Impact of Early Hemodynamic Screening on Extremely Preterm Outcomes in a High-Performance Center.

Rationale: Increasing survival of extremely preterm infants with a stable rate of severe intraventricular hemorrhage represents a growing health risk for neonates. Objectives: To evaluate the role of early hemodynamic screening (HS) on the risk of death or severe intraventricular hemorrhage. Methods: All eligible patients 22-26+6 weeks' gestation born and/or admitted <24 hours postnatal age were included. As compared with standard neonatal care for control subjects (January 2010-December 2017), patients admitted in the second epoch (October 2018-April 2022) were exposed to HS using targeted neonatal echocardiography at 12-18 hours. Measurements and Main Results: A primary composite outcome of death or severe intraventricular hemorrhage was decided a priori using a 10% reduction in baseline rate to calculate sample size. A total of 423 control subjects and 191 screening patients were recruited with a mean gestation and birth weight of 24.7 ± 1.5 weeks and 699 ± 191 g, respectively. Infants born at 22-23 weeks represented 41% (n = 78) of the HS epoch versus 32% (n = 137) of the control subjects (P = 0.004). An increase in perinatal optimization (e.g., antepartum steroids) but with a decline in maternal health (e.g., increased obesity) was seen in the HS versus control epoch. A reduction in the primary outcome and each of severe intraventricular hemorrhage, death, death in the first postnatal week, necrotizing enterocolitis, and severe bronchopulmonary dysplasia was seen in the screening era. After adjustment for perinatal confounders and time, screening was independently associated with survival free of severe intraventricular hemorrhage (OR 2.09, 95% CI [1.19, 3.66]). Conclusions: Early HS and physiology-guided care may be an avenue to further improve neonatal outcomes; further evaluation is warranted.

Acute kidney injury surveillance in the high-risk neonatal population following implementation of creatinine screening protocol.

AIM: Acute kidney injury (AKI) in neonates is associated with longer hospital stays and higher mortality rates. However, there is significant variability in prevalence rates of AKI and the true burden is incompletely understood. In November 2020, the University of Iowa Stead Family Children's Hospital Neonatal Intensive Care Unit implemented a creatinine screening protocol to enhance kidney function monitoring. We sought to evaluate adherence to the protocol to determine if increased surveillance led to increased detection of AKI events. METHODS: A retrospective chart review was conducted for neonates born at <30 weeks' gestation admitted between 2015 and 2020. We reviewed 100 charts in both the pre (2015-2016) and post (2020-2021) implementation era of the AKI surveillance protocol. AKI was defined according to neonatal modified KDIGO criteria. RESULTS: Following implementation of the protocol, neonates were significantly more likely to have creatinine checked (p < 0.001). Serum creatinine was drawn according to protocol guidelines 68% of the time, and 42% of patients (34/82) had an 80% or higher adherence to the protocol. There was a significant increase in detection of AKI in the post-protocol cohort (13/82, incidence of 16%) compared to the pre-protocol cohort (5/83, incidence of 6%), (p = 0.047). CONCLUSION: The implementation of a serum creatinine screening protocol increased the frequency of creatinine draws and detection of AKI.

First intention high-frequency jet ventilation for periviable infants.

PURPOSE OF REVIEW: Ventilation of periviable infants born at 22-23 weeks gestation remains a challenge in neonatology. This review highlights the evidence surrounding the use of first intention high-frequency jet ventilation (HFJV) in infants born near the limits of viability with a review of pulmonary fetal development and a focused overview of HFJV strategies including an in-depth analysis of the management strategies used in the initial randomized trials. RECENT FINDINGS: A paucity of recent trials exists, with no randomized control trials assessing the use of first intention HFJV performed in the last 25 years. A retrospective observational cohort trial of the use of HFJV for infants born at less than 750 g has been recently published demonstrating the efficacy of HFJV for this population even with 2.0-mm endotracheal tubes. SUMMARY: The lack of recent randomized trials contributes to the controversy surrounding the use of first intention HFJV. Although new research is needed in the area, this review includes the ventilation strategy of an experienced center with a focus on the use of first intention HFJV for the care of premature infants born less than 24 weeks gestation.

Hypothyroxinemia Detected at 4 Weeks of Life in Preterm Infants Born at Less than 30 Weeks of Gestation.

OBJECTIVE: Data on free thyroxine (FT4) concentrations beyond first 2 weeks of preterm infants are limited. This study was aimed to describe the association between perinatal characteristics and FT4 concentrations and the incidence of hypothyroxinemia at 4 weeks. STUDY DESIGN: Retrospective analysis of serum thyroid function tests at 4 weeks in preterm infants <30 weeks of gestation. Association between FT4 at 4 weeks of life and perinatal characteristics were determined by bivariate analysis and multivariable regression. Incidence of hypothyroxinemia was determined using a gestational age adjusted definition based on in utero levels at the equivalent postmenstrual age. RESULTS: The study cohort consisted of 280 infants. FT4 concentrations at 4 weeks of life were significantly associated with gestational age, birth weight, gender, and maternal history of thyroid disease. Hypothyroxinemia was found in 32.8% of the study cohort. CONCLUSION: Perinatal characteristics are associated with FT4 concentrations at 4 weeks of life. Nearly one-third of infants born <30 weeks had hypothyroxinemia at 4 weeks of life when compared with in utero levels at the equivalent postmenstrual age.

Causes and circumstances of death in a neonatal unit over 20 years.

BackgroundWe examined changes in the causes and circumstances of death in our neonatal intensive care unit (NICU) over 20 years.MethodsFor 551 infants who died between 1993 and 2013, the principal cause of death was recorded. Circumstances of death were assigned to one of the following four categories: death following cardiopulmonary resuscitation (CPR), death while being mechanically ventilated without CPR, death after withholding life-support interventions, and death after withdrawal of life support. Data were compared across four 5-year epochs.ResultsThe mortality rate decreased from 5.9% in the first epoch to 3.0% in the last epoch (P<0.0001). The leading cause of death in all epochs was congenital anomalies. The percentage of deaths due to all other categories decreased or remained stable. Withdrawal of life support was the most common circumstance of death in all four epochs. Only 16% of deaths followed CPR. The percentage of neonates with documented do-not-resuscitate orders was highest in the final cohort (52%).ConclusionsThe mortality rate per admission decreased between 1993 and 2013. Each cause of death was stable or decreased as a percentage of all deaths except for deaths due to congenital anomalies. Withdrawal of life-support interventions is the most common circumstance of death in neonates.

Polymorphisms in urea cycle enzyme genes are associated with persistent pulmonary hypertension of the newborn.

BackgroundPersistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated pulmonary vascular resistance. Endogenous nitric oxide is critical for regulation of pulmonary vascular resistance. Nitric oxide is generated from L-arginine, supplied by the urea cycle (UC). We hypothesized that polymorphisms in UC enzyme genes and low concentrations of UC intermediates are associated with PPHN.MethodsWe performed a family-based candidate gene analysis to study 48 single-nucleotide polymorphisms (SNPs) in six UC enzyme genes. Genotyping was carried out in 94 infants with PPHN and their parents. We also performed a case-control analysis of 32 cases with PPHN and 64 controls to identify an association between amino-acid levels on initial newborn screening and PPHN.ResultsThree SNPs (rs41272673, rs4399666, and rs2287599) in carbamoyl phosphate synthase 1 gene (CPS1) showed a significant association with PPHN (P=0.02). Tyrosine levels were significantly lower (P=0.003) and phenylalanine levels were significantly higher (P=0.01) in cases with PPHN. There was no difference in the arginine or citrulline levels between the two groups.ConclusionsThis study suggests an association (P<0.05) between SNPs in CPS1 and PPHN. These findings warrant further replication in larger cohorts of patients.

The changing relationship between bronchopulmonary dysplasia and cognition in very preterm infants.

AIM: To characterise the relationship between bronchopulmonary dysplasia (BPD) severity and cognition in the post-surfactant era. METHODS: This was a single-centre retrospective analysis of a cohort of infants born 2009-2012. Inclusion criteria were as follows: admission within 48 hours of birth, gestational age 22-0/7-31-6/7 weeks, birthweight 400-1500 g and Bayley Scales of Infant and Toddler Development-III testing at 18-26 months corrected age. Infants (n = 151) were classified by BPD severity with the NIH Workshop definition. Generalised linear modelling and multivariate logistic regression were performed. RESULTS: Bayley cognitive score was not associated with BPD severity in univariate (p = 0.053) or multivariate (p = 0.503) analysis. About 27% of infants with no/mild BPD, 33% of infants with moderate BPD and 40% of infants with severe BPD had a cognitive score <85. There was no difference in the odds of cognitive score <85 based on BPD severity in univariate (p = 0.485) or multivariate analysis (p = 0.225). All infants with cognitive score <70 had severe BPD, although the association between cognitive score <70 and BPD severity was not significant. CONCLUSION: We found no independent effect of BPD severity level on cognition. The likelihood of a cognitive score <85 was not associated with BPD severity.

Noninvasive Neurally Adjusted Ventilatory Assist in Premature Infants Postextubation.

Background Neurally adjusted ventilatory assist (NAVA) has distinct advantages when used invasively compared with conventional ventilation techniques. Evidence supporting the use of noninvasive NAVA is less robust, especially in the very low birth weight (VLBW) population. Objective To determine whether synchronized noninvasive ventilation via neurally adjusted ventilatory assist (NIV NAVA) supports ventilation postextubation in premature infants. Methods A retrospective analysis of a cohort of twenty-four former VLBW (<1.5 kg) infants from July 2011 to October 2012. Decreased or unchanged capillary pCO2 after increasing NAVA support was used as a marker for adequately supported noninvasive ventilation. The Wilcoxon signed-rank test was used to compare pre- and post-NAVA intervention (α = 0.05). Results Ventilation improved after an increase in NIV NAVA level in 83% of the premature infants studied (20/24) with a decrease in median pCO2 by 5 mm Hg (p = 0.0001). Conclusion NIV NAVA can provide synchronized postextubation ventilatory support as measured by decreased pCO2 in premature infants.

Development and validation of the Proxy-Reported Pulmonary Outcomes Scale for premature infants.

OBJECTIVE: Test the feasibility of using a bedside nurse-reported tool (Proxy-Reported Pulmonary Outcome Scale, PRPOS) for evaluating the severity of bronchopulmonary dysplasia (BPD) by assessing functional, disease-related measures. STUDY DESIGN: Bedside nurses tested the 26-item instrument by observing preterm infants (23-30 weeks at birth) at 36 to 37(4/7) weeks postmenstrual age before, during, and after a care time. We analyzed item reliability, validity, and model fit to determine the six items to include in the final measurement tool. RESULT: We completed assessments on 188 preterm infants. The frequency of an abnormal PRPOS item score increased with increasing National Institute of Child Health and Development (NICHD) BPD category. The six-candidate items produced an internally consistent scale. Addition of the NICHD BPD classification increased reliability moderately; addition of feeding items decreased reliability. The PRPOS score correlated with postmenstrual age at discharge. Infants discharged on oxygen or diuretics had higher median PRPOS scores than did infants who were not prescribed those therapies. CONCLUSION: The PRPOS is an internally consistent, proxy-reported measure of respiratory function in premature infants, based on observable, functional performance measures. Initial testing demonstrates known-groups validity and ongoing testing can assess predictive validity.

Care from Birth to Discharge of Infants Born at 22 to 23 Weeks' Gestation.

The clinical care of infants born at 22 weeks' gestation must be well-designed and standardized if optimal results are to be expected. Although several approaches to care in this vulnerable population are possible, protocols should be neither random nor inconsistent. We describe the approach taken at the University of Iowa Stead Family Children's Hospital neonatal intensive care unit with respect to preterm infants born at 22 weeks' gestation. We have chosen to present our standardize care plan with respect to prenatal, neurologic, nutritional, gastrointestinal, and skin management. Respiratory and cardiopulmonary care will be briefly reviewed, as these strategies have been published previously.

Exposure to persistent hemodynamically significant patent ductus arteriosus is associated with retinopathy of prematurity.

BACKGROUND: Hemodynamically significant patent ductus arteriosus (hsPDA) shunt may predispose infants to retinopathy of prematurity (ROP) because of its higher preductal cardiac output and blood oxygen content, which may augment ocular oxygen delivery. METHODS: A retrospective cohort study of preterm infants, born at <27 weeks' gestation and admitted at <24h postnatal age to a large quaternary referral was conducted. The primary composite outcome was death at <32 weeks or moderate-to-severe ROP (≥stage 2 or requiring treatment) in either eye. Secondary outcomes included ROP requiring treatment, and any ROP. Univariate analysis of patient characteristics and outcomes was performed as well as logistic regression. A receiver operating characteristics curve was generated for the outcome of ROP ≥stage 2 or requiring treatment. RESULTS: A total of 91 patients were screened, of whom 86 (54 hsPDA, 32 controls) were eligible for inclusion. hsPDA patients were younger and lighter at birth and had a higher burden of hyperglycemia and respiratory illness. The rates of the composite outcome (death <32 weeks or moderate-to-severe ROP) and of any ROP were more frequent in the hsPDA group. hsPDA shunt exposure was independently associated with development of any ROP among survivors to assessment (P = 0.006). PDA cumulative exposure score of 78 (clinical equivalent = 7 days high-volume shunt exposure) predicts moderate-to-severe ROP with 80% sensitivity and 78% specificity. CONCLUSIONS: Among infants <27 weeks, hsPDA shunt is associated with increased risks of a composite outcome of death or moderate-to-severe ROP, as well as ROP of any stage. Shunt modulation as a strategy to reduce ROP represents a biologically plausible avenue for investigation.

Response categorization and outcomes in extremely premature infants born at 22-26 weeks gestation that received inhaled nitric oxide for hypoxic respiratory failure.

OBJECTIVE: To evaluate the outcomes of extremely premature infants who received inhaled nitric oxide(iNO) for hypoxic respiratory failure(HRF). STUDY DESIGN: Retrospective analysis of 107 infants born 22-26 weeks gestation who received iNO for HRF at a single institution. Infants were categorized as positive, negative, or no responders based on change in FiO2 or OI. Underlying physiology was determined using Echocardiography/Radiography/Biochemistry. RESULTS: 63% of infants had a positive response; they received iNO earlier and were more likely to have acute pulmonary hypertension(PH). Positive response correlated with decreased incidence of death or grade 3 BPD at 36 weeks postmenstrual age, as compared to a negative response. CONCLUSIONS: Extremely premature infants have a positive response rate to iNO comparable to term infants when used for PH in the transitional period. Infants with a negative response to iNO had worse outcomes, necessitating the determination of the underlying physiology of HRF prior to iNO initiation.

Patent ductus arteriosus (PDA) and response to late surfactant treatment in premature infants.

OBJECTIVE: To determine the clinical/echocardiography (ECHO) phenotype of patients with hypoxic respiratory failure (HRF) and response to late surfactant, according to patent ductus arteriosus (PDA) status. STUDY DESIGN: This retrospective study included infants ≤26+6 weeks gestation who received ≥1 surfactant dose after 6 postnatal days and where PDA status was available by ECHO. Response to surfactant was appraised based on change in respiratory severity score over 48 h. The relationship between PDA status and response to surfactant was evaluated via univariate analysis. RESULT: We studied late surfactant (n = 71 doses) administration in 35 preterm infants born at a mean weight and GA at birth were 595 g (508, 696) and 23.3 (22.7, 25) weeks, respectively of whom 16 (46%) had a diagnosis of PDA. Positive response to late surfactant treatment was independently associated with absence of PDA [OR 26 (2, 334), p = 0.01] whereas presence of PDA was independently associated with negative response [OR 12 (1.1, 126), p = 0.04]. CONCLUSIONS: In neonates ≤26+6 weeks gestation, with HRF, response to surfactant after postnatal day 6 is influenced by PDA status. Future trials should consider PDA status which may enhance diagnostic precision and refine patient selection for late surfactant treatment.

Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn.

INTRODUCTION: Persistent pulmonary hypertension of the newborn (PPHN) is associated with substantial infant morbidity and mortality. Recently, genetic associations have been found in idiopathic pulmonary arterial hypertension. RESULTS: PPHN was significantly (P < 0.05) associated with genetic variants in corticotropin-releasing hormone (CRH) receptor 1, CRHR1 and CRH-binding protein, CRHBP. Association with CRHR1 rs4458044 passed the Bonferroni threshold for significance. No mutations were found in the bone morphogenetic protein receptor type II (BMPR2) gene. DISCUSSION: We describe previously unreported genetic associations between PPHN and CRHR1 and CRHBP. These findings may have implications for further understanding the pathophysiology of PPHN and treatment. METHODS: We performed a family-based candidate gene study to examine a genetic association with PPHN and sequenced the BMPR2 gene in 72 individuals. We enrolled 110 families with infants diagnosed with PPHN based on inclusion criteria. After medical chart review, 22 subjects were excluded based on predefined criteria, and DNA samples from 88 affected infants and at least one parent per infant were collected and genotyped. Thirty-two single-nucleotide polymorphisms in 12 genes involved in vasoconstriction/vasodilation, lung development, surfactant regulation, or vascular endothelial cell function were investigated using family-based association tests.

Prediction of survival in infants with congenital diaphragmatic hernia based on stomach position, surgical timing, and oxygenation index.

OBJECTIVE: To identify characteristics predictive of survival of patients with congenital diaphragmatic hernia (CDH). STUDY DESIGN: Retrospective analysis of clinical characteristics including severity of lung disease measured by oxygenation index (OI) associated with single-center survival in CDH patients (n = 81) from 1992 to 2008. Data were analyzed using univariate and multivariable logistic regression, effect plots, and receiver operating characteristic (ROC) plots. RESULTS: No patient died if the stomach was located in the abdomen. A left thoracic stomach position predicted decreased survival with ROC area under the curve (AUC) = 0.70. OI of ≤ 26 averaged over the first 12 hours of life predicted ≥ 50% survival for all patients, with AUC = 0.86. OI effect plots allow prediction of survival over a continuous OI range. No patient survived if mean OI was >51 in the first 12 hours of life. Delaying surgery for a median of 6 days improved survival probability for all patients with presurgery OI values ≤ 51. CONCLUSION: Position of the stomach in the abdomen, delayed surgery, and less severe cardiopulmonary disease during the first 12 hours of life, as measured by mean OI, predicted improved survival probability among patients with CDH. Our CDH model, using mean OI, permits specific individual prediction of survival probability over a range of OI values.

Respiratory management for extremely premature infants born at 22 to 23 weeks of gestation in proactive centers in Sweden, Japan, and USA.

Survival of preterm newborn infants have increased steadily since the introduction of surfactant treatment and antenatal steroids. In the absence of randomized controlled trials on ventilatory strategies in extremely preterm infants, we present ventilatory strategies applied during the initial phase and the continued ventilatory care as applied in three centers with proactive prenatal and postnatal management and well documented good outcomes in terms of mortality and morbidity in this cohort of infants.

Ventilator Management in Extremely Preterm Infants.

Advances in ventilation strategies for infants in the NICU have led to increased survival of extremely preterm infants. More than 75% of infants born at less than or equal to 27 weeks' gestation require initial mechanical ventilation for survival due to developmental immaturity of their lungs and respiratory drive. Various ventilators using different technologies and involving multiple management strategies are available for use in this population. Centers across the world have successfully used conventional, high-frequency oscillatory and high-frequency jet ventilation to manage respiratory failure in extremely preterm infants. This review explores the existing evidence for each mode of ventilation and the importance of individualizing ventilator management strategies when caring for extremely preterm infants.

Survival and short-term respiratory outcomes of <750 g infants initially intubated with 2.0 mm vs. 2.5 mm endotracheal tubes.

OBJECTIVES: To compare survival and short-term respiratory outcomes of infants weighing <750 g initially intubated with 2.0 mm versus 2.5 mm endotracheal tube (ETT). STUDY DESIGN: Retrospective, observational cohort study. RESULTS: Of 149 inborn infants weighing <750 g admitted to the NICU, 69 (46%) were intubated with 2.0 mm ETT, 78 with 2.5 mm ETT (53%), and 2 infants never required intubation. Infants intubated with 2.0 mm ETT were more premature (median gestational age (GA) 23 weeks (22, 24) vs. 24 weeks (24, 25) p < 0.0001), smaller (median birth weight 545 g (450, 616) vs. 648 g (579, 700), p < 0.0001), and more frequently intubated at delivery (96% vs. 68%, p < 0.00001). Survival to discharge was similar 77%, 53/69 and 87%, 68/78 (p = 0.09). Adjusted for GA, there were no significant differences in ventilator days (p = 0.7338) or Grade 3 BPD. CONCLUSIONS: Premature infants born at a median GA of 23 weeks and median birth weight of 545 g can be successfully managed with 2.0 mm ETT.

Cardiorespiratory management of infants born at 22 weeks' gestation: The Iowa approach.

The approach to clinical care of infants born at 22 weeks' gestation must be consistent and well-designed if optimal results are to be expected. Publications from several international centers have demonstrated that, although there may be variance in aspects of care in this vulnerable population, treatment should be neither random nor inconsistent. In designing a standardized approach, careful attention should be paid to the unique anatomy, physiology, and biochemistry of this vulnerable patient population. Emerging evidence, suggesting a link between cardiopulmonary health and longer-term sequela, highlights the importance of understanding the relationship between cardiorespiratory illnesses of the 22-week infant, treatments provided, and subsequent cardiopulmonary development. In this review we will provide an overview to our approach to cardiopulmonary assessment and treatment, with a particular emphasis on the importance of early recognition of atypical phenotypes, timely interventions with evidence-based treatments, and longitudinal monitoring.