Objective To investigate the relationships between early blood pressure (BP) changes, receipt of antihypotensive therapy and 18–22 months’ corrected age (CA) outcomes for extremely preterm infants.
Design Prospective observational study of infants 230/7–266/7 weeks’ gestational age (GA). Hourly BP values and antihypotensive therapy exposure in the first 24 h were recorded. Four groups were defined: infants who did or did not receive antihypotensive therapy in whom BP did or did not rise at the expected rate (defined as an increase in the mean arterial BP of ≥5 mm Hg/day). Random-intercept logistic modelling controlling for centre clustering, GA and illness severity was used to investigate the relationship between BP, antihypotensive therapies and infant outcomes.
Setting Sixteen academic centres of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.
Main outcome measures Death or neurodevelopmental impairment/developmental delay (NIDD) at 18–22 months’ CA.
Results Of 367 infants, 203 (55%) received an antihypotensive therapy, 272 (74%) survived to discharge and 331 (90%) had a known outcome at 18–22 months’ CA. With logistic regression, there was an increased risk of death/NIDD with antihypotensive therapy versus no treatment (OR 1.836, 95% CI 1.092 to 3.086), but not NIDD alone (OR 1.53, 95% CI 0.708 to 3.307).
Conclusions Independent of early BP changes, antihypotensive therapy exposure was associated with an increased risk of death/NIDD at 18–22 months’ CA when controlling for risk factors known to affect survival and neurodevelopment.
Clinical trial registration number clinicaltrials.gov #NCT00874393.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
What is already known on this topic
Extremely preterm infants who receive antihypotensive therapies have worse inhospital outcomes.
The relationship between toddler age outcomes, early blood pressure values and antihypotensive therapies is unclear.
Investigating these relationships is challenging in part because of changes in blood pressure values occurring shortly after birth.
What this study adds
Infants given antihypotensive therapy were more likely to have impaired or delayed development than untreated infants irrespective of whether blood pressure increased.
These results cannot be explained by differences in the markers of severity of illness investigated.
Many investigations in the last 25 years suggest preterm infants considered hypotensive in the immediate postnatal period are at increased risk for adverse outcomes.1–14 This observation has led some clinicians to administer therapies in an effort to raise arterial blood pressure (BP) and, presumably, improve an infant's chances of survival without major morbidity.12–16 To date, no such improvement in outcomes has been observed.1–16 More concerning is the possibility that commonly prescribed antihypotensive therapies may increase risks to preterm infants.3 ,7 ,12–14
The evolving physiology of extremely preterm infants and the dynamic nature of the cardiovascular system are some of the inherent challenges to investigating BP management in the immediate newborn period. The wide range of BP values observed at any given postnatal hour and the spontaneous rise in BP which typically occurs after birth5 ,8 ,9 make it difficult to determine whether a BP value for a given infant at a specific postnatal age is too high, too low, rising too quickly or not increasing quickly enough. There are no placebo-controlled randomised trials to guide therapeutic decisions.3 ,17–19 As such, BP management for this population varies considerably with a wide range in the frequency of antihypotensive therapy administration for perceived low BP.12–14 ,16
Data on the relationship between early BP management and neurodevelopmental impairment/developmental delay (NIDD) are insufficient and difficult to interpret. This is related in part to the limited number of studies reporting rates of NIDD, patient sample sizes, data on specific antihypotensive therapies and heterogeneous study populations.9–11 Perhaps most importantly, previous investigations did not account for the spontaneous rise in BP that occurs after birth in preterm infants.5 ,8 ,9 As a result, it is difficult to determine whether infant outcomes after the administration of antihypotensive therapies are related to BP increasing in conjunction with therapy. The objectives of this study were to evaluate toddler age outcomes in a cohort of extremely preterm infants divided into groups defined by early changes in BP and receipt of antihypotensive therapy in an effort to clarify: (1) whether adverse outcomes in infants with a concerning BP are related to lack of antihypotensive therapy administration and (2) whether survival and/or intact neurodevelopment in treated infants are related to a rise in BP.
This study reports the outcomes at 18–22 months’ corrected age (CA) for infants enrolled in a prospective observational study of inborn extremely preterm infants born at 230/7–266/7 weeks’ gestational age (GA) at 16 academic centres of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) enrolled from 21 July 2010 to 21 January 2011. A detailed description of the patient population, explanation of the informed consent process and inhospital outcomes have been reported previously.8 ,14 Briefly, hourly BP measurements (both invasive and non-invasive) and the administration of all antihypotensive therapies in the first 24 h were recorded. Antihypotensive therapy included a fluid bolus (≥10 mL/kg of crystalloid), dopamine, dobutamine, hydrocortisone, epinephrine or any blood product. All treatment decisions were made by the clinical care team. Inborn infants born at 23–26 weeks’ GA admitted to the neonatal intensive care unit were included in this study. Infants were excluded if they died in the delivery room, had a major birth defect or had intensive care withheld or withdrawn shortly after birth because the clinical care team felt the situation was hopeless. This study was approved by the institutional review board of each participating centre. At two centres, infants were enrolled after parents signed a study-specific informed consent form. At the remaining 14 centres, this study was incorporated into the ongoing Generic Database (GDB) study of the NRN because all infants in this study qualified for GDB enrolment (on the basis of their GA at birth), and both studies collected deidentified patient information. The institutional review board of some NRN centres allowed for GDB data collection with a waiver of consent.8
The primary outcome for this investigation was the incidence of death or NIDD at 18–22 months’ CA. NIDD was defined as a Bayley Scales of Infant Development, Third Edition20 cognitive or motor score <70, cerebral palsy (Gross Motor Function Classification System level >2),21 hearing impairment requiring hearing aids in both ears or blindness (some or no useful vision in either eye). Secondary outcomes were the rates of any NIDD and individual components of NIDD among infants who survived to 18–22 months’ CA. Outcomes were compared among four infant groups defined by the administration of antihypotensive therapy and the rate of rise in BP: (1) infants who did not receive an antihypotensive therapy in whom the BP rose as expected, (2) untreated infants in whom BP did not rise at the expected rate, (3) infants who received an antihypotensive therapy in the first 24 h in whom BP rose as expected and (4) treated infants who did not experience the expected rise in BP. The expected rise in BP was defined a priori as an increase in the mean arterial BP of ≥5 mm Hg from postnatal hour 4 to postnatal hour 24. This definition was chosen because this rate of rise was reported previously for extremely preterm infants, this was the average rate of rise in mean arterial BP for this cohort of infants, the average rate of rise was the same for each week of gestation across this GA range and the average rate of rise for this cohort was the same for infants who did versus did not receive an antihypotensive therapy.5 ,8
Data analysis was performed at the NRN Data Coordinating Center (RTI International, Research Triangle Park, North Carolina, USA). Statistical analysis was performed using SAS V.9.3 software (SAS Institute, Cary, North Carolina, USA). For univariable analysis, χ2 or Fisher's exact tests were used for comparison of proportions and analysis of variance was used for comparison of means. Logistic regression models that included a random intercept to account for potential centre clustering were estimated for the outcomes of death/NIDD and NIDD (alone). Infant-level covariates of GA at birth and severity of illness were used as covariates in addition to antihypotensive therapy exposure (treated vs untreated) and early changes in BP (expected rate of rise vs less than the expected rate of rise).14 Severity of illness was defined as the cumulative number of any of the following: a 1 min Apgar score ≤3, presence of early anaemia (an initial haematocrit ≤30%), any pH <7.10 in the first 24 h after birth, a positive early blood culture (drawn within 72 h of birth) or delivery room chest compressions.14
There were 367 infants enrolled in the study (figure 1). Of these, 158 infants survived the first 24 h without receiving an antihypotensive therapy, including 91 (58%) in whom the mean arterial BP increased by ≥5 mm Hg and 67 (42%) infants in whom it did not. BP rose as expected for 128 (65%) of the 198 infants who received an antihypotensive therapy. Of the 203 infants who received an antihypotensive therapy, 135 (67%) received a fluid bolus, 102 (50%) received a blood product and 92 (45%), 25 (12%), 18 (9%) and 1 (<1%) received dopamine, hydrocortisone, dobutamine and vasopressin, respectively. Five infants who received an antihypotensive therapy died in the first 24 h. Inhospital variables and outcome data for the four infant cohorts are presented in table 1.
Eighteen to 22 months’ CA outcomes (death or neurodevelopmental assessment) were known for 331 (90%) infants. This included 99 infants who died and 232 infants who underwent neurodevelopmental testing. Thirty-six infants were lost to follow-up. There were no significant differences in known inhospital morbidities or therapies between infants lost to follow-up and hospital survivors with known 18–22 months’ outcomes. On univariable analysis, death or NIDD was significantly higher in treated infants compared with untreated infants (table 2) irrespective of whether BP rose as expected. The rates of individual components of NIDD varied across the four groups, but these differences did not reach statistical significance (table 2; p>0.05 for each).
There were significant differences in the incidence of NIDD or the composite outcome of death/NIDD from random-effects logistic regression models (table 3). For each 1-week increase in GA at birth, both the likelihood of NIDD or death/NIDD decreased. The presence of any marker of severity of illness increased the odds of both NIDD and death/NIDD as did the cumulative number of severity of illness markers. When incorporating these variables and changes in BP into regression models, treatment with any antihypotensive therapy was a significant predictor of death/NIDD, but not NIDD alone. In similar regression models incorporating antihypotensive treatment, the rise in BP (at the expected rate vs less than the expected rate) was not significantly associated with either outcome.
Previous studies examining the relationship between early BP management and infant outcomes either evaluated hypotensive infants versus normotensive infants or infants with treated versus untreated hypotension.6 ,9–11 Hypotension was defined as either receipt of an antihypotensive therapy (irrespective of BP values) or a BP value below a numerical threshold (eg, a mean arterial BP less than or equal to the numerical equivalent of the infant's GA), which was not necessarily used clinically. Difficulties with investigating early BP management include the spontaneous rise in BP that occurs after birth, the positive correlation between BP values and GA at birth, and the wide range of BP values observed at any specific postnatal hour for infants at all GA ranges.5 ,6 ,8 The findings of this study underscore the importance of considering multiple factors when examining BP in relation to infant outcomes.
Infants given an antihypotensive therapy had a higher rate of death/NIDD irrespective of early BP changes. The significance of this finding remains unclear. It is possible that the parameters other than a numerical threshold for low BP may better identify infants at risk for a poor outcome who would benefit from therapy. Incorporation of indirect measures of systemic or cerebral blood flow may also partially explain the observed variability in BP management, including why some infants without low BP received an antihypotensive therapy while other infants with low BP did not.3 ,14 ,22 ,23
Although not statistically significant (p=0.055), there was a trend towards higher mortality in treated infants (29%) versus untreated infants (17%) in this study, irrespective of the rate of rise in BP. Other reports have also suggested that infants who receive an antihypotensive therapy have a higher mortality rate.5–7 ,24 Definitive conclusions regarding this association cannot be made since to date, there are no randomised trials. Potential confounders include higher illness severity in treated infants, a greater likelihood of a condition known to increase mortality (eg, sepsis), inclusion of infants in extremis who received an antihypotensive therapy, but were likely to die irrespective of the degree of therapeutic support provided and omission of other factors that may predispose an infant to both perceived low BP requiring intervention and death (such as a low Apgar score or early acidosis). Attempts were made to control for these concerns in the current study such as excluding infants deemed terminally ill in the first 24 h and incorporating severity of illness into the regression analyses using factors, which both impact BP management and are associated with lower survival.14
In a previous multicentre study, the ELGAN Study investigators evaluated the relationship between indicators of hypotension and rates of NIDD at 24 months’ CA.9 Similar to this study, those investigators found little evidence of an association between early BP values and subsequent neurodevelopment. Other studies report similar findings.10 ,11 ,18 The association between antihypotensive therapy and hearing loss reported by Fanaroff et al6 was not observed in this investigation, possibly due to the low rate of deafness overall (<3%).
Data from this study and others demonstrate the complex relationship between early BP management, mortality and neurodevelopment. Death and NIDD are distinct outcomes, and it is likely that circumstances which lead to death are distinct but overlap with factors which lead to brain injury such that these therapies—or factors influencing the decision to administer them—may influence mortality risk differently than they influence the risk of NIDD.25 ,26 Alternatively, factors beyond the immediate postnatal period may have more influence on toddler age outcomes thus masking the impact of early BP management on neurodevelopment.25 Lastly, given the complexity of the immature cardiovascular system, antihypotensive therapies may inconsistently influence cardiac function such that they do not uniformly alter early postnatal cerebrovascular blood flow or oxygen delivery.18 ,22 ,23
Study strengths include consistent prospective data collected by trained research personnel, inclusion of a large multicentre population of extremely preterm infants, analysis based on GA rather than birth weight and systematic assessment of neurodevelopment by examiners masked to the infant's early BP management who were trained in the standardised administration of the Bayley Scales of Infant Development, Third Edition. Importantly, this study may have been underpowered to demonstrate statistically significant, but clinically relevant, differences in some infant outcomes. Additional study limitations reported previously include the observational study design, a lack of data for some variables that may have contributed to BP management decisions, variability in infant enrolment across NRN centres and inconsistency in how BP values were obtained.14 There was substantial heterogeneity in the treatment of perceived low BP, and this also may limit the applicability of the study findings.
Extremely preterm infants who received an antihypotensive therapy in the first 24 h after birth had a significantly higher rate of death or impaired neurodevelopment at 18–22 months’ CA than untreated infants irrespective of early changes in BP. These results cannot be explained by differences in the markers of illness severity collected for this study, which include factors known to impact infant survival and morbidity. There is limited evidence to suggest that antihypotensive therapies improve outcomes for preterm infants, and growing concern that these therapies may be harmful. It is possible that therapeutic interventions for perceived low BP increase the risk of adverse outcomes in extremely preterm infants.
The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provided grant support, including funding from the Best Pharmaceuticals for Children Act, for the Neonatal Research Network's Early Blood Pressure Observational Study. 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 Lei Li (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. 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, in addition to the authors, participated in this study: NRN Steering Committee Chair: Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine (2006–2011). Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904)—Abbot R. Laptook, MD; William Oh, MD; Angelita M. Hensman, RNC-NIC BSN; Kristin Basso, RN MaT. Case Western Reserve University, Rainbow Babies & Children’s Hospital (U10 HD21364)—Avroy A. Fanaroff, MD; Bonnie S. Siner, RN; Deanne E. Wilson-Costello, MD. Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853)—Kurt Schibler, MD; Barbara Alexander, RN; Cathy Grisby, BSN CCRC; Lenora Jackson, CRC; Kristin Kirker, CRC; Estelle E. Fischer, MHSA MBA. Duke University School of Medicine, University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital (U10 HD40492)—Ronald N. Goldberg, MD; C. Michael Cotten, MD MHS; Kimberley A. Fisher, PhD FNP-BC IBCLC; Sandy Grimes, RN BSN. Emory University, Children's Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, UL1 RR25008)—David P. Carlton, MD; Ellen C. Hale, RN BS CCRC. 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)—Brenda B. Poindexter, MD MS; Leslie D. Wilson, BSN CCRC; Dianne E. Herron, RN; Cassandra Stahlke, BS CCRC. RTI International (U10 HD36790)—Dennis Wallace, PhD; Jeanette O'Donnell Auman, BS; Margaret Cunningham, BS; Carolyn M. Petrie Huitema, MS; James W. Pickett II, BS; Kristin M. Zaterka-Baxter, RN BSN. Stanford University, Lucile Packard Children’s Hospital (U10 HD27880)—Krisa P. Van Meurs, MD; David K. Stevenson, MD; M. Bethany Ball, BS CCRC; Melinda S. Proud, RCP. Tufts Medical Center, Floating Hospital for Children (U10 HD53119)—Ivan D. Frantz III, MD; John M. Fiascone, MD; Anne Furey, MPH; Brenda L. MacKinnon, RNC; Ellen Nylen, RN BSN. University of Alabama at Birmingham Health System and Children's Hospital of Alabama (U10 HD34216)—Waldemar A. Carlo, MD; Namasivayam Ambalavanan, MD; Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN. University of Iowa Children’s Hospital and Mercy Medical Center (U10 HD53109, UL1 RR24979)—Edward F. Bell, MD; Dan L. Ellsbury, MD; Karen J. Johnson, RN BSN; Donia D. Campbell, RNC-NIC; Rachael M. Hyland, BA. University of New Mexico Health Sciences Center (U10 HD53089)—Robin K. Ohls, MD; Conra Backstrom Lacy, RN; Sandra Brown, BSN. The University of North Carolina at Chapel Hill (UL1 RR25747)—Carl L. Bose, MD; Gennie Bose, RN; Janice Bernhardt, MS RN; Cindy Clark, RN. University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children’s Medical Center Dallas (U10 HD40689, M01 RR633)—Pablo J. Sánchez, MD; Luc P. Brion, MD; Lizette E. Torres, RN; Diana M. Vasil, RNC-NIC; Lijun Chen, RN PhD; Alicia Guzman. University of Texas Health Science Center at Houston Medical School, Children’s Memorial Hermann Hospital—Kathleen A. Kennedy, MD MPH; Jon E. Tyson, MD MPH; Georgia E. McDavid, RN; Patti L. Pierce Tate, RCP; Sharon L. Wright, MT (ASCP). University of Utah, University Hospital, Intermountain Medical Center, and Primary Children’s Medical Center (U10 HD53124, UL1 RR25764)—Karen A. Osborne, RN BSN CCRC; Jill Burnett, RNC; Cynthia Spencer, RNC; Kimberlee Weaver-Lewis, RN BSN; Karie Bird, RN; Karen Zanetti, RN; Laura Cole, RN. Wayne State University, University of Michigan, Hutzel Women's Hospital, and Children's Hospital of Michigan (U10 HD21385)—Seetha Shankaran, MD; Beena G. Sood, MD MS; Rebecca Bara, RN BSN; Mary Johnson, RN BSN. Yale University, Yale-New Haven Children's Hospital (U10 HD27871, UL1 RR24139)—Richard A. Ehrenkranz, MD; Monica Konstantino, RN BSN; JoAnn Poulsen, RN.
Contributors BB was the principal study investigator, wrote the first draft of the manuscript and oversaw subsequent revisions. LL was responsible for all statistical analyses, co-wrote portions of the manuscript relevant to data analysis and interpretation, and actively participated in the review and revision of all drafts of the manuscript. NSN assisted with patient enrolment, data collection and participated in the review and revision of all drafts of the manuscript. AD was responsible for statistical analysis and interpretation and actively participated in the review and revision of all drafts of the manuscript. KLW, BAY, RGF, MML and BJS assisted with patient enrolment, data collection and actively participated in the review and revision of all drafts of the manuscript. RDH was a senior study investigator, assisted with data collection and actively participated in the review and revision of all drafts of the manuscript. MCW was a senior study investigator, assisted with patient enrolment, data collection and actively participated in the review and revision of all drafts of the manuscript. All authors participated in the study design and implementation.
Funding This study was funded by the Best Pharmaceuticals for Children Act.
Competing interests None declared.
Ethics approval The local institutional review board at each hospital.
Provenance and peer review Not commissioned; externally peer reviewed.