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.

Safety and Feasibility of Riociguat Therapy for the Treatment of Chronic Pulmonary Arterial Hypertension in Infancy.

The effects of riociguat, an oral-soluble guanylate-cyclase stimulator, were studied in 10 infants with chronic pulmonary arterial hypertension. Respiratory status (n = 8/10), right heart dilation (n = 7/10), function (n = 9/10), and chronic pulmonary arterial hypertension (n = 8/10) improved. Median decrement in systolic (12 [4, 14]), diastolic (14 [7, 20]), and mean arterial (14 [10, 17]) pressures were noted; no critical hypotension or hypoxemia occurred.

Left ventricular function before and after percutaneous patent ductus arteriosus closure in preterm infants.

BACKGROUND: Definitive closure of the patent ductus arteriosus (PDA) is associated with significant changes in the loading conditions of the left ventricle (LV), which may lead to cardiovascular and respiratory instability. The objective of the study was to evaluate targeted neonatal echocardiography (TnECHO) characteristics and the clinical course of preterm infants ≤2 kg undergoing percutaneous PDA closure. METHODS: Retrospective cohort study of prospectively acquired pre- and post-closure TnECHOs to assess hemodynamic changes. Cardiorespiratory parameters in the first 24 h following PDA closure were also evaluated. RESULTS: Fifty patients were included with a mean age of 30.6 ± 9.6 days and weight of 1188 ± 280 g. LV global longitudinal strain decreased from -20.6 ± 2.6 to -14.9 ± 2.9% (p < 0.001) after 1 h. There was a decrease in LV volume loading, left ventricular output, LV systolic and diastolic parameters. Cardiorespiratory instability occurred in 24 (48%) [oxygenation failure in 44%] but systolic hypotension and/or need for cardiovascular medications was only seen in 6 (12%). Patients with instability had worse baseline respiratory severity score and lower post-closure early diastolic strain rates. CONCLUSIONS: Percutaneous PDA closure leads to a reduction in echocardiography markers of LV systolic/diastolic function. Post-closure cardiorespiratory instability is characterized primarily by oxygenation failure and may relate to impaired diastolic performance. IMPACT: Percutaneous patent ductus arteriosus closure leads to a reduction in echocardiography markers of left ventricular volume loading, cardiac output, and left ventricular systolic/diastolic function. Post-procedural cardiorespiratory instability is characterized primarily by oxygenation failure. Post-procedural cardiorespiratory instability may relate to impaired diastolic performance.

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.

Assessment of superior vena cava flow and cardiac output in different patterns of patent ductus arteriosus shunt.

BACKGROUND: Despite the widespread use of superior vena cava (SVC) flow as a marker of systemic blood flow from the upper body, no previous studies have systematically evaluated the correlation between SVC flow and other echocardiography measures of systemic blood flow in the context of different patterns of patent ductus arteriosus (PDA) shunt direction METHODS: A retrospective cohort study of preterm infants (< 30 weeks, < 21 days of life) who underwent comprehensive targeted neonatal echocardiography (TnECHO) was performed. Patients were categorized as follows: (i) Hemodynamically significant left-to-right shunt; (ii): Bidirectional shunt; (iii) No PDA or insignificant shunt. SVC flow, as measured by two distinct methods, was compared to left and right ventricular outputs (LVO and RVO). Intra- and inter-observer reliability testing was performed RESULTS: In total, 45 patients were included (15 in each group) with a median [IQR] weight of 720 [539, 917] grams at the time of assessment. SVC dimensions and flow measurements were not different between the groups, although patients with left-to-right shunt had higher LVO/RVO ratio. SVC flow, as estimated using the modified method, had a strong correlation with LVO (r = .63, p = 0.012) and RVO (r = .635, p = 0.011) in patients with no PDA. Inter- and intra-observer reliability were both stronger for LVO and RVO when compared to SVC flow measurements CONCLUSION: SVC flow was comparable across all three groups irrespective of higher LVO and LVO/RVO ratio in patients with left-to-right shunts. This may reflect poor measurement reliability or compensation for left-to-right ductal shunt by increased LVO to maintain systemic perfusion.

A direct comparison of mouse and human intestinal development using epithelial gene expression patterns.

BACKGROUND: Preterm infants are susceptible to unique pathology due to their immaturity. Mouse models are commonly used to study immature intestinal disease, including necrotizing enterocolitis (NEC). Current NEC models are performed at a variety of ages, but data directly comparing intestinal developmental stage equivalency between mice and humans are lacking. METHODS: Small intestines were harvested from C57BL/6 mice at 3-4 days intervals from birth to P28 (n = 8 at each age). Preterm human small intestine samples representing 17-23 weeks of completed gestation were obtained from the University of Pittsburgh Health Sciences Tissue Bank, and at term gestation during reanastamoses after resection for NEC (n = 4-7 at each age). Quantification of intestinal epithelial cell types and messenger RNA for marker genes were evaluated on both species. RESULTS: Overall, murine and human developmental trends over time are markedly similar. Murine intestine prior to P10 is most similar to human fetal intestine prior to viability. Murine intestine at P14 is most similar to human intestine at 22-23 weeks completed gestation, and P28 murine intestine is most similar to human term intestine. CONCLUSION: Use of C57BL/6J mice to model the human immature intestine is reasonable, but the age of mouse chosen is a critical factor in model development.

Echocardiography Assessment of Left Ventricular Function in Extremely Preterm Infants, Born at Less Than 28 Weeks' Gestation, With Bronchopulmonary Dysplasia and Systemic Hypertension.

BACKGROUND: The survival of smaller and more immature premature infants has been associated with lifelong cardiorespiratory comorbidities. Infants with bronchopulmonary dysplasia (BPD) undergo routine screening echocardiography to evaluate for development of chronic pulmonary hypertension, a late manifestation of pulmonary vascular disease. METHODS: Our aim was to evaluate left ventricular (LV) performance in infants with BPD and pulmonary vascular disease who developed systemic hypertension. We hypothesized that infants with hypertension were more likely to have impaired LV performance. We present a single-center cross-sectional study of premature infants born at less than 28 0/7 weeks' gestational age with a clinical diagnosis of BPD. Infants were categorized by the systolic arterial pressure (SAP) at time of echocardiography as hypertensive (SAP ≥90 mm Hg) or normotensive (SAP <90 mm Hg). Sixty-four patients were included. RESULTS: Infants with hypertension showed altered LV diastolic function with prolonged tissue Doppler imaging-derived isovolumic relaxation time (54.2 ± 5.1 vs 42.9 ± 8.2, P < .001), lower E:A, and higher E:e'. Indices of left heart volume/pressure loading (left atrium:aorta and LV end-diastolic volume [6.1 ± 2 vs 4.2 ± 1.2, P < .001]) were also higher in the hypertensive group. Finally, infants in the hypertensive group had higher pulmonary vascular resistance index (4.42 ± 1.1 vs 3.69 ± 0.8, P = .004). CONCLUSIONS: We conclude that extremely preterm infants with BPD who develop systemic hypertension are at risk of abnormal LV diastolic dysfunction. Increased pulmonary vascular resistance index in the hypertensive group may relate to pulmonary venous hypertension secondary to LV dysfunction. This is an important consideration in this cohort when selecting the physiologically most appropriate treatment.

A Severe Reaction After Phototherapy in a Neonate With X-Linked Protoporphyria.

Protoporphyria is a subtype of porphyria characterized primarily by painful phototoxic skin reactions after light exposure at specific wavelengths. Historically, phototherapy is not contraindicated in patients with protoporphyria since there have not been any reports of phototoxic reactions. However, patients with protoporphyria are advised to avoid direct sunlight. In this case report, we describe a neonate not known to have X-linked protoporphyria who received phototherapy for 1 to 2 hours. Within hours after initiation of phototherapy, this neonate developed a life-threatening reaction consisting of rash over the distribution of phototherapy, acute liver failure with coagulopathy, diffuse hypotonia with diaphragmatic failure, and subsequent acute respiratory failure that required mechanical ventilation. As in this case, patients with protoporphyria-related acute liver failure can have signs and symptoms similar to that of an acute hepatic porphyria attack. Neither neonatal reactions to phototherapy nor liver failure temporally associated with phototherapy have been reported in patients with X-linked protoporphyria. Early recognition of this entity is crucial in light of potential life-threatening complications. Therefore, providers must react quickly when neonates have abnormal reactions to phototherapy and consider protoporphyria in the differential diagnosis.

Neonatal cardiac POCUS-a survey of academic neonatal centers in the United States.

OBJECTIVE: To investigate the current state of clinical practice and training regarding the use of cardiac point of care ultrasound (cPOCUS) in neonatal intensive care units. STUDY DESIGN: An online survey was disseminated through the Association of Academic Directors of Neonatology to appraise clinical usage, infrastructure, and training for cPOCUS. A single response per center was obtained. RESULTS: Overall survey response rate was 51% (48/94). Of respondents [40/48 (83%)] who reported having a POCUS program, 19/40 (47%) reported performing cPOCUS. In 74% of centers, <10 cPOCUS studies are performed monthly. Only 16% (3/19) of centers had standardized imaging protocols. The most common indication for cPOCUS was central line evaluation. Only 9 (19%) programs reported cPOCUS training, of whom 4 had a formalized process of ongoing competency assessment. CONCLUSION: Although use of cPOCUS is increasing, program infrastructure and governance, training, and evaluation vary markedly between institutions and are missing in many. There is an urgent need to develop consensus standards regarding clinical practice and training.

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.

Host defense peptides human ß defensin 2 and LL-37 ameliorate murine necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a leading cause of preterm infant morbidity and mortality. Treatment for NEC is limited and non-targeted, which makes new treatment and prevention strategies critical. Host defense peptides (HDPs) are essential components of the innate immune system and have multifactorial mechanisms in host defense. LL-37 and hBD2 are two HDPs that have been shown in prior literature to protect from neonatal sepsis-induced mortality or adult inflammatory bowel disease, respectively. Therefore, this article sought to understand if these two HDPs could influence NEC severity in murine preclinical models. NEC was induced in P14-16 C57Bl/6 mice and HDPs were provided as a pretreatment or treatment. Both LL-37 and hBD2 resulted in decreased NEC injury scores as a treatment and hBD2 as a pretreatment. Our data suggest LL-37 functions through antimicrobial properties, while hBD2 functions through decreases in inflammation and improvement of intestinal barrier integrity.

Surfactant and neonatal hemodynamics during the postnatal transition.

Surfactant replacement therapy (SRT) has revolutionized the management of respiratory distress syndrome (RDS) in premature infants, leading to improved survival rates and decreased morbidity. SRT may, however, be associated with hemodynamic changes, which can have both positive and negative effects on the immature cardiovascular system, during the transitional adaptation from fetal to extrauterine environment. However, there is a relative paucity of evidence in this domain, with most of them derived from small heterogeneous observational studies providing conflicting results. In this review, we will discuss the hemodynamic changes that occur with surfactant administration during this vulnerable period, focusing on available evidence regarding changes in pulmonary and systemic blood flow, cerebral circulation and their clinical implications.

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.

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.

Hemodynamic consequences of respiratory interventions in preterm infants.

Advances in perinatal management have led to improvements in survival rates for premature infants. It is known that the transitional period soon after birth, and the subsequent weeks, remain periods of rapid circulatory changes. Preterm infants, especially those born at the limits of viability, are susceptible to hemodynamic effects of routine respiratory care practices. In particular, the immature myocardium and cardiovascular system is developmentally vulnerable. Standard of care (but essential) respiratory interventions, administered as part of neonatal care, may negatively impact heart function and/or pulmonary or systemic hemodynamics. The available evidence regarding the hemodynamic impact of these respiratory practices is not well elucidated. Enhanced diagnostic precision and therapeutic judiciousness are warranted. In this narrative, we outline (1) the vulnerability of preterm infants to hemodynamic disturbances (2) the hemodynamic effects of common respiratory practices; including positive pressure ventilation and surfactant therapy, and (3) identify tools to assess cardiopulmonary interactions and guide management.

Short-term ventriculo-arterial coupling and myocardial work efficiency in preterm infants undergoing percutaneous patent ductus arteriosus closure.

Definitive closure of a patent ductus arteriosus (PDA) causes significant changes in loading conditions of the left ventricle (LV) which can lead to cardiorespiratory instability including hypotension, low cardiac output, oxygenation, and ventilation impairment. Physiological insights of the adaptation of the LV can be gained by looking at ventriculo-arterial coupling (VAC) and myocardial work-energetics. We conducted a retrospective cohort study of preterm infants with echocardiographic assessment of VAC parameters, including end-systolic and arterial elastance (EES , EA ), and myocardial work indices derived from longitudinal strain analysis before and 1-h after percutaneous PDA closure. A total of 35 patients were included with mean [±SD] age at intervention of 30.8 ± 9.9 days and median [IQR] weight of 1130 [995, 1318] grams. There was a reduction in preload and stroke volume, an increase in EA (38.6 ± 11.4 vs. 60 ± 15.1 mmHg/ml/kg, p < 0.001) and in EES (72 [61.5, 109.8] vs. 91.6 [72.2, 125.2] mmHg/ml/kg, p = 0.003) post-closure. Myocardial work indices reduced after PDA closure, including global work efficiency (93.9 ± 2.3 vs. 91.1 ± 3.6%, p < 0.001). A total of 17 (48.6%) patients developed post-closure instability which was associated with younger age, lower preload, and higher EA and EES . Percutaneous PDA closure is associated with major short-term changes in VAC and myocardium energetics, which may provide novel insights on the physiology of PDA closure and on the differential vulnerability to changes in loading conditions.

Safety, Feasibility, and Impact of Enalapril on Cardiorespiratory Physiology and Health in Preterm Infants with Systemic Hypertension and Left Ventricular Diastolic Dysfunction.

Neonatal hypertension has been increasingly recognized in premature infants with bronchopulmonary dysplasia (BPD); of note, a sub-population of these infants may have impaired left ventricular (LV) diastolic function, warranting timely treatment to minimize long term repercussions. In this case series, enalapril, an angiotensin-converting enzyme (ACE) inhibitor, was started in neonates with systemic hypertension and echocardiography signs of LV diastolic dysfunction. A total of 11 patients were included with birth weight of 785 ± 239 grams and gestational age of 25.3 (24, 26.1) weeks. Blood pressure improvement was noticed within 2 weeks of treatment. Improvement in LV diastolic function indices were observed with a reduction in Isovolumic Relaxation Time (IVRT) from 63.1 ± 7.2 to 50.9 ± 7.4 msec and improvement in the left atrium size indexed to aorta (LA:Ao) from1.73 (1.43, 1.88) to 1.23 (1.07, 1.29). Neonatal systemic hypertension is often underappreciated in ex-preterm infants and may be associated with important maladaptive cardiac changes with long term implications. It is biologically plausible that identifying and treating LV diastolic dysfunction in neonates with systemic hypertension may have a positive modulator effect on cardiovascular health in childhood and beyond.