Early respiratory system reactance predicts respiratory outcomes in preterm infants: a retrospective, multicentre study.

OBJECTIVE: This multicenter, international, retrospective study aims to investigate whether respiratory system reactance (Xrs) assessed by respiratory oscillometry on the 7th day of life is associated with respiratory outcomes in preterm infants below 32 weeks' gestation. METHODS: Sinusoidal pressure oscillations (2-5 cmH2O peak-to-peak, 10 Hz) were superimposed on the positive end-expiratory pressure (PEEP). We assessed the association of Xrs z-score with the duration of respiratory support using linear regression and with bronchopulmonary dysplasia (BPD, according to Jensen et al. 2019) using logistic regression. We used the likelihood ratio test to evaluate whether Xrs z-score adds significantly to clinical predictors, including gestational age (GA), birth weight (BW) and the National Institute of Child Health and Human Development (NICHD) BPD prediction model. RESULTS: One hundred and thirty-seven infants (median (Q1, Q3) GA=28.43 (26.11, 30.29) weeks) were included; 44 (32%) developed BPD. Xrs z-score was significantly associated with the duration of respiratory support (R2=0.35). Xrs z-score was significantly higher in infants who developed BPD (p<0.001); the optimal cut-off value was 2.6, associated with 77% sensitivity and 80% specificity. In univariable analysis, per z-score increase in Xrs, the OR for BPD increased by 60% and the respiratory support by eight days. In multivariable analysis, Xrs z-score added significantly to the NICHD model and to GA and BW z-score to predict respiratory support duration (p=0.016 and p=0.014, respectively) and BPD development (p=0.003 and p<0.001, respectively). CONCLUSION: Xrs z-score on the 7th day after birth improves the prediction of respiratory outcome in preterm infants.

Collagen type IV alpha 1 chain (COL4A1) expression in the developing human lung.

BACKGROUND: Collagen type IV alpha 1 chain (COL4A1) in the basement membrane is an important component during lung development, as suggested from animal models where COL4A1 has been shown to regulate alveolarization and angiogenesis. Less is known about its role in human lung development. Our aim was to study COL4A1 expression in preterm infants with different lung maturational and clinical features. METHODS: COL4A1 expression in 115 lung samples from newborn infants (21-41 weeks' gestational age; 0-228 days' postnatal age [PNA]) was studied by immunohistochemistry combined with digital image analysis. Cluster analysis was performed to find subgroups according to immunohistologic and clinical data. RESULTS: Patients were automatically categorized into 4 Groups depending on their COL4A1 expression. Expression of COL4A1 was mainly extracellular in Group 1, low in Group 2, intracellular in Group 3, and both extra- and intracellular in Group 4. Intracellular/extracellular ratio of COL4A1 expression related to PNA showed a distinctive postnatal maturational pattern on days 1-7, where intracellular expression of COL4A1 was overrepresented in extremely preterm infants. CONCLUSIONS: COL4A1 expression seems to be highly dynamic during the postnatal life due to a possible rapid remodeling of the basement membrane. Intracellular accumulation of COL4A1 in the lungs of extremely premature infants occurs more frequently between 1 and 7 postnatal days than during the first 24 hours. In view of the lung arrest described in extremely preterm infants, the pathological and/or developmental role of postnatally increased intracellular COL4A1 as marker for basement membrane turnover, needs to be further investigated.

Reduced Expression of REG4 as a Sign of Altered Goblet Cell Function in Necrotizing Enterocolitis.

OBJECTIVE: Defective Goblet cells have been proposed to be involved in necrotizing enterocolitis (NEC). The aim was to study the expression of the Goblet cell marker REG4 and its potential involvement in NEC in preterm infants with and without NEC. STUDY DESIGN: Seventy histologically intact intestinal biopsies were studied: 43 were collected during surgery due to NEC (NEC group: 26.5 ± 3.0 weeks' gestational age [wGA]), and 27 from individuals who underwent surgery due to other conditions (Control group; 36.1 ± 4.5 wGA). The tissue samples were immunohistochemically stained for REG4. REG4 expression was quantified with a semiautomated digital image analysis and with clinical data compared between the groups. RESULTS: REG4 expression was lower in the NEC group than in the Control group (p = 0.035). Low REG4 expression correlated to the risk of NEC (p = 0.023). In a multivariable logistic regression analysis including GA and REG4 expression for NEC risk, only GA (p < 0.001) and not REG4 expression (p = 0.206) was associated with NEC risk. CONCLUSION: This study concludes that Goblet cell dysfunction may be involved in NEC development, as low expression of the Goblet cell marker REG4 was related to an increased NEC risk in preterm infants. Maturity could however not be excluded as a potential confounder for REG4 expression. KEY POINTS: · REG4 is a specific Goblet cell marker not yet studied in NEC.. · REG4 was quantified in intestinal biopsies from infants with and without NEC.. · REG4 expression was lower in infants with NEC, and expression seems to be maturity dependent..

Paneth cell proteins DEFA6 and GUCA2A as tissue markers in necrotizing enterocolitis.

Previous studies suggest that Paneth cells are involved in NEC development. Defensin alpha 6 (DEFA6) and guanylate cyclase activator 2A (GUCA2A) are selective protein markers of Paneth cells. The objective was to explore DEFA6 and GUCA2A expression in intestinal tissue samples from newborn infants with and without NEC. Tissue samples from histologically intact intestine were analyzed from 70 infants: 43 underwent bowel resection due to NEC and 27 controls were operated due to conditions such as intestinal atresia, dysmotility, aganglionosis, pseudo-obstruction or volvulus. Each tissue sample was immunohistochemically stained for DEFA6 and GUCA2A. Semi-automated digital image analysis was performed to determine protein expression. Clinical data and protein expressions were compared between the groups. DEFA6 expression was lower in the NEC group (p = 0.006). Low DEFA6 correlated with risk of developing NEC in a logistic regression analysis, independently of gestational age and birth weight (OR 0.843 [CI 0.732-0.971]; p = 0.018). GUCA2A expression did not differ between the two groups. CONCLUSION: Lower expression of DEFA6 together with intact GUCA2A expression indicates that NEC patients have well-defined Paneth cells but diminished defensin activity. Our results suggest that DEFA6 could be used as a biomarker for NEC. WHAT IS KNOWN: • Previous studies of defensin activity in NEC have been inconsistent, showing that defensin levels may be increased or diminished in NEC. GUCA2A has to our knowledge never been studied in NEC. WHAT IS NEW: • This study benchmarks two specific Paneth cell markers (DEFA6 and GUCA2A) and their activity in individuals with and without NEC. • The key finding is that the NEC group had a lower DEFA6 expression compared to the Controls, while the expression of GUCA2A did not differ between the groups.

Ventilatory Strategies in Infants with Established Severe Bronchopulmonary Dysplasia: A Multicenter Point Prevalence Study.

We performed a point prevalence study on infants with severe bronchopulmonary dysplasia (BPD), collecting data on type and settings of ventilatory support; 187 infants, 51% of whom were on invasive positive-pressure ventilation (IPPV), from 15 centers were included. We found a significant center-specific variation in ventilator modes.

Approaches to Interdisciplinary Care for Infants with Severe Bronchopulmonary Dysplasia: A Survey of the Bronchopulmonary Dysplasia Collaborative.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) remains the most common late morbidity for extremely premature infants. Care of infants with BPD requires a longitudinal approach from the neonatal intensive care unit to ambulatory care though interdisciplinary programs. Current approaches for the development of optimal programs vary among centers. STUDY DESIGN: We conducted a survey of 18 academic centers that are members of the BPD Collaborative, a consortium of institutions with an established interdisciplinary BPD program. We aimed to characterize the approach, composition, and current practices of the interdisciplinary teams in inpatient and outpatient domains. RESULTS: Variations exist among centers, including composition of the interdisciplinary team, whether the team is the primary or consult service, timing of the first team assessment of the patient, frequency and nature of rounds during the hospitalization, and the timing of ambulatory visits postdischarge. CONCLUSION: Further studies to assess long-term outcomes are needed to optimize interdisciplinary care of infants with severe BPD. KEY POINTS: · Care of infants with BPD requires a longitudinal approach from the NICU to ambulatory care.. · Benefits of interdisciplinary care for children have been observed in other chronic conditions.. · Current approaches for the development of optimal interdisciplinary BPD programs vary among centers..

CD44 and RHAMM expression patterns in the human developing lung.

BACKGROUND: The hyaluronan (HA) receptors CD44 and RHAMM (CD168) are involved in cellular proliferation, differentiation, and motility. As previously investigated, HA and RHAMM expression in human neonatal lungs correlates to gestational age (GA) and air content. METHODS: CD44 immunofluorescence was analyzed in postmortem lung samples from infants (n = 93; 22-41 GA) by digital image analysis together with clinical data, including RHAMM expression, lung air, and HA content by hierarchical clustering. RESULTS: Five groups were defined according to RHAMM/CD44 expression, GA, and postnatal age (PNA): extremely to very preterm (EVP; 22-31 GA; Groups 1-2), moderately preterm to term (MPT; 31-41 GA; Groups 3-4), and mixed preterm to term (27-40 GA; Group 5). CD44 correlated linearly with RHAMM in MPT (r = 0.600; p < 0.004). In EVP, high CD44 and low RHAMM corresponded with high PNA and lung air content independently of HA and GA (Group 1 vs 2; p < 0.05). In MPT, high and low CD44 corresponded with low and high RHAMM independently of GA, HA, and lung air content (Group 3 vs 4; p < 0.001). No correlation between CD44 and GA/PNA at death was observed. CONCLUSIONS: A linear correlation between CD44 and RHAMM expression occurs during the late saccular phase of lung development at birth, whereas postnatal influences on CD44 and RHAMM expression in extremely to very preterm infants cannot be excluded. IMPACT: The interplay between CD44 and RHAMM, two receptors of hyaluronic acid, can be dependent on the lung developmental stage at birth. This is the second study that analyzes the distribution pattern of CD44 in the human lung during development and the first study performed with quantitative analysis of CD44 expression together with RHAMM expression in the human lung. Our results suggest a relationship in a subset of infants between CD44 and RHAMM expression, which appears at birth during the late saccular stage but not during the earlier stages of lung development.

Established severe BPD: is there a way out? Change of ventilatory paradigms.

Improved survival of extremely preterm newborn infants has increased the number of infants at risk for developing bronchopulmonary dysplasia (BPD). Despite efforts to prevent BPD, many of these infants still develop severe BPD (sBPD) and require long-term invasive mechanical ventilation. The focus of research and clinical management has been on the prevention of BPD, which has had only modest success. On the other hand, research on the management of the established sBPD patient has received minimal attention even though this condition poses large economic and health problems with extensive morbidities and late mortality. Patients with sBPD, however, have been shown to respond to treatments focused not only on ventilatory strategies but also on multidisciplinary approaches where neurodevelopmental support, growth promoting strategies, and aggressive treatment of pulmonary hypertension improve their long-term outcomes. In this review we will try to present a physiology-based ventilatory strategy for established sBPD, emphasizing a possible paradigm shift from acute efforts to wean infants at all costs to a more chronic approach of stabilizing the infant. This chronic approach, herein referred to as chronic phase ventilation, aims at allowing active patient engagement, reducing air trapping, and improving ventilation-perfusion matching, while providing sufficient support to optimize late outcomes. IMPACT: Based on pathophysiological aspects of evolving and established severe BPD in premature infants, this review presents some lung mechanical properties of the most severe phenotype and proposes a chronic phase ventilatory strategy that aims at reducing air trapping, improving ventilation-perfusion matching and optimizing late outcomes.

Modes and strategies for providing conventional mechanical ventilation in neonates.

Neonatal respiratory failure is a common and serious clinical problem which in a considerable proportion of infants requires invasive mechanical ventilation. The basic goal of mechanical ventilation is to restore lung function while limiting ventilator-induced lung injury, which is considered an important risk factor in the development of bronchopulmonary dysplasia (BPD). Over the last decades, new conventional mechanical ventilation (CMV) modalities have been introduced in clinical practice, aiming to assist clinicians in providing lung protective ventilation strategies. These modalities use more sophisticated techniques to improve patient-ventilator interaction and transfer control of ventilation from the operator to the patient. Knowledge on how these new modalities work and how they interact with lung physiology is essential for optimal and safe use. In this review, we will discuss some important basic lung physiological aspects for applying CMV, the basic principles of the old and new CMV modalities, and the evidence to support their use in daily clinical practice.

Multicenter Experience with Neurally Adjusted Ventilatory Assist in Infants with Severe Bronchopulmonary Dysplasia.

OBJECTIVE: The aim of this study is to determine patterns of neurally adjusted ventilatory assist (NAVA) use in ventilator-dependent preterm infants with evolving or established severe bronchopulmonary dysplasia (sBPD) among centers of the BPD Collaborative, including indications for its initiation, discontinuation, and outcomes. STUDY DESIGN: Retrospective review of infants with developing or established sBPD who were placed on NAVA after ≥4 weeks of mechanical ventilation and were ≥ 30 weeks of postmenstrual age (PMA). RESULTS: Among the 13 sites of the BPD collaborative, only four centers (31%) used NAVA in the management of infants with evolving or established BPD. A total of 112 patients met inclusion criteria from these four centers. PMA, weight at the start of NAVA and median number of days on NAVA, were different among the four centers. The impact of NAVA therapy was assessed as being successful in 67% of infants, as defined by the ability to achieve respiratory stability at a lower level of ventilator support, including extubation to noninvasive positive pressure ventilation or support with a home ventilator. In total 87% (range: 78-100%) of patients survived until discharge. CONCLUSION: We conclude that NAVA can be used safely and effectively in selective infants with sBPD. Indications and current strategies for the application of NAVA in infants with evolving or established BPD, however, are highly variable between centers. Although this pilot study suggests that NAVA may be successfully used for the management of infants with BPD, sufficient experience and well-designed clinical studies are needed to establish standards of care for defining the role of NAVA in the care of infants with sBPD.

Physiological Stability in Very Preterm Infants During Skin-to-Skin Contact as Assessed by Near-Infrared Spectroscopy.

BACKGROUND: Skin-to-skin contact (SSC) has been demonstrated to allow adequate thermal stability in high-technology settings with extremely preterm infants, while other aspects on how SSC influences basic physiological parameters have been less extensively investigated. PURPOSE: To evaluate physiological stability during SSC and incubator care in a group of preterm infants born at a gestational age (GA) of 32 weeks or less and receiving respiratory support. METHODS: Descriptive, observational study including 10 preterm infants (GA 22-32 weeks, postnatal age 2-48 days) were evaluated during SSC compared with flanking time periods in the incubator. Cerebral and systemic regional oxygen saturation (rSaO2), pulse oximetry (SpO2), heart rate (HR), and body temperature were recorded, and the fractional tissue oxygen extraction (fTOE) was calculated. RESULTS: A total of 16 periods of SSC (mean duration 3 hours 30 minutes) were evaluated, 9 during nasal continuous positive airway pressure and 7 during mechanical ventilation. Cerebral rSaO2 was 68% ± 4% (SE) and 69% ± 4% during incubator care and SSC, respectively (P = .56). Somatic rSao2 was 64% ± 4% during incubator care and 66% ± 4% during SSC (P = .54). Also, fTOE, HR, and SpO2 was similar during the 2 modes of care. Body temperature increased during SSC (P < .01). IMPLICATIONS FOR PRACTICE: The present study reveals no differences in cerebral and somatic tissue oxygenation between periods of SSC and care in the incubator. The findings indicate that SSC supports physiological stability also during management of very preterm infants receiving respiratory support. IMPLICATIONS FOR RESEARCH: Further studies directed to further optimize SSC performance should enable its safe implementation at gradually lower gestational and postnatal ages.

Oscillatory respiratory mechanics on the first day of life improves prediction of respiratory outcomes in extremely preterm newborns.

BACKGROUND: We aimed to evaluate if lung mechanics measured by forced oscillatory technique (FOT) during the first day of life help identify extremely low gestational age newborns (ELGANs) at risk of prolonged mechanical ventilation (MV) and oxygen dependency. METHODS: Positive end-expiratory pressure (PEEP) was increased 2 cmH2O above the clinically set PEEP, then decreased by four 5-min steps of 1 cmH2O, and restored at the clinical value. At each PEEP, FOT measurements were performed bedside during MV. Changes in respiratory mechanics with PEEP, clinical parameters, and chest radiographs were evaluated. RESULTS: Twenty-two newborns (24+4 ± 1+4 wks gestational age (GA); birth weight 653 ± 166 g) on assist/control ventilation were studied. Infants were ventilated for 40 ± 36 d (range 1-155 d), 11 developed severe bronchopulmonary dysplasia (BPD) and one died before 28 d. Early lung mechanics correlated with days on MV, days of respiratory support, and BPD grade. Effects of increasing PEEP on oscillatory reactance assessed by FOT together with GA and radiographic score predicted days on MV (multilinear model, r2 = 0.73). A logistic model considering the same FOT parameter together with GA predicts BPD development. CONCLUSIONS: FOT can be applied bedside in ELGANs, where early changes in lung mechanics with PEEP improve clinical prediction of respiratory outcomes.

Exploration of potential biochemical markers for persistence of patent ductus arteriosus in preterm infants at 22-27 weeks' gestation.

BACKGROUND: Early identification of infants at risk for complications from patent ductus arteriosus (PDA) may improve treatment outcomes. The aim of this study was to identify biochemical markers associated with persistence of PDA, and with failure of pharmacological treatment for PDA, in extremely preterm infants. METHODS: Infants born at 22-27 weeks' gestation were included in this prospective study. Blood samples were collected on the second day of life. Fourteen biochemical markers associated with factors that may affect PDA closure were analyzed and related to persistent PDA and to the response of pharmacological treatment with ibuprofen. RESULTS: High levels of B-type natriuretic peptide, interleukin-6, -8, -10, and -12, growth differentiation factor 15 and monocyte chemotactic protein 1 were associated with persistent PDA, as were low levels of platelet-derived growth factor. High levels of erythropoietin were associated with both persistent PDA and failure to close PDA within 24 h of the last dose of ibuprofen. CONCLUSIONS: High levels of inflammatory markers were associated with the persistence of PDA. High levels of erythropoietin were associated with both the persistence of PDA and failure to respond to pharmacological treatment.

Early haemodynamically significant patent ductus arteriosus does not predict future persistence in extremely preterm infants.

AIM: We assessed whether early haemodynamically significant patent ductus arteriosus (hsPDA) predicted persistent patent ductus arteriosus (PDA) in extremely preterm infants. METHODS: This prospective observational study of 60 infants born at 22-27 weeks of gestational age (GA) without any major congenital anomalies or heart defects was conducted at Uppsala University Children's Hospital from November 2012 to May 2015. Respiratory and systemic circulatory parameters were continuously recorded, and echocardiographic examinations performed daily during the first three days of life. Pharmacological treatment was initiated if hsPDA was found on days two to seven. Persistent PDA was diagnosed if hsPDA remained after pharmacological treatment or pharmacological treatment was contraindicated. RESULTS: The infants (56% male) had a median GA of 25 + 2 weeks and 50% received pharmacological treatment. PDA was persistent in 30% and ultimately closed or insignificant in 70%. hsPDA on days two to seven was not associated with future persistent PDA (p = 1.000). Mechanical ventilation (p = 0.025), high mean airway pressure (p = 0.020) and low ductal maximal flow velocity (Vmax ) (p = 0.024) on day two were associated with future persistent PDA. CONCLUSION: Early hsPDA did not predict persistent PDA, but the early need for assisted ventilation and low ductal Vmax were associated with future persistent PDA in these extremely preterm infants.

Critically ill neonates displayed stable vital parameters and reduced metabolic acidosis during neonatal emergency airborne transport in Sweden.

AIM: This study evaluated the medical quality of acute airborne transports carried out by a neonatal emergency transport service in a Swedish healthcare region from 2012 to 2015. METHODS: The transport charts and patient records of all infants transported to the regional centre were reviewed for transport indications and vital parameters and outcomes. RESULTS: We identified 187 acute airborne transports and the main indications for referral were therapeutic hypothermia after perinatal asphyxia, extremely preterm birth and respiratory failure. There were 37 deaths, but none of these occurred during transport and none of the deaths that occurred within 24 hours after transport were found to be related to the transport per se. No differences were found in vital parameters or ventilator settings before and after transport, except for an improvement in blood pH (7.22 ± 0.13 versus 7.27 ± 0.13, mean ± SD, p < 0.01), due to a decrease in base deficit (-8.0 ± 6.8 versus -5.4 ± 6.3 mmol, p < 0.001), while the partial pressure of carbon dioxide remained unchanged. CONCLUSION: During air transport, critically ill neonates displayed stable vital parameters and reduced metabolic acidosis. No transport-related mortality was found, but the high number of extremely preterm infants transported indicates the potential for improving in-utero transport.

Invasive ventilation at the boundary of viability: A respiratory pathophysiology study of infants born between 22 and 24 weeks of gestation.

BACKGROUND: Invasive ventilation of infants born before 24 weeks of gestation is critical for survival and long-term respiratory outcomes, but currently there is a lack of evidence to guide respiratory management. We aimed to compare respiratory mechanics and gas exchange in ventilated extremely preterm infants born before and after 24 weeks of gestation. METHODS: Secondary analysis of two prospective observational cohort studies, comparing respiratory mechanics and indices of gas exchange in ventilated infants born at 22-24 weeks of gestation (N=14) compared to infants born at 25-27 weeks (N=37). The ventilation/perfusion ratio (VA/Q), intrapulmonary shunt, alveolar dead space (VDalv) and adjusted alveolar surface area (SA) were measured in infants born at the Neonatal Unit of King's College Hospital NHS Foundation Trust, London, UK. RESULTS: Compared to infants of 25-27 weeks, infants of 22-24 weeks had higher median (IQR) intrapulmonary shunt [18 (4 - 29) % vs 8 (2 - 12) %, p=0.044] and higher VDalv [0.9 (0.6 - 1.4) vs 0.6 (0.5 - 0.7) ml/kg, p=0.036], but did not differ in VA/Q. Compared to infants of 25-27 weeks, the infants of 22-24 weeks had a lower adjusted SA [509 (322- 687) vs 706 (564 - 800) cm2, p=0.044]. The infants in the two groups did not differ in any of the indices of respiratory mechanics. CONCLUSION: Ventilated infants born before 24 completed weeks of gestation exhibit abnormal gas exchange, with higher alveolar dead space and intrapulmonary shunt and a decreased alveolar surface area compared to extreme preterms born after 24 weeks of gestation.