Cardiac function in congenital diaphragmatic hernia.

Cardiac function is known to play critical role in the pathophysiological progression and ultimate clinical outcome of patients with congenital diaphragmatic hernia (CDH). While often anatomically normal, the fetal and neonatal heart in CDH can suffer from both right and left ventricular dysfunction. Here we explore the abnormal fetal heart, early postnatal right and left ventricular dysfunction, the interplay between cardiac dysfunction and pulmonary hypertension, evaluation and echocardiographic assessment of the heart, and therapeutic strategies for managing and supporting the pathophysiologic heart and CDH. Further, we take a common clinical scenario and provide clinically relevant guidance for the diagnosis and management of this complex process.

Evaluation of the association between patent ductus arteriosus approach and neurodevelopment in extremely preterm infants.

OBJECTIVE: Assess if unit-level PDA management correlates with neurodevelopmental impairment (NDI) at 18-24 months corrected postnatal age (CPA) in extremely preterm infants. STUDY DESIGN: Retrospective analysis of infants born at <29 weeks (2014-2017) across two units having distinct PDA strategies. Site 1 utilized an echocardiography-based treatment strategy aiming for accelerated closure (control). Site 2 followed a conservative approach. PRIMARY ENDPOINT: NDI, characterized by cerebral palsy, any Bayley-III composite score <85, sensorineural/mixed hearing loss, or at least unilateral visual impairment. RESULTS: 377 infants were evaluated. PDA treatment rates remained unchanged in Site 1 but eventually reached 0% in Site 2. Comparable rates of any/significant NDI were seen across both sites (any NDI: 38% vs 36%; significant NDI: 13% vs 10% for Site 1 and 2, respectively). After adjustments, NDI rates remained similar. CONCLUSION: PDA management strategies in extremely preterm newborns showed no significant impact on neurodevelopment outcomes at 18-24 months CPA.

Neurodevelopmental outcomes of preterm neonates receiving rescue inhaled nitric oxide in the first week of age: a cohort study.

OBJECTIVE: To assess the neurodevelopmental outcomes of preterm neonates who received inhaled nitric oxide (iNO) in the first week of age for hypoxaemic respiratory failure (HRF). METHODS: In this retrospective cohort study, we included neonates born at <29 weeks gestational age (GA) between January 2010 and December 2018 who had a neurodevelopmental assessment at 18-24 months corrected age (CA) at one of the Canadian Neonatal Follow-Up Network clinics. The primary outcome was neurodevelopmental impairment (NDI). We performed propensity score-matched analysis to compare the outcomes of those who received and did not receive iNO. RESULTS: Of the 5612 eligible neonates, 460 (8.2%) received iNO in the first week of age. Maternal age, receipt of antenatal corticosteroids, GA and birth weight were lower in the iNO group compared with the no-iNO group. Neonates in the iNO group had higher illness severity scores and higher rates of preterm prolonged rupture of membranes and were small for GA. Severe brain injury, bronchopulmonary dysplasia and mortality were higher in the iNO group. Of the 4889 survivors, 3754 (77%) neonates had follow-up data at 18-24 months CA. After propensity score matching, surviving infants who received rescue iNO were not associated with higher odds of NDI (adjusted OR 1.34; 95% CI 0.85 to 2.12). CONCLUSIONS: In preterm neonates <29 weeks GA with HRF, rescue iNO use was not associated with worse neurodevelopmental outcomes among survivors who were assessed at 18-24 months CA.

Impact of persistent pulmonary hypertension and oxygenation on brain injury in neonates with neonatal encephalopathy treated with therapeutic hypothermia.

OBJECTIVE: To investigate the effects of persistent pulmonary hypertension (PPHN) and oxygenation on outcome of neonates with neonatal encephalopathy (NE) treated with therapeutic hypothermia (TH). STUDY DESIGN: We compared the outcome of neonates with NE treated with TH with or without PPHN. RESULTS: 384 neonates with NE were treated with TH; 24% had PPHN. The fraction of inspired oxygen was higher in the first 4 days of life (p < 0.001) in neonates with PPHN. They had a significantly lower arterial partial pressure of oxygen in the first 4 days of life (p = 0.005) and higher on days 3-4 of life (p < 0.001). They were more often intubated (p < 0.001) and more often had concomitant hypotension (p < 0.001). They had higher mortality (p = 0.009) and more often developed brain injury (p = 0.02). CONCLUSION: PPHN occurred frequently in neonates with NE treated with TH and was associated with a higher incidence of adverse outcome.

Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial.

OBJECTIVE: To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH). STUDY DESIGN: We performed a randomized, double-blind, placebo-controlled phase Ib clinical trial between 2016 and 2019 in neonates with moderate or severe NE, displaying brain injury on day-2 magnetic resonance imaging (MRI) despite TH. Neonates were randomized (2:1) to 7-day sildenafil or placebo (2 mg/kg/dose enterally every 12 hours, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), and day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory). RESULTS: Of the 24 enrolled neonates, 8 were randomized to sildenafil and 3 to placebo. A mild decrease in blood pressure was reported in 2 of the 8 neonates after initial dose, but not with subsequent doses. Sildenafil plasma steady-state concentration was rapidly reached, but decreased after TH discontinuation. Twelve percent of neonates (1/8) neonates died in the sildenafil group and 0% (0/3) in the placebo group. Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 magnetic resonance imaging were noted in 71% (5/7) of the sildenafil group and in 0% (0/3) of the placebo group. The rate of death or survival to 18 months with severe neurodevelopmental impairment was 57% (4/7) in the sildenafil group and 100% (3/3) in the placebo group. CONCLUSIONS: Sildenafil was safe and well-absorbed in neonates with NE treated with TH. Optimal dosing needs to be established. Evaluation of a larger number of neonates through subsequent phases II and III trials is required to establish efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02812433.

Association of nurse staffing and unit occupancy with mortality and morbidity among very preterm infants: a multicentre study.

OBJECTIVE: In a healthcare system with finite resources, hospital organisational factors may contribute to patient outcomes. We aimed to assess the association of nurse staffing and neonatal intensive care unit (NICU) occupancy with outcomes of preterm infants born <33 weeks' gestation. DESIGN: Retrospective cohort study. SETTING: Four level III NICUs. PATIENTS: Infants born 23-32 weeks' gestation 2015-2018. MAIN OUTCOME MEASURES: Nursing provision ratios (nursing hours worked/recommended nursing hours based on patient acuity categories) and unit occupancy rates were averaged for the first shift, 24 hours and 7 days of admission of each infant. Primary outcome was mortality/morbidity (bronchopulmonary dysplasia, severe neurological injury, retinopathy of prematurity, necrotising enterocolitis and nosocomial infection). ORs for association of exposure with outcomes were estimated using generalised linear mixed models adjusted for confounders. RESULTS: Among 1870 included infants, 823 (44%) had mortality/morbidity. Median nursing provision ratio was 1.03 (IQR 0.89-1.22) and median unit occupancy was 89% (IQR 82-94). In the first 24 hours of admission, higher nursing provision ratio was associated with lower odds of mortality/morbidity (OR 0.93, 95% CI 0.89 to 0.98), and higher unit occupancy was associated with higher odds of mortality/morbidity (OR 1.19, 95% CI 1.04 to 1.36). In causal mediation analysis, nursing provision ratios mediated 47% of the association between occupancy and outcomes. CONCLUSIONS: NICU occupancy is associated with mortality/morbidity among very preterm infants and may reflect lack of adequate resources in periods of high activity. Interventions aimed at reducing occupancy and maintaining adequate resources need to be considered as strategies to improve patient outcomes.

The association between BMI trajectories and bronchopulmonary dysplasia among very preterm infants.

OBJECTIVE: To investigate the association between change in body mass index (BMI) from birth to 36 weeks gestation (ΔBMI) and bronchopulmonary dysplasia (BPD) among infants born <30 weeks gestation. METHODS: This was a multicenter retrospective cohort study (2015-2018) of infants born <30 weeks gestation and alive at ≥34 weeks corrected. Main exposure was a change in BMI z score from birth to 36 weeks corrected age grouped into quartiles of change. Association between ΔBMI z scores and BPD was assessed using generalized linear mixed models. RESULTS: Among 772 included infants, 51% developed BPD. From birth to 36 weeks CGA, the weight z score of infants with BPD decreased less than for BPD-free infants, despite a greater decrease in length z score and similar caloric intake resulting in increases in BMI z score (median [IQR], 0.16 [-0.64; 1.03] vs -0.29 [-1.03; 0.49]; P < 0.01). In the adjusted analysis, higher ΔBMI z score quartiles were associated with higher odds of BPD (Q3 vs Q2, AOR [95% CI], 2.02 [1.23; 3.31] and Q4 vs Q2, AOR [95% CI], 2.00 [1.20; 3.34]). CONCLUSION: Among preterm infants, an increase in BMI z score from birth to 36 weeks corrected is associated with higher odds of BPD. IMPACT: Preterm infants with evolving lung disease often experience disproportionate growth in the neonatal period. In this multicenter cohort study, increases in BMI z score from birth to 36 weeks CGA were associated with higher odds of BPD. Despite similar caloric intake, infants with BPD had a higher weight- but lower length-for-age, resulting in higher BMI z score compared to BPD-free infants. This suggests that infants with evolving BPD may require different growth and nutritional targets compared to BPD-free infants.

Association of 24-Hour In-house Neonatologist Coverage with Outcomes of Extremely Preterm Infants.

OBJECTIVE: This study aimed to assess if 24-hour in-house neonatologist (NN) coverage is associated with delivery room (DR) resuscitation/stabilization and outcomes among inborn infants <29 weeks' gestational age (GA). STUDY DESIGN: Survey-linked cohort study of 2,476 inborn infants of 23 to 28 weeks' gestation, admitted between 2014 and 2015 to Canadian Neonatal Network Level-3 neonatal intensive care units (NICUs) with a maternity unit. Exposures were classified using survey responses based on the most senior provider offering 24-hour in-house coverage: NN, fellow, and no NN/fellow. Primary outcome was death and/or major morbidity (bronchopulmonary dysplasia, severe neurological injury, late-onset sepsis, necrotizing enterocolitis, and retinopathy of prematurity). Multivariable logistic regression analysis was used to assess the association between exposures and outcomes and adjust for confounders. RESULTS: Among the 28 participating NICUs, most senior providers ensuring 24-hour in-house coverage were NN (32%, 9/28), fellows (39%, 11/28), and no NN/fellow (29%, 8/28). No NN/fellow coverage and 24-hour fellow coverage were associated with higher odds of infants receiving DR chest compressions/epinephrine compared with 24-hour NN coverage (adjusted odds ratio [aOR] = 4.72, 95% confidence interval [CI]: 2.12-10.6 and aOR = 3.33, 95% CI: 1.44-7.70, respectively). Rates of mortality/major morbidity did not differ significantly among the three groups: NN, 63% (249/395 infants); fellow, 64% (1092/1700 infants); no NN/fellow, 70% (266/381 infants). CONCLUSION: 24-hour in-house NN coverage was associated with lower rates of DR chest compressions/epinephrine. There was no difference in neonatal outcomes based on type of coverage; however, further studies are needed as ecological fallacy cannot be ruled out. KEY POINTS: · Lower rates of DR cardiopulmonary resuscitation with 24h in-house NN coverage. · The type of 24h in-house coverage was not associated with mortality and/or major morbidity.. · High-volume centers more often have 24h in-house neonatal fellow coverage.

Outcomes of Extremely Premature Infants Comparing Patent Ductus Arteriosus Management Approaches.

OBJECTIVE: To evaluate the change in the proportion of deaths/bronchopulmonary dysplasia (BPD) among premature infants (born <26 and 26-29 weeks of gestational age) following a policy change to a strict nonintervention approach, compared with standard treatment. STUDY DESIGN: We examined 1249 infants (341 born <26 weeks of gestational age) at 2 comparable sites. Site 1 (control) continued medical treatment/ligation, and site 2 (exposed) changed to a nonintervention policy in late 2013. Using the difference-in-differences approach, which accounts for time-invariant differences between sites and secular trends, we assessed changes in death or BPD separately among infants born 26-29 weeks and <26 weeks of gestational age in 2 epochs (epoch 1: 2011-2013; epoch 2: 2014-2017). RESULTS: Baseline characteristics were similar across sites and epochs. Medical treatment/ligation use remained stable at site 1 but declined progressively to 0% at site 2, indicating adherence to policy. We saw no difference in death/BPD among infants born at 26-29 weeks of gestational age (12%, 95% CI -1% to 24%). However, incidence of death/BPD increased by 31% among infants born <26 weeks of gestational age (95% CI 10%-51%) in site 2, whereas there was no change in outcomes in site 1. The Score for Neonatal Acute Physiology-Version II, used as a control outcome, did not change in either site, suggesting that our findings were not due to changes in patients' severity. CONCLUSIONS: Adherence to a strict conservative policy did not impact death or BPD among 26 weeks but was associated with a significant rise in infants born <26 weeks.

Association of Bronchopulmonary Dysplasia and Right Ventricular Systolic Function in Young Adults Born Preterm.

BACKGROUND: Adults born preterm are at a higher risk of cardiopulmonary disease and premature death. Preterm birth is associated with abnormalities in right ventricular (RV) structure and function, but the impact of bronchopulmonary dysplasia (BPD), a common complication of extremely preterm birth, on these parameters remains unknown. RESEARCH QUESTION: Are preterm birth and BPD associated with alterations in RV structure and function in early adulthood? STUDY DESIGN AND METHODS: Echocardiographic and spirometry data were obtained from the Health of Adults Born Preterm Investigation (HAPI). RV structure and performance were evaluated by using echocardiography, and respiratory function was assessed by using spirometry. RESULTS: The study comprised 86 young adults born preterm before 30 weeks of gestation, including 28 with moderate to severe BPD, and 85 adults of the same age born full term. Individuals were assessed at a mean age of 23 years. RV systolic function was altered in the preterm group, with lower tricuspid annular plane systolic excursion and lower RV s' and RV outflow tract velocity time integral values, especially in those born preterm with BPD. Nine (36%) participants born preterm with BPD, six (13%) participants born preterm without BPD, and six (8%) participants born full term had a tricuspid annular plane systolic excursion value < 16 mm, a marker of RV systolic dysfunction (P value for the comparison between preterm no BPD and BPD, .032). No difference was found in RV diastolic function or estimates of pulmonary artery pressure between groups. Although respiratory function was altered in those born preterm, and more so in the case of BPD, no association was observed between spirometry indices of respiratory function and RV systolic function. INTERPRETATION: Preterm birth is associated in adulthood with alterations in RV systolic function, which are more pronounced in the case of BPD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03261609; URL: www.clinicaltrials.gov.

Renal functional markers in extremely premature infants with and without twin-twin transfusion syndrome.

OBJECTIVE: Describe renal function of preterm infants <29 weeks of gestational age (GA) with twin-twin transfusion syndrome (TTTS) who received laser therapy. DESIGN: Retrospective analysis of premature TTTS compared with dichorionic-diamniotic (di-di) twins from 2006 to 2015. Primary outcome was biomarkers of renal injury. RESULTS: Thirty-three TTTS-laser and 101 di-di newborns with similar GA at birth (26.4 ± 1.4 vs 26.9 ± 1.6 weeks, p = 0.07) were included. Creatinine and urea levels were higher in TTTS-laser group at day of life (DOL) 2-7 (123.5 ± 12.4 vs 75.8 ± 2 µmol/L, p = 0.0001 and 11.9 ± 1.1 mmol/L vs 8.7 ± 0.3 mmol/L, p = 0.0001) and DOL 8-14, (98.1 ± 14.2 vs 64.8 ± 2.3 µmol/L, p = 0.0001 and 9.1 ± 1.2 vs 5.4 ± 0.3 mmol/L, p = 0.0001). There was a significant effect of TTTS status on creatinine level at DOL 8-14. CONCLUSION: In extremely preterm with TTTS treated by laser, biomarkers of renal function were higher compared with di-di twins in the first 2 weeks of life.

Early Caffeine Administration and Neurodevelopmental Outcomes in Preterm Infants.

BACKGROUND: Although caffeine use for apnea of prematurity is well studied, the long-term safety and benefit of routine early caffeine administration has not been explored. Our objective was to determine the association between early (within 2 days of birth) versus late caffeine exposure and neurodevelopmental outcomes in preterm infants. METHODS: Infants of <29 weeks' gestation born between April 2009 and September 2011 and admitted to Canadian Neonatal Network units and then assessed at Canadian Neonatal Follow-up Network centers were studied. Neonates who received caffeine were divided into early- (received within 2 days of birth) and late-caffeine (received after 2 days of birth) groups. The primary outcome was significant neurodevelopmental impairment, defined as cerebral palsy, or a Bayley Scales of Infant and Toddler Development, Third Edition composite score of <70 on any component, hearing aid or cochlear implant, or bilateral visual impairment at 18 to 24 months' corrected age. RESULTS: Of 2108 neonates who were eligible, 1545 were in the early-caffeine group and 563 were in the late-caffeine group. Rates of bronchopulmonary dysplasia, patent ductus arteriosus, and severe neurologic injury were lower in the early-caffeine group than in the late-caffeine group. Significant neurodevelopmental impairment (adjusted odds ratio 0.68 [95% confidence interval 0.50-0.94]) and odds of Bayley Scales of Infant and Toddler Development, Third Edition cognitive scores of <85 (adjusted odds ratio 0.67 [95% confidence interval 0.47-0.95]) were lower in the early-caffeine group than in the late-caffeine group. Propensity score-based matched-pair analyses revealed lower odds of cerebral palsy and hearing impairment only. CONCLUSIONS: Early caffeine therapy is associated with better neurodevelopmental outcomes compared with late caffeine therapy in preterm infants born at <29 weeks' gestation.

Outcomes of extremely premature infants with twin-twin transfusion syndrome treated by laser therapy.

OBJECTIVE: To compare short-term and long-term outcomes of preterm infants born at <29 weeks of gestational age (GA) with twin-twin transfusion syndrome (TTTS) treated with laser therapy to preterm twin infants without TTTS. DESIGN: Retrospective case-control study comparing 33 preterm TTTS twins to 101 preterm diamniotic-dichorionic (di-di) twins born at our institution between 2006 and 2015. RESULTS: GA at birth were 26.4 ± 1.4 weeks (TTTS) and 26.9 ± 1.6 weeks (di-di) (p = 0.07). TTTS premature newborns were less exposed to antenatal steroids (p = 0.01), more frequently born by C-section (p = 0.005), received more surfactant therapy (p = 0.004, and were smaller for GA (p < 0.001). When adjusted for antenatal steroids and birth weight, TTTS status was not associated with increased mortality (HR 1.66, 95% CI 0.77-3.56, p = 0.20). No differences were found on neurodevelopmental outcomes at 18 months of corrected GA. CONCLUSION: Premature TTTS newborns treated with fetal laser therapy had similar survival and neurodevelopmental outcomes compared to preterm di-di twins without TTTS.

Correlations between near-infrared spectroscopy, perfusion index, and cardiac outputs in extremely preterm infants in the first 72 h of life.

Haemodynamic assessment during the transitional period in preterm infants is challenging. We aimed to describe the relationships between cerebral regional tissue oxygen saturation (CrSO2), perfusion index (PI), echocardiographic, and clinical parameters in extremely preterm infants in their first 72 h of life. Twenty newborns born at < 28 weeks of gestation were continuously monitored with CrSO2 and preductal PI. Cardiac output was measured at H6, H24, H48, and H72. The median gestational age and birth weight were 25.0 weeks (24-26) and 750 g (655-920), respectively. CrSO2 and preductal PI had r values < 0.35 with blood gases, lactates, haemoglobin, and mean blood pressure. Cardiac output significantly increased over the 72 h of the study period. Fifteen patients had at least one episode of low left and/or right ventricular output (RVO), during which there was a strong correlation between CrSO2 and superior vena cava (SVC) flow (at H6 (r = 0.74) and H24 (r = 0.86)) and between PI and RVO (at H6 (r = 0.68) and H24 (r = 0.92)). Five patients had low SVC flow (≤ 40 mL/kg/min) at H6, during which PI was strongly correlated with RVO (r = 0.98). CONCLUSION: CrSO2 and preductal PI are strongly correlated with cardiac output during low cardiac output states. What is Known: • Perfusion index and near-infrared spectroscopy are non-invasive tools to evaluate haemodynamics in preterm infants. • Pre- and postductal perfusion indexes strongly correlate with left ventricular output in term infants, and near-infrared spectroscopy has been validated to assess cerebral oxygenation in term and preterm infants. What is New: • Cerebral regional tissue oxygen saturation and preductal perfusion index were strongly correlated with cardiac output during low cardiac output states. • The strength of the correlation between cerebral regional tissue oxygen saturation, preductal perfusion index, and cardiac output varied in the first 72 h of life, reflecting the complexity of the transitional physiology.

Adrenal function in preterm infants undergoing patent ductus arteriosus ligation.

BACKGROUND: Targeted milrinone treatment for low left ventricular output (LVO) reduces the incidence of acute cardiorespiratory instability following ligation of patent ductus arteriosus (PDA) in preterm infants. Despite this, some infants continue to experience postoperative deterioration. Adrenal insufficiency related to prematurity has been postulated as a possible mechanism. OBJECTIVES: To describe adrenal function in premature infants undergoing PDA ligation and to investigate its association with pre- and postoperative clinical and echocardiography-derived indices of disease severity. METHODS: A retrospective cohort study was conducted over a 2-year period on infants who underwent PDA ligation and had preoperative adrenocorticotropic hormone (ACTH) stimulation. All infants were screened by echocardiography for low LVO at 1 h after surgery and treated with intravenous milrinone if LVO <200 ml/kg/min. The primary outcome evaluated was low LVO at 1 h after surgery. Secondary outcomes included hypotension and oxygenation and ventilation failure occurring within 24 h. RESULTS: A total of 35 infants at a median gestation of 25.4 (24.5-26.4) weeks and weight at birth of 700 (600-810) g were included. Baseline median cortisol measured preoperatively was 202 (137-403) nmol/l. Following the ACTH stimulation test, 3 infants had cortisol ≤500 nmol/l while 15 had ≤750 nmol/l. There was no association seen between any cortisol value and low LVO postoperatively. Post-ACTH cortisol ≤750 nmol/l was significantly associated with hypotension (p = 0.03) and oxygenation (p = 0.04) and ventilation (p = 0.008) failure. Receiver-operator characteristic curve showed a high predictive value of post-ACTH cortisol for all clinical outcomes. CONCLUSIONS: Post-ACTH cortisol (≤750 nmol/l) may be associated with clinical indices of postoperative cardiorespiratory instability. Relative adrenal insufficiency may play a role in the etiology of post-PDA ligation hemodynamic and respiratory instability.