Fetal sex and the relative reactivity of human umbilical vein and arteries are key determinants in potential beneficial effects of phosphodiesterase inhibitors.

Intrauterine growth restriction (IUGR) is a common complication of pregnancy. We previously demonstrated that IUGR is associated with an impaired nitric oxide (NO)-induced relaxation in the human umbilical vein (HUV) of growth-restricted females compared to appropriate for gestational age (AGA) newborns. We found that phosphodiesterase (PDE) inhibition improved NO-induced relaxation in HUV, suggesting that PDEs could represent promising targets for therapeutic intervention. This study aimed to investigate the effects of PDE inhibition on human umbilical arteries (HUAs) compared to HUV. Umbilical vessels were collected in IUGR and AGA term newborns. NO-induced relaxation was studied using isolated vessel tension experiments, in the presence or absence of the non-specific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX). PDE1B, PDE1C, PDE3A, PDE4B and PDE5A were investigated by Western blot. NO-induced vasodilation was similar between IUGR and AGA HUAs. In HUAs precontracted with serotonin, IBMX enhanced NO-induced relaxation only in IUGR females, whereas in HUV IBMX increased NO-induced relaxation in all groups except IUGR males. In umbilical vessels pre-constricted with the thromboxane A2 analog U46619, IBMX improved NO-induced relaxation in all groups, in a greater extent in HUV than HUAs. However, the PDEs protein content was higher in HUAs than HUV, in all study groups. Therefore, the effects of PDE inhibition depend on the presence of IUGR, fetal sex, vessel type and vasoconstrictors implicated. Despite a higher PDEs protein content, HUAs are less sensitive to IBMX than HUV, which could lead to adverse effects of PDE inhibition in vivo, by impairment of the fetoplacental hemodynamics.

Shape of Pulmonary Artery Doppler Flow Profile and Right Ventricular Hemodynamics in Neonates.

OBJECTIVES: To characterize pulmonary artery Doppler flow profile (PAFP) patterns among infants receiving care in neonatal intensive care units and to examine the association of PAFP patterns with pulmonary and right ventricular (RV) hemodynamics. STUDY DESIGN: This is a retrospective study at 2 tertiary intensive care units over 4 years that included neonates who demonstrated a complete tricuspid regurgitation envelope on targeted neonatal echocardiography. Separate personnel reviewed TNEs to characterize PAFP patterns, divide cohort into PAFP groups, and measure quantitative indices of RV hemodynamics (RV systolic pressure, pulmonary artery acceleration time and its ratio with RV ejection time, tricuspid annular plane systolic excursion, and RV output), for intergroup comparisons. RESULTS: We evaluated TNEs from 186 neonates with median gestational age of 28.5 weeks (IQR, 25.9-35.9 weeks). Four distinct PAFP patterns were identified (A) near-isosceles triangle (22%), (B) right-angled triangle (29%), (C) notching (40%), and (D) low peak velocity (<0.4 m/s; 9%). Groups A-C demonstrated a stepwise worsening in all indices of PH, whereas pattern D was associated with lower tricuspid annular plane systolic excursion and RV output. Using common definitions of pulmonary hypertension (PH), pattern A performed best to rule out PH (sensitivity range, 81%-90%) and pattern C for diagnosing PH (specificity range, 63%-78%). CONCLUSIONS: Inspection of PAFP is a simple bedside echocardiography measure that provides clinically meaningful information on underlying RV hemodynamics and may aid in screening and monitoring of patients for PH in intensive care units.

Cardiopulmonary physiological effects of diuretic therapy in preterm infants with chronic pulmonary hypertension.

OBJECTIVE: Using targeted neonatal echocardiography (TNE) to examine cardiopulmonary physiological impact of diuretics in preterm infants with chronic pulmonary hypertension (cPH). STUDY DESIGN: Retrospective study comparing TNE indices pre- and ≤2 weeks (post) of initiating diuretic therapy in infants born <32 weeks gestational age with cPH. RESULTS: Twenty-seven neonates with mean gestational age, birthweight and interval between pre-post diuretic TNE of 27.0 ± 2.8 weeks, 859 ± 294 grams, and 7.8 ± 3.0 days respectively were studied. Diuretics was associated with improvement in pulmonary vascular resistance [pulmonary artery acceleration time (PAAT); 34.27(9.76) vs. 40.24(11.10)ms, p = 0.01), right ventricular (RV) ejection time:PAAT ratio [5.92(1.66) vs. 4.83(1.14), p < 0.01)], RV fractional area change [41.6(9.8) vs. 46.4(6.5%), p = 0.03)] and left ventricular myocardial performance index [0.55(0.09) vs. 0.41(0.23), p < 0.01)]. Post-treatment, frequency of bidirectional/right-to-left inter-atrial shunts decreased significantly (24% vs. 4%, p = 0.05). CONCLUSION: Primary diuretic treatment in neonates with cPH may result in improvement in PVR, RV and LV function and compliance.

Dopamine or norepinephrine for sepsis-related hypotension in preterm infants: a retrospective cohort study.

The purpose of this study is to compare the clinical effectiveness of dopamine (DA) versus norepinephrine (NE) as first-line therapy for sepsis-related hypotension in preterm infants. This is a retrospective cohort study over 10 years at two tertiary neonatal units. Preterm infants born < 35 weeks post-menstrual age (PMA), who received DA or NE as primary therapy for hypotension during sepsis, defined as culture-positive or culture-negative infections or necrotizing enterocolitis (NEC), were included. Episode-related mortality (< 7 days from treatment), pre-discharge mortality, and major morbidities among survivors were compared between two groups. Analyses were adjusted using the inverse probability of treatment weighting estimated by propensity score (PS). A total of 156 infants were included, 113 received DA and 43 NE. The mean ± SD PMA at birth and at treatment for the DA and NE groups were 25.8 ± 2.3 vs. 25.2 ± 2.0 weeks and 27.7 ± 3.0 vs. 27.1 ± 2.6 weeks, respectively (p > 0.05). Pre-treatment, the NE group had higher mean airway pressure (14 ± 4 vs. 12 ± 4 cmH2O), heart rate (185 ± 17 vs. 175 ± 17 beats per minute), and median (IQR) fraction of inspired oxygen [0.67 (0.42, 1.0) vs. 0.52 (0.32, 0.82)] (p < 0.05 for all). After PS adjustment, NE was associated with lower episode-related mortality [adjusted odds ratio (95% CI) 0.55 (0.33, 0.92)], pre-discharge mortality [0.60 (0.37, 0.97)], post-illness new diagnosis of significant neurologic injury [0.32 (0.13, 0.82)], and subsequent occurrence of NEC/sepsis among the survivors [0.34, (0.18, 0.65)]. CONCLUSION: NE may be more effective than DA for management of sepsis-related hypotension among preterm infants. These data provide a rationale for prospective evaluation of these commonly used agents. WHAT IS KNOWN: •Dopamine is the commonest vasoactive agent used to support blood pressure among preterm infants. •For adult patients, norepinephrine is recommended as the preferred therapy over dopamine for septic shock. WHAT IS NEW: •This is the first study examining the relative clinical effectiveness of dopamine and norepinephrine as first-line pharmacotherapy for sepsis-related hypotension among preterm infants. •Norepinephrine use may be associated with lower mortality and morbidity than dopamine in preterm infants with sepsis.

Validity of the vasoactive-inotropic score in preterm neonates receiving cardioactive therapies.

BACKGROUND: Vasoactive-Inotropic Score (VIS) is a weighted sum of various vasopressors and inotropes; its utility among preterm neonates is understudied. OBJECTIVE: To investigate the association between maximum VIS (VISmax) during the first 12, 24 and 48 h of treatment among preterm neonates who received vasopressors/inotropes, and the composite outcome of death/severe neuroinjury (sNI). METHODS: Retrospective cohort study, over 6-years, including neonates <35 weeks gestational age (GA). Infants who met the primary composite outcome of death or sNI (defined as new intraventricular hemorrhage ≥grade 3 or periventricular leukomalacia) were compared to those who survived without sNI. Maximum VIS was categorized as <10, 10-19 or ≥ 20 for comparison. RESULTS: 192 infants (mean GA and birth weight 26.8 ± 3.3 weeks and 952 ± 528 g, respectively) were included. The most common primary diagnosis was sepsis/necrotizing enterocolitis (69 %). Median VIS for the entire cohort was 10. Death/sNI was associated with lower GA at birth and treatment, as well as higher frequency of VISmax of 10-19 or ≥20, compared to <10, during each time period (all p < 0.01). Multivariable regression revealed GA at treatment and VISmax ≥ 20 [not 10-19, referenced to <10] were associated death/sNI; adjusted odds ratio (95 % CI) for VISmax ≥ 20 within 12, 24, and 48 h were 4.2 (1.6-11.0), 4.9 (1.9-12.3), and 6.7 (2.7-16.7), respectively. CONCLUSIONS: Vasoactive-Inotropic Score may be a valid measure to quantify cardiovascular support in preterm infants needing hemodynamic support. Maximum VIS ≥20 within 48 h of treatment initiation may identify patients at high risk of adverse outcomes.

Multicentre prospective observational study exploring the predictive value of functional echocardiographic indices for early identification of preterm neonates at risk of developing chronic pulmonary hypertension secondary to chronic neonatal lung disease.

INTRODUCTION: Although chronic pulmonary hypertension (cPH) secondary to chronic neonatal lung disease is associated with increased mortality and respiratory and neurodevelopmental morbidities, late diagnosis (typically ≥36 weeks postmenstrual age, PMA) and the use of qualitative echocardiographic diagnostic criterion (flat interventricular septum in systole) remain significant limitations in clinical care. Our objective in this study is to evaluate the utility of relevant quantitative echocardiographic indices to identify cPH in preterm neonates, early in postnatal course and to develop a diagnostic test based on the best combination of markers. METHODS AND ANALYSIS: In this ongoing international prospective multicentre observational diagnostic accuracy study, we aim to recruit 350 neonates born <27 weeks PMA and/or birth weight <1000 g and perform echocardiograms in the third week of age and at 32 weeks PMA (early diagnostic assessments, EDA) in addition to the standard diagnostic assessment (SDA) for cPH at 36 weeks PMA. Predefined echocardiographic markers under investigation will be measured at each EDA and examined to create a scoring system to identify neonates who subsequently meet the primary outcome of cPH/death at SDA. Diagnostic test characteristics will be defined for each EDA. Pulmonary artery acceleration time and tricuspid annular plane systolic excursion are the primary markers of interest. ETHICS AND DISSEMINATION: Ethics approval has been received by the Mount Sinai Hospital Research Ethics Board (REB) (#16-0111-E), Sunnybrook Health Sciences Centre REB (#228-2016), NHS Health Research Authority (IRAS 266498), University of Iowa Human Subjects Office/Institutional Review Board (201903736), Rotunda Hospital Research and Ethics Committee (REC-2019-008), and UBC Children's and Women's REB (H19-02738), and is under review at Boston Children's Hospital Institutional Review Board. Study results will be disseminated to participating families in lay format, presented to the scientific community at paediatric and critical care conferences and published in relevant peer-reviewed journals. TRAIL REGISTRATION NUMBER: NCT04402645.

Intrauterine growth restriction is associated with sex-specific alterations in the nitric oxide/cyclic GMP relaxing pathway in the human umbilical vein.

INTRODUCTION: Intrauterine growth restriction (IUGR) is a leading cause of perinatal mortality and morbidity, and is linked to an increased risk to develop chronic diseases in adulthood. We previously demonstrated that IUGR is associated, in female neonates, with a decreased nitric oxide (NO)-induced relaxation of the umbilical vein (UV). The present study aimed to investigate the contribution of the smooth muscle components of the NO/cyclic GMP (cGMP) pathway to this alteration. METHODS: UVs were collected in growth-restricted or appropriate for gestational age (AGA) human term newborns. Soluble guanylyl cyclase (sGC) and cGMP-dependent protein kinase (PKG) were studied by Western blot, cGMP production by ELISA and cyclic nucleotide phosphodiesterases (PDEs) activity using a colorimetric assay. Contribution of PDEs was evaluated using the non-specific PDEs inhibitor 3-isobutyl-1-methylxanthine (IBMX) in isolated vessel tension studies. RESULTS: NO-induced relaxation was reduced in IUGR females despite increased sGC protein and activity, and some increase in PKG protein compared to AGA. In males, no significant difference was observed between both groups. In the presence of IBMX, NO-stimulated cGMP production was significantly higher in IUGR than AGA females. Pre-incubation with IBMX significantly improved NO-induced relaxation in all groups and abolished the difference between IUGR and AGA females. CONCLUSION: IUGR is associated with sex-specific alterations in the UV's smooth muscle. The impaired NO-induced relaxation observed in growth-restricted females is linked to an imbalance in the NO/cGMP pathway. The beneficial effects of IBMX suggest that PDEs are implicated in such alteration and they could represent promising targets for therapeutic intervention.

Invasive pneumococcal infection despite 7-valent conjugated vaccine.

Despite good cover with 7-valent vaccination, invasive pneumococcal infections may still be misdiagnosed and may lead to lifethreatening situations or death in young children. New serotypes are emerging and, therefore, clinicians must keep a high level of suspicion in young children regardless of their vaccination status. We report three cases of invasive pneumococcal infection due to new serotypes not covered by the 7-valent conjugated vaccine, two of which led children to death.