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PaCO2 in Surfactant, Positive Pressure, and Oxygenation Randomised Trial (SUPPORT)
  1. Namasivayam Ambalavanan1,
  2. Waldemar A Carlo1,
  3. Lisa A Wrage2,
  4. Abhik Das3,
  5. Matthew Laughon4,
  6. C Michael Cotten5,
  7. Kathleen A Kennedy6,
  8. Abbot R Laptook7,
  9. Seetha Shankaran8,
  10. Michele C Walsh9,
  11. Rosemary D Higgins10,
  12. For the SUPPORT Study Group of the NICHD Neonatal Research Network
  1. 1Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
  2. 2Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina, USA
  3. 3Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, Maryland, USA
  4. 4Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, USA
  5. 5Department of Pediatrics, Duke University, Durham, North Carolina, USA
  6. 6Department of Pediatrics, University of Texas Medical School at Houston, Houston, Texas, USA
  7. 7Department of Pediatrics, Women and Infants Hospital, Providence, Rhode Island, USA
  8. 8Department of Pediatrics, Wayne State University, Detroit, Michigan, USA
  9. 9Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University, Cleveland, Ohio, USA
  10. 10Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
  1. Correspondence to Dr Namasivayam Ambalavanan, University of Alabama at Birmingham, 176F Suite 9380, Women and Infants Center, 619 South 20th St., Birmingham, AL 35249, USA; ambal{at}uab.edu

Abstract

Objective To determine the association of arterial partial pressure of carbon dioxide PaCO2 with severe intraventricular haemorrhage (sIVH), bronchopulmonary dysplasia (BPD), and neurodevelopmental impairment (NDI) at 18–22 months in premature infants.

Design Secondary exploratory data analysis of Surfactant, Positive Pressure, and Oxygenation Randomised Trial (SUPPORT).

Setting Multiple referral neonatal intensive care units.

Patients 1316 infants 24 0/7 to 27 6/7 weeks gestation randomised to different oxygenation (SpO2 target 85–89% vs 91–95%) and ventilation strategies.

Main outcome measures Blood gases from postnatal day 0 to day14 were analysed. Five PaCO2 variables were defined: minimum (Min), maximum (Max), SD, average (time-weighted), and a four level categorical variable (hypercapnic (highest quartile of Max PaCO2), hypocapnic (lowest quartile of Min PaCO2), fluctuators (hypercapnia and hypocapnia), and normocapnic (middle two quartiles of Max and Min PaCO2)). PaCO2 variables were compared for infants with and without sIVH, BPD and NDI (±death). Multivariable logistic regression models were developed for adjusted results.

Results sIVH, BPD and NDI (±death) were associated with hypercapnic infants and fluctuators. Association of Max PaCO2 and outcomes persisted after adjustment (per 10 mm Hg increase: sIVH/death: OR 1.27 (1.13 to 1.41); BPD/death: OR 1.27 (1.12 to 1.44); NDI/death: OR 1.23 (1.10 to 1.38), death: OR 1.27 (1.12 to 1.44), all p<0.001). No interaction was found between PaCO2 category and SpO2 treatment group for sIVH/death, NDI/death or death. Max PaCO2 was positively correlated with maximum FiO2 (rs0.55, p<0.0001) and ventilator days (rs0.61, p<0.0001).

Conclusions Higher PaCO2 was an independent predictor of sIVH/death, BPD/death and NDI/death. Further trials are needed to evaluate optimal PaCO2 targets for high-risk infants.

  • Neonatology
  • Respiratory
  • Neurodisability
  • Mortality
  • Intensive Care
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What is already known on this topic

  • Variations in arterial partial pressure of carbon dioxide (PaCO2) are associated with adverse outcomes of prematurity such as intraventricular haemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia and subsequent neurodevelopmental impairment.

  • PaCO2 is an important regulator of cerebral blood flow.

What this study adds

  • Higher PaCO2 was associated with death or severe intraventricular haemorrhage, bronchopulmonary dysplasia and neurodevelopmental impairment.

  • Maximum PaCO2 is a marker of respiratory illness severity in extremely premature infants.

Introduction

Variations in arterial partial pressure of carbon dioxide (PaCO2) are associated with outcomes of prematurity such as intraventricular haemorrhage (IVH),1 periventricular leukomalacia (PVL),2 ,3 bronchopulmonary dysplasia (BPD),4 and neurodevelopmental impairment (NDI).5 We have previously shown that high and low PaCO2 and wide fluctuations in PaCO2 are associated with severe IVH (sIVH; IVH Grades III or IV).1 PVL is associated with hypocapnia.2 ,3 ,6

Increased PaCO2 increases cerebral blood flow,7–9 while decreased PaCO2 reduces cerebral blood flow.10 Cerebral blood flow decreases with increased oxygenation9 but interactions between PaCO2 and oxygenation have not been assessed in preterm infants. Lung injury may be reduced by tolerance of higher PaCO24 ,11 ,12 as well as lower oxygen saturation (SpO2).13 The combination of higher PaCO2 (permissive hypercapnia) and lower SpO2 might reduce BPD more than with either permissive hypercapnia or a lower SpO2 target alone.

The National Institute of Child Health and Human Development Neonatal Research Network Surfactant, Positive Pressure, and Oxygenation Randomised Trial (SUPPORT) trial compared outcomes in infants randomly assigned to SpO2 targets of either 85–89% or 91–95%, while also randomly allocated to either early continuous positive airway pressure (CPAP) and a limited ventilation strategy (PaCO2 >65 mm Hg permitted intubation, while PaCO2 <65 mm Hg with pH>7.20 was an extubation criterion) or intubation and surfactant (PaCO2 <50 mm Hg with pH>7.30 was an extubation criterion).13 ,14 Death and other major outcomes did not differ significantly by CPAP versus intubation/surfactant groups although CPAP group infants received fewer days of mechanical ventilation.13 ,14 In the lower SpO2 target group, death occurred more frequently (19.9% vs 16.2%; p=0.04) while severe retinopathy among survivors occurred less often (8.6% vs 17.9%; p<0.001), without significant differences in other outcomes.13 However, no significant differences in the composite outcome of death or NDI were noted among infants in any of the treatment groups.15

Clinical outcomes not significantly different by SpO2 target groups might be different when the combination of PaCO2 and SpO2 (actual or target group) is analysed. We hypothesised that both extremes of PaCO2 would be associated with sIVH, and that effect modification by SpO2 would be observed, with hypercapnia associated with sIVH in the low but not high SpO2 group (due to greater cerebral blood flow at lower SpO2). We also hypothesised that BPD would be lower in infants with hypercapnia in the low SpO2 group (due to less mechanical ventilation), and that higher PaCO2 will be associated with a higher NDI (due to increased risk of sIVH).

Patients and methods

Patient characteristics

This was a secondary exploratory analysis of data from infants (n=1316) in the SUPPORT trial.13 ,14 Characteristics of this population13 (mean birth weight approximately 830 g, gestational age 26 weeks, 54% male) and the follow-up cohort15 (93.6% evaluated at 18–22 months corrected age, 20.1% death, 28.8% with NDI/death) have been previously reported.

PaCO2 variables

Five PaCO2 variables were defined, using routine blood gas (arterial or capillary) measurements not governed by protocol. PaCO2 closest to 8:00, 16:00 and midnight was recorded for postnatal days 1–14. From these data, the minimum, maximum (Max PaCO2), SD, and average (time-weighted) PaCO2 were derived. Average (time-weighted) PaCO2 was calculated as defined previously:1 the sum of all PaCO2 values multiplied by the time interval from previous blood gas was divided by the overall time period. This measure enables an estimate of the magnitude of exposure to PaCO2 by taking into account the duration of time for each PaCO2 value. To avoid any one blood gas value from having an unduly large effect in this ‘time-weighting’, we capped the maximum duration for any PaCO2 at 24 h. Infants were categorised into four groups (hypercapnic, hypocapnic, fluctuators and normocapnic) by first separately ranking the maximum and minimum PaCO2 over days 1–14 into quartiles. Infants with minimum PaCO2 in lowest quartile and not in highest quartile of maximum PaCO2 were categorised as ‘hypocapnic’. Infants with maximum PaCO2 in highest quartile and not in lowest quartile of minimum PaCO2 were considered ‘hypercapnic’. Infants in lowest quartile of minimum PaCO2 and highest quartile of maximum PaCO2 were considered ‘fluctuators’. Remaining infants with minimum PaCO2 level in quartiles 2–4 and maximum PaCO2 in quartiles 1–3 were categorised as ‘normocapnic’.

Other variables

Maternal hypertension was defined as pregnancy-induced hypertension (PIH). Premature rupture of membranes was rupture of membranes >24 h prior to birth. Prenatal steroids were any use of antenatal steroids. Maximum FiO2 was the maximum FiO2 at 24 h and on days 3, 7 and 14. Severe illness was defined a priori as FiO2 >0.4 and mechanical ventilation for 8+ h in the first 14 days. sIVH was IVH grade 3–4.16 BPD was defined using the physiological definition at 36w PMA.17 ,18 NDI was any of: a cognitive composite score on the Bayley Scales of Infant and Toddler Development, third edition <70, a modified Gross Motor Function Classification System score ≥2, moderate or severe cerebral palsy, hearing impairment, or bilateral visual impairment.15 PVL was not evaluated as the incidence (4%) was too low for detailed analysis.

Statistical analysis

PaCO2 and other variables for infants with outcome were compared with those without outcome for each of seven outcomes: sIVH, sIVH or death, BPD, BPD or death, NDI, and NDI or death, and death by discharge. PaCO2 variables were also compared by SpO2 treatment groups. Statistical significance (p<0.05) for these unadjusted comparisons was assessed by χ2 tests for categorical variables and the Wilcoxon-Mann-Whitney test for continuous variables. In keeping with the exploratory goals of this study, no adjustments were made for multiple comparisons.

Adjusted results for maximum PaCO2, four level PaCO2 variable, as well as average PaCO2 were obtained using generalised estimating equations, assuming an exchangeable correlation between infants within familial clusters (ie, multiples). Other variables included were birth weight, gestational age group (24–25 weeks vs 26–27 weeks), gender, race, prenatal steroids, PIH, premature rupture of membranes, centre and three measures of illness severity: maximum FiO2, severe illness, number of mechanical ventilation days in first 14 days. SUPPORT treatment group variables (High/Low SpO2; CPAP/ventilator) were included in models containing maximum PaCO2 and the four-level PaCO2 variable. Interactions of PaCO2 and treatment group variables assessed if effect of PaCO2 varied by SUPPORT treatment group. Evaluation of interaction of actual median SpO2 in the first 14 days and average PaCO2 determined if the effect of average PaCO2 varied by level of actual SpO2. Results are expressed as adjusted ORs and 95% CIs.

As higher maximum PaCO2 may be either deliberate (clinician intent for permissive hypercapnia, possibly accompanied by fewer days of mechanical ventilation for comparable illness severity) or due to more severe pulmonary disease (associated with higher maximum FiO2, days of mechanical ventilation and severe illness), correlations of maximum PaCO2 with maximum FiO2 and days of ventilation, and its relationship with severe illness (as previously defined) were calculated.

All analyses were done using SAS software V.9.3 (SAS Institute, Cary, North Carolina, USA).

Results

Adjusted results for sIVH /death are given in table 1.

Table 1

Adjusted results for PaCO2 variables in relation to outcome of sIVH/death

Higher maximum PaCO2 was associated with increased odds of sIVH/death. Hypercapnic infants had higher odds of sIVH/death compared with normocapnic infants whereas hypocapnic and fluctuators did not differ significantly. No interaction was found between PaCO2 category (hypocapnic, hypercapnic, etc) and treatment group (higher or lower SpO2). Average PaCO2 was not associated with the outcome. Other variables associated with sIVH/death included severe illness, lower birth weight and gestational age, male gender, no PIH and centre.

Adjusted results for BPD/death are given in table 2.

Table 2

Adjusted results for PaCO2 variables in relation to outcome of bronchopulmonary dysplasia/death

Higher maximum and average PaCO2 were associated with BPD/death. Interaction (p=0.026) was noted between the PaCO2 category ‘fluctuators’ and treatment group (higher or lower SpO2), hence results for PaCO2 category are presented separately. For fluctuators in the higher SpO2 group, the OR was 3.3 vs 0.62 for fluctuators in the lower SpO2 group. Other variables associated with BPD/death were severe illness, lower birth weight, male gender, not being non-Hispanic white and centre. As growth restriction increases the risk of BPD/death,19 birthweight z-score was initially included in the model, but did not change ORs, and was therefore excluded from the final model.

Adjusted results for NDI/death are given in table 3.

Table 3

Adjusted results for PaCO2 variables in relation to outcome of neurodevelopmental impairment/death

Higher maximum PaCO2 was associated with NDI/death. No interactions were noted between PaCO2 category and SpO2 treatment group. Hypercapnic infants and fluctuators, but not hypocapnic infants, had increased odds of NDI/death. Other variables associated with NDI/death were severe illness, lower birth weight and gestational age, male gender and no PIH.

Adjusted results for death before discharge are given in table 4.

Table 4

Adjusted results for PaCO2 variables in relation to outcome of death before discharge

Higher maximum PaCO2 was associated with death before discharge. No interactions were noted between PaCO2 category and SpO2 treatment group. Hypercapnic infants, but not hypocapnic and fluctuators, had increased odds of death, versus normocapnic infants. Other variables associated with death were severe illness, lower birth weight, male gender and no PIH.

Maximum PaCO2 was positively correlated with maximum FiO2 (Spearman's correlation coefficient (rs)=0.55, p<0.0001) and days of ventilation (rs=0.61, p<0.0001). PaCO2 in infants having severe illness was higher than in infants without severe illness (median maximum PaCO2=78 vs 61, p<0.0001).

For unadjusted results see online supplementary table S1.

Infants developing sIVH had a lower minimum, higher maximum and greater variation in PaCO2 compared with those without sIVH. Maximum PaCO2 demonstrated the largest magnitude of separation, with a difference of almost 10 mm Hg in the mean and median maximum PaCO2. Separation in minimum, SD and average PaCO2 was statistically significant (p<0.01) but clinically small (∼2 mm Hg). Results for BPD, BPD or death, NDI, and NDI or death were similar to results for sIVH and sIVH/death. There were no significant differences in the PaCO2 variables by SpO2 treatment groups.

Discussion

We found that a higher maximum PaCO2 in the first two postnatal weeks was an independent predictor of worse outcome even after adjustment for available indicators of illness severity such as maximum FiO2, days of ventilation and severe illness. However, it is not certain that high PaCO2 is in the causal pathway of these outcomes. As statistical adjustment in the analysis can only adjust for known variables and not unknown or unmeasured variables (eg, oxygenation index), and PaCO2 was correlated with duration of ventilation and oxygen requirement, generally considered markers of illness severity, it is possible that high PaCO2 is a surrogate marker for some of these unknown/unmeasured variables. Our results suggest that further trials are needed to evaluate optimal PaCO2 targets in extremely premature infants.

A limitation is that data on ventilator settings and oxygenation index were not available to better estimate lung disease severity. However, this study has the strengths of prospective data collection by trained research coordinators and follow-up in almost 94% of infants by certified personnel in SUPPORT, a large recent multicentre trial.15 An additional strength is that we evaluated interaction with actual saturation and treatment group (higher or lower SpO2 target), to distinguish illness severity and effects of treatment group allocation.

In this cohort, the average PaCO2 even in infants without sIVH was ≥48 mm Hg with a relatively narrow IQR (∼10 mm Hg). Our data suggest clinical practices have evolved to maintain PaCO2 in the ‘permissive hypercapnia’ range (45–55 mm Hg).12 However, tight control of PaCO2 within this narrow range is difficult as the maximum PaCO2 exceeded this range even in infants without sIVH.

Hypercapnic infants had higher odds of sIVH/death and death even after statistical adjustment for illness severity, indicating that higher maximum PaCO2 is an independent risk factor for these adverse outcomes. Maximum PaCO2 correlated with longer mechanical ventilation and higher oxygen supplementation, suggesting that infants with higher maximum PaCO2 had more severe lung disease, rather than permissive hypercapnia and more aggressive weaning from mechanical ventilation. No interaction was observed between maximum PaCO2 and SpO2 groups for sIVH, probably because randomisation in this trial likely led to a similar range of lung disease severity and resultant PaCO2 in both SpO2 groups.

A higher maximum, average and greater fluctuation in PaCO2 were associated with a greater risk of BPD and BPD/death (see table 2). This may be due to more severe lung disease being associated with a higher PaCO2 (even after statistical adjustment for maximum FiO2, days of ventilation and severe illness) rather than because of physician intent (similar to sIVH/death). Although hypercapnia was associated with increased illness severity and worse outcomes, hypercapnia within a limited range may be acceptable and beneficial. Hypercapnia increases CO2 elimination for a given minute ventilation, due to a higher alveolar CO2. Also, hypercapnia stimulates respiratory drive, assisting in ventilator weaning. An interesting unexplained finding was that greater fluctuation in PaCO2 was associated with BPD/death only in the higher SpO2 group but not in the low SpO2 group. It is speculated that greater oxygen exposure in the higher SpO2 group may interact with volutrauma/atelectrauma associated with fluctuating PaCO2 possibly increasing the risk for BPD/death.

Maximum PaCO2 was associated with higher NDI/death (see table 3). This association may be secondary to maximum PaCO2 being an indicator of illness severity, but it is also known that alterations in PaCO2 can directly mediate brain injury. Increased cerebral blood flow secondary to a spike in PaCO27–9 may result in sIVH1 while reduced flow due to decreased PaCO210 may result in PVL.2 ,3 ,6

In conclusion, our work demonstrates that higher and greater fluctuations of PaCO2 are independent predictors of worse outcome in extremely low birth weight (ELBW) infants. Higher PaCO2 levels are also correlated with a greater magnitude of lung disease. Therefore, similar to oxygenation index, maximum PaCO2 or magnitude of fluctuation of PaCO2 may be useful for risk stratification in clinical trials or for prognosis. However, physician intent cannot be entirely ruled out, and caution may be needed about intentional use of high PaCO2 soon after birth in ELBW infants, until optimal targets of PaCO2 range are established in randomised clinical trials.

Acknowledgments

Data collected at participating sites of the NICHD Neonatal Research Network (NRN) were transmitted to RTI International, the data coordinating centre (DCC) for the network, which stored, managed and analysed the data for this study. On behalf of the NRN, Drs Abhik Das (DCC Principal Investigator) and Lisa Wrage (DCC Statistician) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis.

References

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Supplementary materials

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Footnotes

  • Collaborators We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators participated in this study: NRN Steering Committee Chairs: Alan H Jobe, MD PhD, University of Cincinnati (2003–2006); Michael S Caplan, MD, University of Chicago, Pritzker School of Medicine (2006–2011). Alpert Medical School of Brown University and Women and Infants Hospital of Rhode Island (U10 HD27904)—Abbot R Laptook, MD; William Oh, MD; Betty R Vohr, MD; Angelita M Hensman, RN BSN; Bonnie E Stephens, MD; Barbara Alksninis, PNP; Susan G Barnett, RRT-NPS BSRC; William J Cashore, MD; Melinda Caskey, MD; Regina A Gargus, MD FAAP; Daniel J Gingras, RRT; Katharine Johnson, MD; Shabnam Lainwala, MD; Theresa M Leach, MEd CAES; Martha R Leonard, BA BS; Sarah Lillie, BS RRT; James R Moore, MD; Lucy Noel; Rachel V Walden; Victoria E Watson, MS CAS. Case Western Reserve University, Rainbow Babies and Children’s Hospital (U10 HD21364, M01 RR80)—Michele C Walsh, MD MS; Avroy A Fanaroff, MD; Deanne E Wilson-Costello, MD; Nancy S Newman, RN; Bonnie S Siner, RN; Arlene Zadell RN BSN; Juliann Di Fiore, BS; Monika Bhola, MD; Harriet G Friedman, MA; Gulgun Yalcinkaya, MD. Cincinnati Children’s Hospital Medical Center, University of Cincinnati Hospital, and Good Samaritan Hospital (U10 HD27853, M01 RR8084)—Kurt Schibler, MD; Edward F Donovan, MD; Kimberly Yolton, PhD; Kate Bridges, MD; Barbara Alexander, RN; Cathy Grisby, BSN CCRC; Marcia Worley Mersmann, RN CCRC; Holly L Mincey, RN BSN; Jody Hessling, RN; Teresa L Gratton, PA. Duke University School of Medicine, University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital (U10 HD40492, M01 RR30)—Ronald N Goldberg, MD; C Michael Cotten, MD MHS; Ricki F Goldstein, MD; Patricia L Ashley, MD PhD; Kathy J Auten, MSHS; Kimberley A Fisher, PhD FNP-BC IBCLC; Katherine A Foy, RN; Sharon Fridovich Freedman, MD; Kathryn E Gustafson, PhD; Melody B Lohmeyer, RN MSN; William F Malcolm, MD; David K Wallace, MD MPH. Emory University, Children's Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, UL1 TR454, M01 RR39)—Barbara J Stoll, MD; Susie Buchter, MD; Anthony J Piazza, MD; David P Carlton, MD; Ira Adams-Chapman, MD; Sheena L Carter, PhD; Ellen C Hale, RN BS CCRC; Amy K Hutchinson, MD; Maureen Mulligan LaRossa, RN. Eunice Kennedy Shriver National Institute of Child Health and Human Development—Stephanie Wilson Archer, MA. Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children and Wishard Health Services (U10 HD27856, M01 RR750)—Brenda B Poindexter, MD MS; Anna M Dusick, MD FAAP; James A Lemons, MD; Leslie D Wilson, BSN CCRC; Faithe Hamer, BS; Ann B Cook, MS; Dianne E Herron, RN; Carolyn Lytle, MD MPH; Heike M Minnich, PsyD HSPP. National Heart, Lung, and Blood Institute –Carol J Blaisdell, MD. RTI International (U10 HD36790)—Abhik Das, PhD; W Kenneth Poole, PhD; Marie G Gantz, PhD; Jamie E Newman, PhD MPH; Betty K Hastings; Jeanette O'Donnell Auman, BS; Carolyn Petrie Huitema, MS CCRP; James W Pickett II, BS; Dennis Wallace, PhD; Kristin M Zaterka-Baxter, RN BSN CCRP. Stanford University and Lucile Packard Children’s Hospital (U10 HD27880, UL1 TR93, M01 RR70)—Krisa P Van Meurs, MD; David K Stevenson, MD; Susan R Hintz, MD MS Epi; M Bethany Ball, BS CCRC; Barbara Bentley, PsychD MSEd; Elizabeth F. Bruno, PhD; Alexis S. Davis, MD MS; Maria Elena DeAnda, PhD; Anne M DeBattista, RN, PNP; Jean G Kohn, MD MPH; Melinda S Proud, RCP; Renee P Pyle, PhD; Nicholas H St John, PhD; Hali E Weiss, MD. Tufts Medical Center, Floating Hospital for Children (U10 HD53119, M01 RR54)—Ivan D Frantz III, MD; John M Fiascone, MD; Elisabeth C McGowan, MD; Anne Furey, MPH; Brenda L MacKinnon, RNC; Ellen Nylen, RN BSN; Ana Brussa, MS OTR/L; Cecelia Sibley, PT MHA. University of Alabama at Birmingham Health System and Children's Hospital of Alabama (U10 HD34216, M01 RR32)—Waldemar A Carlo, MD; Namasivayam Ambalavanan, MD; Myriam Peralta-Carcelen, MD MPH; Monica V Collins, RN BSN MaEd; Shirley S Cosby, RN BSN. Vivien A Phillips, RN BSN; Kirstin J Bailey, PhD; Fred J Biasini, PhD; Kristen C Johnston, MSN CRNP; Sara Krzywanski, MS; Kathleen G Nelson, MD; Cryshelle S Patterson, PhD; Richard V Rector, PhD; Leslie Rodrigues, PhD; Amanda D Soong, MD; Sally Whitley, MA OTR-L FAOTA; Sheree Chapman York, PT DPT PCS. University of California—San Diego Medical Center and Sharp Mary Birch Hospital for Women (U10 HD40461)—Neil N Finer, MD; Maynard R. Rasmussen, MD; Paul R Wozniak, MD; Yvonne E Vaucher, MD MPH; Wade Rich, RRT; Kathy Arnell, RNC; Renee Bridge, RN; Clarence Demetrio, RN; Martha G Fuller, RN MSN; Paul Zlotnik. University of Iowa Children’s Hospital (U10 HD53109, UL1 TR442, M01 RR59)—Edward F Bell, MD; John A Widness, MD; Jonathan M Klein, MD; Michael J Acarregui, MD; Tarah T Colaizy, MD MPH; Karen J Johnson, RN BSN; Diane L Eastman, RN CPNP MA. University of Miami, Holtz Children’s Hospital (U10 HD21397, M01 RR16587)—Shahnaz Duara, MD; Charles R Bauer, MD; Ruth Everett-Thomas, RN MSN; Maria Calejo, MEd; Alexis N Diaz, BA; Silvia M Frade Eguaras, BA; Andrea Garcia, MS; Kasey Hamlin-Smith, PhD; Michelle Harwood Berkowits, PhD; Sylvia Fajardo-Hiriart, MD; Elaine E Mathews, RN; Helina Pierre, BA; Arielle Riguard, MD; Alexandra Stroerger, BA. University of New Mexico Health Sciences Center (U10 HD53089, M01 RR997)—Kristi L Watterberg, MD; Robin K Ohls, MD; Janell Fuller, MD; Conra Backstrom Lacy, RN; Jean Lowe, PhD; Rebecca Montman, BSN. University of Rochester Medical Center, Golisano Children’s Hospital (U10 HD40521, M01 RR44) –Dale L Phelps, MD; Gary J Myers, MD; Gary David Markowitz, MD; Linda J Reubens, RN CCRC; Diane Hust, MS RN CS; Julie Babish Johnson, MSW; Erica Burnell, RN; Rosemary L Jensen; Emily Kushner, MA; Joan Merzbach, LMSW; Kelley Yost, PhD. University of Texas Southwestern Medical Center at Dallas, Parkland Health and Hospital System, and Children’s Medical Center Dallas (U10 HD40689, M01 RR633)—Pablo J Sánchez, MD; Charles R Rosenfeld, MD; Walid A Salhab, MD; Roy J Heyne, MD; Luc P Brion, MD; Sally S Adams, MS RN CPNP; James Allen, RRT; Laura Grau, RN BSN; Alicia Guzman; Gaynelle Hensley, RN; Elizabeth T Heyne, MS MA PA-C PsyD; Melissa H Leps, RN; Linda A Madden, RN CPNP; Melissa Swensen Martin, RN BSN RNC-NIC; Nancy A Miller, RN; Janet S Morgan, RN; Araceli Solis, BS RRT RCP; Lizette E Torres, RN; Catherine Twell Boatman, MS CIMI; Diana M Vasil, RNC-NIC. University of Texas Health Science Center at Houston Medical School and Children’s Memorial Hermann Hospital (U10 HD21373)—Kathleen A Kennedy, MD MPH; Jon E Tyson, MD MPH; Nora I Alaniz, BS; Patricia W Evans, MD; Beverly Foley Harris, RN BSN; Charles Green, PhD; Margarita Jiminez, MD MPH; Anna E Lis, RN BSN; Sarah Martin, RN BSN; Georgia E McDavid, RN; Brenda H Morris, MD; Margaret L. Poundstone, RN BSN; Stacy Reddoch, BA; Saba Siddiki, MD; Patti L. Pierce Tate, RCP; Laura L Whitely, MD; Sharon L Wright, MT (ASCP). University of Utah Medical Center, Intermountain Medical Center, LDS Hospital and Primary Children’s Medical Center (U10 HD53124, M01 RR64)—Roger G Faix, MD; Bradley A Yoder, MD; Shawna Baker, RN; Karie Bird, RN; Jill Burnett, RN; Karen A Osborne, RN BSN CCRC; Cynthia Spencer, RNC; Michael Steffen, MS CPM; Kimberlee Weaver-Lewis, RN BSN. Wake Forest University, Baptist Medical Center, Brenner Children’s Hospital and Forsyth Medical Center (U10 HD40498, M01 RR7122)—T Michael O'Shea, MD MPH; Robert G Dillard, MD; Lisa K Washburn, MD; Nancy J Peters, RN CCRP; Barbara G Jackson, RN BSN; Korinne Chiu, MA; Deborah Evans Allred, MA LPA; Donald J Goldstein, PhD; Raquel Halfond, MA; Carroll Peterson, MA; Ellen L Waldrep, MS; Cherrie D Welch, MD MPH; Melissa Whalen Morris, MA; Gail Wiley Hounshell, PhD. Wayne State University, Hutzel Women's Hospital and Children's Hospital of Michigan (U10 HD21385)—Seetha Shankaran, MD; Beena G Sood, MD MS; Athina Pappas, MD; Rebecca Bara, RN BSN; Laura A Goldston, MA; Mary E Johnson, RN BSN. Yale University, Yale-New Haven Children's Hospital and Bridgeport Hospital (U10 HD27871, UL1 TR142, M01 RR125)—Richard A Ehrenkranz, MD; Vineet Bhandari, MD DM; Harris C Jacobs, MD; Pat Cervone, RN; Patricia Gettner, RN; Monica Konstantino, RN BSN; JoAnn Poulsen, RN; Janet Taft, RN BSN; Christine G Butler, MD; Nancy Close, PhD; Walter Gilliam, PhD; Sheila Greisman, RN; Elaine Romano, MSN; Joanne Williams, RN BSN.

  • Contributors NA: conceptualised and designed the study, drafted the initial manuscript, revised the manuscript and approved the final manuscript as submitted. LAW and AD: assisted with the study design, acquisition of data, performed statistical analysis of the data, revised the manuscript and approved the final manuscript as submitted. WAC, ML, CMC, KAK, ARL, SS, MCW, RDH: assisted with the study design, critically reviewed the manuscript and approved the final manuscript as submitted.

  • Funding Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Heart, Lung, and Blood Institute (NHLBI) (U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27904, U10 HD34216, U10 HD36790, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40521, U10 HD40689, U10 HD53089, U10 HD53109, U10 HD53119, U10 HD53124) and the National Institutes of Health (M01 RR30, M01 RR32, M01 RR39, M01 RR44, M01 RR54, M01 RR59, M01 RR64, M01 RR70, M01 RR80, M01 RR125, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587, UL1 TR93, UL1 TR142, UL1 TR442, UL1 TR454). The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Heart, Lung, and Blood Institute (NHLBI) provided grant support for the Neonatal Research Network's SUPPORT Trial. The study sponsors were not involved in: (1) study design; (2) the collection, analysis, and interpretation of data; (3) the writing of the report; and (4) the decision to submit the paper for publication. No honorarium, grant, or other form of payment was given to anyone to produce the manuscript.

  • Competing interests None.

  • Ethics approval IRBs at all participating institutions had approved the SUPPORT trial, of which this study is a secondary analysis.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All analyses performed for this study are available either in the manuscript or in the online supplementary table.

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