactant therapy, developing a unit-based strategy and measurable goals for surfactant treatment, identifying change ideas to achieve those goals, and monitoring the success of the changes. This approach is being applied by units in the VON Neonatal Intensive Care Quality Improvement Collaboratives.²³ We are also currently conducting a cluster randomized trial with hospitals as the units of randomization to assess the efficacy of a multifaceted quality improvement intervention designed to promote evidence-based surfactant therapy.

There are important tradeoffs to be considered in developing a surfactant treatment strategy. Prophylactic surfactant administration will likely result in more infants being exposed to surfactant and to endotracheal intubation, both of which are associated with specific risks and financial costs. Unit-based teams should assess these tradeoffs carefully. As our observations have shown, at some gestational ages, a high proportion of infants are intubated in the delivery room and ultimately receive surfactant, yet the first dose of surfactant is delayed, often beyond 2 hours. These infants could be treated sooner after birth, realizing the potential benefits of earlier treatment with little additional risk or cost.

Several strategies of surfactant therapy are consistent with the available evidence. After reviewing the evidence, assessing local practices, and addressing the tradeoffs, some units may decide to implement a strategy of prophylactic surfactant for selected groups of high-risk infants on the basis of gestational age, tests of fetal lung maturity, or other factors. Some units may choose to focus on the unintended delays that occur between the decision to administer surfactant and its actual delivery. Still others may identify opportunities for modifying practices related to the stabilization and transport of outborn infants to achieve earlier treatment of these infants.

We do not claim that there is a single correct policy or guideline. We do suggest that there is a gap between what the evidence suggests should be done and what is actually done in routine practice at many units. It is the responsibility of each unit to review and modify its own practices in light of its interpretation of the evidence and how it applies in its unit. Between 1998 and 2000, the trend toward earlier administration of the first dose of surfactant that we have documented suggests that this process has already begun.

	APPENDIX: PARTICIPATING HOSPITALS

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Abington Memorial Hospital, Abington, Pennsylvania; Adventist Center for Children, Rockville, Maryland; Advocate Lutheran General Hospital, Park Ridge, Illinois; Albany Medical Center, Albany, New York; All Saints Episcopal Hospital, Fort Worth, Texas; Alta Bates Medical Center, Berkeley, California; Anne Arundal Medical Center, Annapolis, Maryland; Antelope Valley Hospital, Lancaster, California; Arnot Ogden Medical Center, Elmira, New York; Aultman Hospital, Canton, Ohio; Aurora Sinai Medical Center, Milwaukee, Wisconsin; Avera McKennan, Sioux Falls, South Dakota; Ball Memorial Hospital, Muncie, Indiana; Baptist Children’s Hospital, Miami, Florida; Baptist Medical Center, Montgomery, Alabama; Baptist Memorial Hospital for Women, Memphis, Tennessee; Baptist St. Anthony’s Health System, Amarillo, Texas; Barbara Bush Children’s at Maine Medical, Portland, Maine; Baylor University Medical Center, Dallas, Texas; Baystate Medical Center, Springfield, Massachusetts; Bellevue Hospital-NYU Medical Center, New York, New York; Benefis Healthcare, Great Falls, Montana; Beth Israel Deaconess Medical Center, Boston, Massachusetts; Bethesda Memorial Hospital, Boynton Beach, Florida; Blank Children’s Hospital, Des Moines, Iowa; Brandon Regional Hospital, Brandon, Florida; Brookdale Hospital Medical Center, Brooklyn, New York; The Brooklyn Hospital Center, Brooklyn, New York; Broward General Medical Center, Fort Lauderdale, Florida; Bryn Mawr Hospital, Bryn Mawr, Pennsylvania; C.R.C.H, Roanoke, Virginia; CA Pacific Medical Center, San Francisco, California; Cape Fear Valley Medical Center, Fayetteville, North Carolina; Cardinal Glennon Children’s Hospital, St. Louis, Missouri; Wake Medical Center, Raleigh, North Carolina; Carle Foundation Hospital, Urbana, Illinois; Cedars-Sinai Medical Center, Los Angeles, California; Centennial Medical Center, Nashville, Tennessee; Central Dupage Hospital, Winfield, Illinois; Central Mississippi Medical Center, Jackson, Mississippi; Charleston Area Medical Center, Charleston, West Virginia; Children’s at Cooper U. Medical Center, Camden, New Jersey; Children’s Hospital Omaha, Omaha, Nebraska; Children’s Hospital & Research Center at Oakland, Oakland, California; Children’s Hospital at Bronson, Kalamazoo, Michigan; Children’s Hospital at Providence Alaska, Anchorage, Alaska; Children’s Hospital Central CA, Madera, California; Children’s Hospital Medical Center Akron, Akron, Ohio; Children’s Hospital of Greenville, Greenville, South Carolina; Children’s Hospital of Iowa, Iowa City, Iowa; Children’s Hospital of Orange County, Orange, California; Children’s Hospital of WI - Fox Valley, Neenah, Wisconsin; Children’s Hospital of Wisconsin, Milwaukee, Wisconsin; Children’s Hospital-Lee Memorial, Ft. Myers, Florida; Children’s Hospitals & Clinics, Minneapolis, Minnesota; Children’s Hospitals and Clinics, St Paul, Minnesota; Children’s Hospital-San Diego, San Diego, California; Children’s Medical Center-Dayton, Dayton, Ohio; Children’s Mercy Hospital, Kansas City, Missouri; CHKD/Sentara Norfolk, Norfolk, Virginia; CHOA/Brackenridge Campus, Austin, Texas; CHOI at OSF St. Francis Medical Center, Peoria, Illinois; Christ Hospital & Medical Center, Oak Lawn, Illinois; Christiana Care Health Services, Newark, Delaware; Christus Santa Rosa Healthcare, San Antonio, Texas; Citrus Valley-Inter-Community Campus/CA, Covina, California; Citrus Valley-Queen of the Valley Campus, W. Covina, California; City Avenue/Allegheny University Hospital, Philadelphia, Pennsylvania; Columbia East Ridge Hospital, Chattanooga, Tennessee; Columbia Hospital for Women, Washington, District of Columbia; Columbia Medical Center of Plano TX, Dallas, Texas; Columbia Women’s Hospital, Indianapolis, Indiana; Columbus Regional Medical Center, Columbus, Georgia; Community Medical Center, Missoula, Montana; Connecticut Children’s Medical Center, Hartford, Connecticut; Cook Children’s Medical Center, Fort Worth, Texas; Coral Springs Medical Center, Coral Springs, Florida; Crozer-Chester Medical Center, Upland, Pennsylvania; Dameron Hospital, Stockton, California; Danbury Hospital, Danbury, Connecticut; Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; Deaconess Medical Center, Spokane, Washington; Desert Regional Medical Center, Palm Springs, California; DeVos Children’s/Spectrum Health, Grand Rapids, Michigan; Doctor’s Medical Center, Modesto, California; Driscoll Children’s Hospital, Corpus Christi, Texas; East Tennessee Children’s Hospital, Knoxville, Tennessee; Eastern Maine Medical Center, Bangor, Maine; Encino Tarzana Regional Medical Center, Tarzana, California; Evanston Hospital, Evanston, Illinois; Exempla St. Joseph Hospital, Denver, Colorado; Fairview University Medical Center, Minneapolis, Minnesota; Fitzgerald Mercy Medical Center, Darby, Pennsylvania; Florida Hospital, Orlando, Florida; Forrest General Hospital, Hattiesburg, Mississippi; Forsyth Memorial Hospital, Winston-Salem, North Carolina; Forum Health - Tod Children’s, Youngstown, Ohio; Frankford Torresdale Hospital, Philadelphia, Pennsylvania; Freeman Hospital & Health System, Joplin, Missouri; Geisinger Medical Center, Danville, Pennsylvania; Glendale Memorial Hospital & Health Center, Glendale, California; Good Samaritan HCA, San Jose, California; Good Samaritan Hospital, Los Angeles, California; Good Samaritan Hospital, West Palm Beach, Florida; Good Samaritan Hospital, Cincinnati, Ohio; Grant Medical Center, Columbus, Ohio; Greater Baltimore Medical Center, Baltimore, Maryland; Gundersen Lutheran, LaCrosse, Wisconsin; Hackensack University Medical Center, Hackensack, New Jersey; Hahnemann University Hospital, Philadelphia, Pennsylvania; Harbor UCLA Medical Center, Torrance, California; Harris Methodist, Fort Worth, Texas; Hennepin County Medical Center, Minneapolis, Minnesota; Henrico Doctor’s Hospital, Richmond, Virginia; Henry Ford Hospital, Detroit, Michigan; Holy Cross Hospital, Silver Spring, Maryland; Hospital of University of Pennsylvania, Philadelphia, Pennsylvania; Houston NW Medical Center, Houston, Texas; Howard County General Hospital, Columbia, Maryland; Huntington Memorial Hospital, Pasadena, California; Huntsville Hospital, Huntsville, Alabama; Hurley Medical Center, Flint, Michigan; Illinois Masonic Medical Center, Chicago, Illinois; Inova Alexandria Hospital, Alexandria, Virginia; Inova Fairfax Hospital for Children, Falls Church, Virginia; IWK Health Centre, Halifax, Nova Scotia, Canada; Jackson-Madison County General Hospital, Jackson, Tennessee; Janeway Children’s Hospital Centre, St. John, Newfoundland, Canada; Joe DiMaggio Children’s Hospital, Hollywood, Florida; John Peter Smith Hospital, Fort Worth, Texas; Kadlec Medical Center NICU, Richland, Washington; Kaiser Foundation, Bellflower, California; Kaiser Foundation, Fontana, California; Kaiser Foundation, Los Angeles, California; Kaiser Foundation-Orange County, Anaheim, California; Kaiser Foundation-Riverside Medical Center, Riverside, California; Kaiser Foundation, San Diego, California; Kaiser Foundation-West Los Angeles, Los Angeles, California; Kaiser Foundation, Woodland Hills, California; Kaiser Permanente, Baldwin Park, California; Kennedy Memorial Hospital, Stratford, New Jersey; Kosair Children’s Hospital, Louisville, Kentucky; Lancaster General Hospital, Lancaster, Pennsylvania; Lankenau Hospital, Bryn Mawr, Pennsylvania; LDS Hospital, Salt Lake City, Utah; Legacy Emanuel Children’s Hospital, Portland, Oregon; Lehigh Valley Hospital, Allentown, Pennsylvania; Lenox Hill Hospital, New York, New York; Little Company of Mary Hospital, Torrance, California; Loma Linda University Children’s, Loma Linda, California; Loyola University Medical Center, Maywood, Illinois; LPCH-Stanford University, Palo Alto, California; Maimonides Medical Center, Brooklyn, New York; Mary Washington Hospital, Fredericksburg, Virginia; McKay-Dee Hospital Center, Ogden, Utah; McLeod Regional Medical Center, Florence, South Carolina; Mease Hospital, Dunedin, Florida; Medical City, Dallas, Texas; Medical College of Georgia, Augusta, Georgia; Medical University of South Carolina, Charleston, South Carolina; Memorial Hermann Southwest, Houston, Texas; Memorial Hospital, South Bend, Indiana; Memorial Hospital, Gulfport, Mississippi; Memorial Hospital West, Pembroke Pines, Florida; Memorial Medical Center, New Orleans, Louisiana; Mercer Medical Center, Trenton, New Jersey; Mercy Children’s Hospital, Toledo, Ohio; Mercy Health Center, Oklahoma City, Oklahoma; Mercy Hospital & Medical Center, Chicago, Illinois; Mercy Hospital of Pittsburgh, Pittsburgh, Pennsylvania; Mercy Hospital South, Charlotte, North Carolina; Mercy San Juan Hospital, Carmichael, California; Meridia Hillcrest Hospital, Mayfield Heights, Ohio; Meritcare Children’s Hospital, Fargo, North Dakota; Methodist Children’s Hospital, San Antonio, Texas; Methodist Hospital of Indiana, Indianapolis, Indiana; Methodist Hospitals, Inc., Gary, Indiana; MHUMC, Savannah, Georgia; Miami Children’s Hospital, Miami, Florida; Miami Valley Hospital, Dayton, Ohio; Midwest Neoped Associates, Oak Brook, Illinois; Miller Children’s Hospital, Long Beach, California; Milton S. Hershey Medical Center, Hershey, Pennsylvania; Mission Hospitals, Asheville, North Carolina; Mississippi Baptist Health Systems, Jackson, Mississippi; Monmouth Medical Center, Long Branch, New Jersey; Morristown Memorial Hospital, Morristown, New Jersey; Mt. Sinai Hospital, Toronto, Ontario, Canada; Mt. Sinai Hospital Medical Center, Chicago, Illinois; Munson Medical Center, Traverse City, Michigan; National Naval Medical Center, Bethesda, Maryland; Naval Medical Center, San Diego, California; Neonatology Associates, Kingsport, Tennessee; New Hanover Regional Medical Center, Wilmington, North Carolina; New York Presbyterian Hospital, New York, New York; Newark Beth Israel Medical Center, Newark, New Jersey; Newborn Specialists of Tulsa, Tulsa, Oklahoma; North Memorial Medical Center, Robbinsdale, Minnesota; North Oaks Medical Center, Hammond, Louisiana; North Shore U. Hospital Manhasset, Manhasset, New York; Northbay Medical Center, Fairfield, California; Northridge Hospital, Northridge, California; Northside Hospital, Atlanta, Georgia; Northwestern Memorial, Chicago, Illinois; Norton Suburban Hospital, Louisville, Kentucky; Oakwood Hospital & Medical Center, Dearborn, Michigan; OH-CHEO, Ottawa, Ontario, Canada; Oregon Health & Sciences University, Portland, Oregon; P.C.M.H., Greenville, North Carolina; Parkview Hospital, Fort Wayne, Indiana; Parkway Regional Medical Center, N. Miami Beach, Florida; Pennsylvania Hospital, Philadelphia, Pennsylvania; Phoenix Children’s Hospital, Phoenix, Arizona; Pinnacle/Harrisburg Campus, Harrisburg, Pennsylvania; Presbyterian Hospital, Albuquerque, New Mexico; Presbyterian Hospital of Dallas, Dallas, Texas; Presbyterian Intercommunity Hospital, Whittier, California; Presbyterian-St. Luke’s Medical Center, Denver, Colorado; Primary Children’s Medical Center, Salt Lake City, Utah; Promina Gwinnett Health, Lawrenceville, Georgia; Provena Covenant Medical Center, Urbana, Illinois; Providence St. Joseph Medical Center, Burbank, California; Providence St. Vincent Medical Center, Portland, Oregon; Rainbow Babies & Children’s Hospital, Cleveland, Ohio; Reading Hospital & Medical Center, Reading, Pennsylvania; Redlands Community Hospital, Redlands, California; Regional Medical Center at Memphis, Memphis, Tennessee; Riverside Hospital, Toledo, Ohio; Riverside Methodist Hospital, Columbus, Ohio; Rockford Memorial Hospital, Rockford, Illinois; Rogue Valley Medical Center, Medford, Oregon; Rose Medical Center, Denver, Colorado; Royal Victoria Hospital, Montreal, Quebec, Canada; Sacred Heart Health System, Pensacola, Florida; Sacred Heart Medical Center, Eugene, Oregon; Sacred Heart Medical Center, Spokane, Washington; San Francisco General Hospital, San Francisco, California; Scott & White Hospital, Temple, Texas; Seton Medical Center, Austin, Texas; Sharp Mary Birch Hospital for Women, San Diego, California; Sheridan Children’s, Plantation, Florida; Sinai Hospital of Baltimore, Baltimore, Maryland; Sioux Valley Children’s Hospital, Sioux Falls, South Dakota; Sisters of Charity, Staten Island, New York; South Fulton Medical Center, East Point, Georgia; Southern Regional Medical Center, Riverdale, Georgia; Sparrow Hospital, Lansing, Michigan; St. Agnes Hospital, Baltimore, Maryland; St. Barnabas Medical Center, Livingston, New Jersey; St. Charles Medical Center, Bend, Oregon; St. Cloud Hospital, St Cloud, Minnesota; St. David’s Medical Center, Austin, Texas; St. Elizabeth Hospital Center, Youngstown, Ohio; St. Elizabeth Regional Medical Center, Lincoln, Nebraska; St. Elizabeth’s Medical Center, Boston, Massachusetts; St. Francis Hospital, Hartford, Connecticut; St. Francis Hospital, Tulsa, Oklahoma; St. Francis Medical Center, Lynwood, California; St. John Hospital & Medical Center, Detroit, Michigan; St. John’s Hospital, Santa Monica, California; St. John’s Hospital, Springfield, Illinois; St. John’s Mercy Medical Center, St. Louis, Missouri; St. John’s Regional Medical Center, Oxnard, California; St. Joseph Hospital & Medical Center, Paterson, New Jersey; St. Joseph Hospital/TX, Houston, Texas; St. Joseph Hospital-Marshfield Clinic, Marshfield, Wisconsin; St. Joseph Mercy Oakland, Pontiac, Michigan; St. Joseph’s Health Center, Syracuse, New York; St. Joseph’s Hospital, Milwaukee, Wisconsin; St. Joseph’s Hospital & Medical Center, Phoenix, Arizona; St. Luke’s Hospital, Kansas City, Missouri; St. Luke’s Hospital, Bethlehem, Pennsylvania; St. Luke’s Hospital, Racine, Wisconsin; St. Luke’s Regional Medical Center, Boise, Idaho; St. Mary Medical Center, Long Beach, California; St. Mary’s Hospital, Milwaukee, Wisconsin; St. Mary’s Hospital & Medical Center, Grand Junction, Colorado; St. Mary’s Hospital Medical Center, Madison, Wisconsin; St. Mary’s Hospital, West Palm Beach, Florida; St. Mary’s Medical Center, Evansville, Indiana; St. Mary’s Medical Center, Duluth, Minnesota; St. Paul Medical Center, Dallas, Texas; St. Peter’s Hospital, Albany, New York; St. Peter’s Medical Center, New Brunswick, New Jersey; St. Vincent Hospital, Indianapolis, Indiana; St. Vincent Hospital, Green Bay, Wisconsin; St. Vincent Hospital & Health Center, Billings, Montana; Stamford Hospital, Stamford, Connecticut; Sunnybrook & Women’s College Health Sciences Center, Toronto, Ontario, Canada; Sunrise Children’s Hospital, Las Vegas, Nevada; Sutter Memorial Hospital, Sacramento, California; Swedish American Hospital, Rockford, Illinois; Swedish Medical Center, Englewood, Colorado; T.C. Thompson Children’s Hospital, Chattanooga, Tennessee; Tacoma General Hospital, Tacoma, Washington; Temple University Hospital, Philadelphia, Pennsylvania; Texas Tech U. Health Science Center, Amarillo, Texas; Thomas Jefferson University Hospital, Philadelphia, Pennsylvania; Tisch Hospital-NYU Medical Center, New York, New York; Toledo Children’s Hospital, Toledo, Ohio; Truman Medical Center, Kansas City, Missouri; Tufts-New England Medical Center, Boston, Massachusetts; Tulane Medical Center, New Orleans, Louisiana; U. Mass Memorial Health Care, Worcester, Massachusetts; U. of TN Medical Center, Knoxville, Tennessee; UC Irvine Medical Center, Orange, California; UCDMC, Sacramento, California; UCHSC, Denver, Colorado; UCSD Medical Center, San Diego, California; UCSF Medical Center, San Francisco, California; University Medical Center, Las Vegas, Nevada; University of Chicago, Chicago, Illinois; University of Illinois at Chicago, Chicago, Illinois; University of Kentucky Children’s Hospital, Lexington, Kentucky; University of Louisville Hospital, Louisville, Kentucky; University of Michigan-Holden NICU, Ann Arbor, Michigan; University of Washington Medical Center, Seattle, Washington; UPMC Lee Regional, Johnstown, Pennsylvania; Utah Valley Regional Medical Center, Provo, Utah; Vassar Brothers Hospital, Poughkeepsie, New York; Ventura County Medical Center, Ventura, California; Via Christi-St. Francis Campus, Wichita, Kansas; Virginia Beach General Hospital, Virginia Beach, Virginia; VT Children’s at Fletcher-Allen Health Care, Burlington, Vermont; Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina; Waukesha Memorial Hospital, Waukesha, Wisconsin; Weiler Hospital-Montefiore, Bronx, New York; Wellstar Cobb Hospital, Kennesaw, Georgia; Wellstar Kennestone Hospital, Marietta, Georgia; Wesley Medical Center, Wichita, Kansas; Western Medical Center, Santa Ana, California; Western Pennsylvania Hospital, Pittsburgh, Pennsylvania; Willis-Knighton South, Shreveport, Louisiana; Woman’s Hospital, Baton Rouge, Louisiana; Women’s & Children’s Hospital, Lafayette, Louisiana; Women’s Hospital of Greensboro, Greensboro, North Carolina; Woodhull Medical Center, Brooklyn, New York; Wyckoff Heights Medical Center, Brooklyn, New York; Yakima Valley Memorial Hospital, Yakima, Washington; Yale-New Haven Children’s Hospital, New Haven, Connecticut; York Hospital, York, Pennsylvania

	ACKNOWLEDGMENTS

 
This study was funded by a grant from the Agency for Healthcare Research and Quality (R01 HS 10528 to Dr Horbar, principal investigator)

	FOOTNOTES

 
Received for publication Sep 15, 2003; Accepted Oct 23, 2003.

Reprint requests to (J.D.H.) Vermont Oxford Network, 33 Kilburn St, Burlington, VT 05401. E-mail: horbar{at}vtoxford.org

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