Comparison of hemodynamic effects of chest compression delivered via machine or human in asphyxiated piglets.

BACKGROUND: High-quality chest compressions (CC) are an important factor of neonatal resuscitation. Mechanical CC devices may provide superior CC delivery and improve resuscitation outcomes. We aimed to compare the hemodynamic effects of CC delivered by machine and human using a neonatal piglet model. METHODS: Twelve asphyxiated piglets were randomized to receive CC during resuscitation using an automated mechanical CC device ("machine") or the two-thumb encircling technique ("human"). CC was superimposed with sustained inflations. RESULTS: Twelve newborn piglets (age 0-3 days, weight 2.12 ± 0.17 kg) were included in the study. Machine-delivered CC resulted in an increase in stroke volume, and minimum and maximum rate of left ventricle pressure change (dp/dtmin and dp/dtmax) compared to human-delivered CC. CONCLUSIONS: During machine-delivered CC, stroke volume and left ventricular contractility were significantly improved. Mechanical CC devices may provide improved cardiopulmonary resuscitation outcomes in neonatal cardiac arrest induced by asphyxia. IMPACT: Machine chest compression leads to changes in hemodynamic parameters during resuscitation of asphyxiated neonatal piglets, namely greater stroke volume and left ventricular contractility, compared with standard two-thumb compression technique. Mechanical chest compression devices may provide improved cardiopulmonary resuscitation outcomes in neonatal and pediatric asphyxia-induced cardiac arrest.

Chest compressions superimposed with sustained inflations during cardiopulmonary resuscitation in asphyxiated pediatric piglets.

BACKGROUND: Pediatric resuscitation guidelines recommend continuous chest compression with asynchronized ventilation (CCaV) during cardiopulmonary resuscitation. We recently described that providing a constant high distending pressure, or sustained inflation (SI) while performing continuous chest compressions (CC = CC + SI) reduces time to return of spontaneous circulation (ROSC) in neonatal and pediatric piglets with asphyxia-induced cardiac arrest. METHODS: To determine if CC + SI compared to CCaV will improve frequency of achieving ROSC and reduce time to ROSC in asphyxiated pediatric piglets. Twenty-eight pediatric piglets (21-24 days old) were anesthetized and asphyxiated by clamping the endotracheal tube. Piglets were randomized to CC + SI or CCaV for resuscitation (n = 14/group). Heart rate, arterial blood pressure, carotid blood flow, cerebral oxygenation, and respiratory parameters were continuously recorded throughout the experiment. RESULTS: The mean(SD) duration of resuscitation was significantly reduced with CC + SI compared to CCaV with 208(190) vs. 388(258)s, p = 0.045, respectively. The number of piglets achieving ROSC with CC + SI and CCaV were 12/14 vs. 6/14, p = 0.046. Minute ventilation, end-tidal carbon dioxide, ventilation rate, and positive end expiratory pressures were also significantly improved with CC + SI. CONCLUSIONS: CC + SI improves duration of resuscitation and increases number of piglets achieving ROSC secondary to improved minute ventilation. IMPACT: Chest compressions superimposed with sustained inflation resulted in shorter duration of resuscitation Chest compressions superimposed with sustained inflation resulted in higher number of piglets achieving return of spontaneous circulation Further animal studies are needed to examine chest compressions superimposed with sustained inflation.

Cardiopulmonary resuscitation with 3:1 Compression:Ventilation or continuous compression with asynchronized ventilation in infantile piglets.

BACKGROUND: To compare neonatal and pediatric resuscitation approaches to ventilation and chest compression by using either continuous chest compression with asynchronized ventilation (CCaV) or 3:1 Compression:Ventilation ration (3:1 C:V) during infant cardiopulmonary resuscitation. We hypothesized that 3:1 C:V compared to CCaV will reduce time to return of spontaneous circulation (ROSC) in infantile piglets with asphyxia-induced bradycardic cardiac arrest. METHODS: Twenty infantile piglets (5-10 days old) were anesthetized and asphyxiated by clamping the endotracheal tube. Piglets were randomized to 3:1 C:V or CCaV for resuscitation (n = 10/group). Heart rate, arterial blood pressure, carotid blood flow, cerebral oxygenation, and respiratory parameters were continuously recorded throughout the experiment. RESULTS: The median time (IQR) to ROSC among survivors was 157 (113-219) vs 421 (118-660) for 3:1 C:V and CCaV, respectively (p = 0.253). The duration of resuscitation with 3:1 C:V compared to CCaV was 206 (119-660) vs 660 (212-660)sec, respectively (p = 0.171). The number of piglets achieving ROSC with 3:1 C:V and CCaV were 7/10 and 6/10, respectively (p = 1.00). There was no difference in hemodynamic and respiratory parameters between groups. CONCLUSIONS: Time to ROSC and survival was not different between 3:1 C:V and CCaV in infantile piglets. Either approach appears reasonable during infantile cardiopulmonary resuscitation. IMPACT: Similar time to return of spontaneous circulation and survival with 3:1 C:V and CCaV in infant piglets equivalent to 28-day-old children. Either approach appears reasonable during infantile cardiopulmonary resuscitation. Lack of scientific data to provide recommendations on when to switch between neonatal to pediatric resuscitation guidelines. No difference in time to return of spontaneous circulation or survival between 3:1 C:V and CCaV in infantile piglets with asphyxia-induced bradycardic cardiac arrest. Both methods are viable options during infant cardiopulmonary resuscitation.

Comparison of various vasopressin doses to epinephrine during cardiopulmonary resuscitation in asphyxiated neonatal piglets.

BACKGROUND: Current neonatal resuscitation guidelines recommend epinephrine for cardiac arrest. Vasopressin might be an alternative during asphyxial cardiac arrest. We aimed to compare vasopressin and epinephrine on incidence and time to return of spontaneous circulation (ROSC) in asphyxiated newborn piglets. DESIGN/METHODS: Newborn piglets (n = 8/group) were anesthetized, intubated, instrumented, and exposed to 30 min of normocapnic hypoxia, followed by asphyxia and asystolic cardiac arrest. Piglets were randomized to 0.2, 0.4, or 0.8IU/kg vasopressin, or 0.02 mg/kg epinephrine. Hemodynamic parameters were continuously measured. RESULTS: Median (IQR) time to ROSC was 172(103-418)s, 157(100-413)s, 122(93-289)s, and 276(117-480)s for 0.2, 0.4, 0.8IU/kg vasopressin, and 0.02 mg/kg epinephrine groups, respectively (p = 0.59). The number of piglets that achieved ROSC was 6(75%), 6(75%), 7(88%), and 5(63%) for 0.2, 0.4, 0.8IU/kg vasopressin, and 0.02 mg/kg epinephrine, respectively (p = 0.94). The epinephrine group had a 60% (3/5) rate of post-ROSC survival compared to 83% (5/6), 83% (5/6), and 57% (4/7) in the 0.2, 0.4, and 0.8IU/kg vasopressin groups, respectively (p = 0.61). CONCLUSION: Time to and incidence of ROSC were not different between all vasopressin dosages and epinephrine. However, non-significantly lower time to ROSC and higher post-ROSC survival in vasopressin groups warrant further investigation. IMPACT: Time to and incidence of ROSC were not statistically different between all vasopressin dosages and epinephrine. Non-significantly lower time to ROSC and higher post-ROSC survival in vasopressin-treated piglets. Overall poorer hemodynamic recovery following ROSC in epinephrine piglets compared to vasopressin groups. Human neonatal clinical trials examining the efficacy of vasopressin during asphyxial cardiac arrest will begin recruitment soon.

Pulmonary and Neurologic Effects of Mesenchymal Stromal Cell Extracellular Vesicles in a Multifactorial Lung Injury Model.

Rationale: Bronchopulmonary dysplasia, a chronic respiratory condition originating from preterm birth, is associated with abnormal neurodevelopment. Currently, there is an absence of effective therapies for bronchopulmonary dysplasia and its associated brain injury. In preclinical trials, mesenchymal stromal cell therapies demonstrate promise as a therapeutic alternative for bronchopulmonary dysplasia. Objectives: To investigate whether a multifactorial neonatal mouse model of lung injury perturbs neural progenitor cell function and to assess the ability of human umbilical cord-derived mesenchymal stromal cell extracellular vesicles to mitigate pulmonary and neurologic injury. Methods: Mice at Postnatal Day 7 or 8 were injected intraperitoneally with LPS and ventilated with 40% oxygen at Postnatal Day 9 or 10 for 8 hours. Treated animals received umbilical cord-mesenchymal stromal cell-derived extracellular vesicles intratracheally preceding ventilation. Lung morphology, vascularity, and inflammation were quantified. Neural progenitor cells were isolated from the subventricular zone and hippocampus and assessed for self-renewal, in vitro differentiation ability, and transcriptional profiles. Measurements and Main Results: The multifactorial lung injury model produced alveolar and vascular rarefaction mimicking bronchopulmonary dysplasia. Neural progenitor cells from lung injury mice showed reduced neurosphere and oligodendrocyte formation, as well as inflammatory transcriptional signatures. Mice treated with mesenchymal stromal cell extracellular vesicles showed significant improvement in lung architecture, vessel formation, and inflammatory modulation. In addition, we observed significantly increased in vitro neurosphere formation and altered neural progenitor cell transcriptional signatures. Conclusions: Our multifactorial lung injury model impairs neural progenitor cell function. Observed pulmonary and neurologic alterations are mitigated by intratracheal treatment with mesenchymal stromal cell-derived extracellular vesicles.

Development, validation, and implementation of an UHPLC-MS/MS method for the quantitation of furosemide in infant urine samples.

Furosemide is a diuretic drug used to increase urine flow in order to reduce the amount of salt and water in the body. It is commonly utilized to treat preterm infants with chronic lung disease of prematurity. There is a need for a simple and reliable quantitation of furosemide in human urine. We have developed and validated an ultra-high performance liquid chromatography-tandem mass spectrometry method for furosemide quantitation in human urine with an assay range of 0.100-50.0 µg/ml. Sample preparation involved solid-phase extraction with 10 µl of urine. Intra-day accuracies and precisions for the quality control samples were 94.5-106 and 1.86-10.2%, respectively, while inter-day accuracies and precision were 99.2-102 and 3.38-7.41%, respectively. Recovery for furosemide had an average of 23.8%, with an average matrix effect of 101%. Furosemide was stable in human urine under the assay conditions. Stability for furosemide was shown at 1 week (room temperature, 4, -20 and -78°C), 6 months (-78°C), and through three freeze-thaw cycles. This robust assay demonstrates accurate and precise quantitation of furosemide in a small volume (10 µl) of human urine. It is currently being implemented in an ongoing pediatric clinical study.

Obesity and patient-reported sexual health outcomes in gynecologic cancer survivors: A systematic review.

As obesity prevalence among gynecologic cancer (GC) survivors is expected to increase, the role of obesity in sexual health needs to be understood. This systematic review examined the impact of obesity on patient-reported sexual health outcomes (SHOs) in this population. PubMed, Embase, Web of Science, CINAHL, and PsycINFO were searched for original studies published between 2015 and 2020 following the Preferred Reporting Items for Systematic Review and Meta-Analyses guideline. We performed a narrative synthesis of findings via cancer type, cancer treatment, sexual health measures, and countries. Eleven observational studies were included. Most were conducted in European countries (n = 7), reported on endometrial cancer survivors (n = 7), and defined obesity as body mass index ≥30 kg/m2 (n = 10). Studies about cervical cancer survivors reported negative effects of obesity on sexual activity and body image while studies about endometrial cancer survivors reported positive effects of obesity on vaginal/sexual symptoms. Findings suggested interaction effects of radiotherapy and obesity on SHOs. Sexual functioning measured by the Female Sexual Function Index was less likely to be associated with obesity than other SHOs. A positive effect of obesity on SHOs was only found in studies conducted in European countries. Current evidence on the association between obesity and sexual health in GC survivors lacks in both quantity and quality. To better understand the effect of obesity on SHOs in the population, more studies are needed with critical evaluations of obesity and sexual health measures, careful considerations of cancer type and treatment, and a focus on the cultural context of obesity.

A pilot study of participatory and rapid implementation approaches to increase depression screening in primary care.

BACKGROUND: Most individuals with depression go unidentified and untreated. In 2016 the US Preventive Services Task Force released guidelines recommending universal screening in primary care to identify patients with depression and to link them to treatment. Feasible, acceptable, and effective strategies to implement these guidelines are needed. METHODS: This three-phased study employed rapid participatory methods to design and test strategies to increase depression screening at Penn Medicine, a large health system with 90 primary care practices. First, researchers solicited ideas and barriers from stakeholders to increase screening using an innovation tournament-a crowdsourcing method that invites stakeholders to submit ideas to address a workplace challenge. Second, a panel of stakeholders and scientists deliberated over and ranked the tournament ideas. An instant runoff election was held to select the winning idea. Third, the research team piloted the winning idea in a primary care practice using rapid prototyping, an approach that quickly refines and iterates strategy designs. RESULTS: The innovation tournament yielded 31 ideas and 32 barriers from diverse stakeholders (12 primary care physicians, 10 medical assistants, 4 nurse practitioners, 2 practice managers, and 4 patient support assistants). A panel of 6 stakeholders and scientists deliberated on the ideas and voted for patient self-report (i.e., through tablet computers, text message, or an online patient portal) as the winning idea. The research team rapid prototyped tablets in one primary care practice with one physician over 5 five-hour shifts to examine the feasibility, acceptability, and effectiveness of the strategy. Most patients, the physician, and medical assistants found the tablets acceptable and feasible. However, patient support assistants struggled to incorporate them in their workflow and expressed concerns about scaling up the process. Depression screening rates were higher using tablets compared to usual care; follow-up was comparable between tablets and usual care. CONCLUSIONS: Rapid participatory methods engaged and amplified the voices of diverse stakeholders in primary care. These methods helped design an acceptable and feasible implementation strategy that showed promise for increasing depression screening in a primary care setting. The next step is to evaluate the strategy in a randomized controlled trial across primary care practices.

Distinctive semantic features in the healthy adult brain.

The role of semantic features, which are distinctive (e.g., a zebra's stripes) or shared (e.g. has four legs) for accessing a concept, has been studied in detail in early neurodegenerative disease such as semantic dementia (SD). However, potential neural underpinnings of such processing have not been studied in healthy adults. The current study examines neural activation patterns using fMRI while participants completed a feature verification task, in which they identified shared or distinctive semantic features for a set of natural kinds and man-made artifacts. The results showed that the anterior temporal lobe bilaterally is an important area for processing distinctive features, and that this effect is stronger within natural kinds than man-made artifacts. These findings provide converging evidence from healthy adults that is consistent with SD research, and support a model of semantic memory in which patterns of specificity of semantic information can partially explain differences in neural activation between categories.

Evidence for vasopressors during cardiopulmonary resuscitation in newborn infants.

An estimated 0.1% of term infants and up to 15% of preterm infants (2-3 million worldwide) need extensive resuscitation, defined as chest compression and 100% oxygen with or without epinephrine in the delivery room. Despite these interventions, infants receiving extensive resuscitation in the DR have a high incidence of mortality and neurologic morbidity. Successful resuscitation from neonatal cardiac arrest requires the delivery of high-quality chest compression using the most effective vasopressor with the optimal dose, timing, and route of administration during CPR. Current neonatal resuscitation guidelines recommend administration of epinephrine once CPR has started at a dose of 0.01-0.03 mg/kg preferably given intravenously, with repeated doses every 3-5 min until return of spontaneous circulation. This review examines the current evidence for epinephrine and alternative vasopressors during neonatal cardiopulmonary resuscitation.

Cabozantinib in Patients with Advanced Merkel Cell Carcinoma.

BACKGROUND: This study sought to determine the efficacy and safety profile of cabozantinib in patients with advanced Merkel cell carcinoma (MCC). EXPERIMENTAL DESIGN: This prospective, phase II, single-institution trial enrolled patients with platinum-failure, recurrent/metastatic MCC to receive cabozantinib 60 mg orally daily until disease progression, withdrawal from study, or severe toxicity. The primary endpoint was disease control rate. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and toxicity. Immunohistochemistry for VEGFR-2, MET, and HGF expression and next-generation sequencing of tumor tissue were performed and correlated with outcome. RESULTS: Eight patients were accrued from January 24, 2014, to June 8, 2016. The study was closed prematurely because of toxicity and lack of responses. The most frequent adverse events were grades 1 and 2 and included anorexia, fatigue, nausea, hypothyroidism, and dysgeusia. Two patients developed nonhealing, painful ulcers and tumor-skin fistula. One patient had stable disease for 8 months. One patient withdrew from the study after 2 weeks of therapy because of adverse events. Three patients required dose reduction because of toxicity. Median PFS and OS were 2.1 and 11.2 months, respectively. No expression of MET, HGF, or VEGFR-2 was identified in tumor cells by immunohistochemistry of patients' tissue samples. CONCLUSION: Cabozantinib was poorly tolerated and did not demonstrate activity in patients with recurrent/metastatic, platinum-failure MCC. It is unclear whether preselection of patients with the specific upregulation or genetic alteration in the targets for cabozantinib would have changed the results of this study. (Clinical trial identification number: NCT02036476) IMPLICATIONS FOR PRACTICE: This phase II study demonstrated poor tolerability and lack of activity of cabozantinib in an unselected group of patients with advanced Merkel cell carcinoma. Although it is unclear whether preselection of patients with the specific upregulation and genetic alterations in targets for cabozantinib would have changed the results of this study, this would have likely led to an extremely rare patient population that would take many years to accrue.

Effects of epinephrine on hemodynamic changes during cardiopulmonary resuscitation in a neonatal piglet model.

BackgroundAsphyxia is the most common reason for newborns to fail to make a successful fetal-to-neonatal transition. There is currently a lack of data evaluating hemodynamic effects of epinephrine during neonatal cardiopulmonary resuscitation.MethodsTwenty-four newborn piglets were exposed to asphyxia. Thereafter, positive pressure ventilation was commenced for 30 s, followed by chest compressions (CC). Piglets were randomized into three experimental groups: 3:1 compression:ventilation ratio; CC during sustained inflation (SI) at a rate of 90 CC per minute, or CC during SI at a rate of 120 CC per minute. Epinephrine (0.01 mg/kg per dose) was administered to a maximum of four doses. Hemodynamic parameters were measured throughout the experiment.ResultsAnimals were divided into survivors and nonsurvivors. End-diastolic and developed pressures declined after epinephrine administration in the survivor group. dp/dt min was significantly higher in the survivor group whereas dp/dt max showed no significant differences. Epinephrine had no effect on either heart rate or cardiac output in both groups. Ejection fraction increased after epinephrine with no significant difference between groups.ConclusionEpinephrine did not affect survival rates or return of spontaneous circulation in our postnatal porcine model of neonatal asphyxia.

Review of Routes to Administer Medication During Prolonged Neonatal Resuscitation.

OBJECTIVE: During neonatal cardiopulmonary resuscitation, early establishment of vascular access is crucial. We aimed to review current evidence regarding different routes for the administration of medications during neonatal resuscitation. DATA SOURCES: We reviewed PubMed, EMBASE, and Google Scholar using MeSH terms "catheterization," "umbilical cord," "delivery room," "catecholamine," "resuscitation," "simulation," "newborn," "infant," "intraosseous," "umbilical vein catheter," "access," "intubation," and "endotracheal." STUDY SELECTION: Articles in all languages were included. Initially, we aimed to identify only neonatal studies and limited the search to randomized controlled trials. DATA EXTRACTION: Due to a lack of available studies, studies in children and adults, as well as animal studies and also nonrandomized studies were included. DATA SYNTHESIS: No randomized controlled trials comparing intraosseous access versus peripheral intravascular access versus umbilical venous catheter versus endotracheal tube versus laryngeal mask airway or any combination of these during neonatal resuscitation in the delivery room were identified. Endotracheal tube: endotracheal tube epinephrine administration should be limited to situations were no vascular access can be established. Laryngeal mask airway: animal studies suggest that a higher dose of epinephrine for endotracheal tube and laryngeal mask airway is required compared with IV administration, potentially increasing side effects. Umbilical venous catheter: European resuscitation guidelines propose the placement of a centrally positioned umbilical venous catheter during neonatal cardiopulmonary resuscitation; intraosseous access: case series reported successful and quick intraosseous access placement in newborn infants. Peripheral intravascular access: median time for peripheral intravascular access insertion was 4-5 minutes in previous studies. CONCLUSIONS: Based on animal studies, endotracheal tube administration of medications requires a higher dose than that by peripheral intravascular access or umbilical venous catheter. Epinephrine via laryngeal mask airway is feasible as a noninvasive alternative approach for drug delivery. Intraosseous access should be considered in situations with difficulty in establishing other access. Randomized controlled clinical trials in neonates are required to compare all access possibilities described above.

Does lack of glutathione peroxidase 1 gene expression exacerbate lung injury induced by neonatal hyperoxia in mice?

Supplemental oxygen (O2) increases the risk of lung injury in preterm infants, owing to an immature antioxidant system. Our objective was to determine whether impairing antioxidant defense by decreasing glutathione peroxidase 1 (GPx1) gene expression increases the injurious effects of hyperoxia (Hyp). GPx1+/+ and GPx1-/- C57Bl/6J mice were exposed to 21% O2 (Air) or 40% O2 (Hyp) from birth to postnatal day 7 (P7d); they were euthanized on P7d or maintained in air until adulthood [postnatal day 56 (P56d)] to assess short-term and long-term effects, respectively. We assessed lung architecture, three markers of pulmonary oxidative stress (P7d, P56d), macrophages in lung tissue (P7d), immune cells in bronchoalveolar lavage fluid (BALF; P56d), and GPx1-4 and catalase gene expression in lung tissue (P7d, P56d). On P7d, macrophages were decreased by lack of GPx1 expression and further decreased by hyperoxia. GPx1 expression was increased in GPx1+/+Hyp mice and decreased in both GPx1-/- groups. On P56d, heme oxygenase-1 was increased by hyperoxia when GPx1 was absent. There were significantly more immune cells from Hyp groups than from the GPx1+/+Air group and a greater proportion of lymphocytes in GPx1-/-Hyp mice. GPx1 expression was significantly decreased in GPx1-/- mice; GPx2-4 and catalase expression was increased in GPx1-/-Hyp mice compared with other groups. Tissue fraction was decreased in GPx1-/-Air mice; bronchiolar smooth muscle was decreased in GPx1-/- mice. GPx1 does not clearly exacerbate hyperoxia-induced increases in oxidative stress or lung injury but may alter pulmonary immune function. Increased expression of GPx2-4 and catalase in GPx1-/-Hyp mice suggests gene redundancy within the model.

Cell-based therapies for neonatal lung disease.

Preterm birth occurs in approximately 11 % of all births worldwide. Advances in perinatal care have enabled the survival of preterm infants born as early as 23-24 weeks of gestation. However, many are affected by bronchopulmonary dysplasia (BPD)-a common respiratory complication of preterm birth, which has life-long consequences for lung health. Currently, there is no specific treatment for BPD. Recent advances in stem cell research have opened new therapeutic avenues for prevention/repair of lung damage. This review summarizes recent pre-clinical data and early clinical translation of cell-based therapies for BPD.

Oxygen Saturation and Heart Rate Ranges in Very Preterm Infants Requiring Respiratory Support at Birth.

OBJECTIVE: To evaluate the changes in preductal oxygen saturation (SpO2) and heart rate in preterm infants receiving continuous positive airway pressure (CPAP) and/or positive-pressure ventilation (PPV) at birth. STUDY DESIGN: A prospective observational study at birth of infants aged <32 weeks separated into 2 gestational age (GA) groups: 230/7-276/7 weeks (group 1) and 280/7-316/7 weeks (group 2). Infants received delayed cord clamping (DCC) in accordance with institutional protocol. CPAP and/or PPV was applied at the clinical team's discretion. SpO2 and heart rate were recorded every minute for 10 minutes. Preductal SpO2 was targeted according to published nomograms. For heart rate, the goal was to maintain a stable heart rate >100 bpm. RESULTS: The study cohort comprised 96 group 1 infants (mean GA, 26 ± 1 weeks; mean birth weight, 818 ± 208 g) and 173 group 2 infants (mean GA, 30 ± 1 weeks; mean birth weight, 1438 ± 374 g). In general, infants requiring respiratory support reached target values for heart rate and SpO2 more slowly than the published nomograms for spontaneously breathing preterm infants without respiratory support. Infants receiving CPAP reached SpO2 and heart rate targets faster than infants receiving PPV. In group 1, but not group 2 infants, DCC resulted in higher SpO2 and heart rate. CONCLUSION: SpO2 and heart rate do not quickly and reliably reach the values achieved by spontaneously breathing preterm infants not requiring respiratory support.

Existence, functional impairment, and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth.

BACKGROUND: Bronchopulmonary dysplasia and emphysema are life-threatening diseases resulting from impaired alveolar development or alveolar destruction. Both conditions lack effective therapies. Angiogenic growth factors promote alveolar growth and contribute to alveolar maintenance. Endothelial colony-forming cells (ECFCs) represent a subset of circulating and resident endothelial cells capable of self-renewal and de novo vessel formation. We hypothesized that resident ECFCs exist in the developing lung, that they are impaired during arrested alveolar growth in experimental bronchopulmonary dysplasia, and that exogenous ECFCs restore disrupted alveolar growth. METHODS AND RESULTS: Human fetal and neonatal rat lungs contain ECFCs with robust proliferative potential, secondary colony formation on replating, and de novo blood vessel formation in vivo when transplanted into immunodeficient mice. In contrast, human fetal lung ECFCs exposed to hyperoxia in vitro and neonatal rat ECFCs isolated from hyperoxic alveolar growth-arrested rat lungs mimicking bronchopulmonary dysplasia proliferated less, showed decreased clonogenic capacity, and formed fewer capillary-like networks. Intrajugular administration of human cord blood-derived ECFCs after established arrested alveolar growth restored lung function, alveolar and lung vascular growth, and attenuated pulmonary hypertension. Lung ECFC colony- and capillary-like network-forming capabilities were also restored. Low ECFC engraftment and the protective effect of cell-free ECFC-derived conditioned media suggest a paracrine effect. Long-term (10 months) assessment of ECFC therapy showed no adverse effects with persistent improvement in lung structure, exercise capacity, and pulmonary hypertension. CONCLUSIONS: Impaired ECFC function may contribute to arrested alveolar growth. Cord blood-derived ECFC therapy may offer new therapeutic options for lung diseases characterized by alveolar damage.

Neonatal exposure to mild hyperoxia causes persistent increases in oxidative stress and immune cells in the lungs of mice without altering lung structure.

Preterm infants often require supplemental oxygen due to lung immaturity, but hyperoxia can contribute to an increased risk of respiratory illness later in life. Our aim was to compare the effects of mild and moderate levels of neonatal hyperoxia on markers of pulmonary oxidative stress and inflammation and on lung architecture; both immediate and persistent effects were assessed. Neonatal mice (C57BL6/J) were raised in either room air (21% O2), mild (40% O2), or moderate (65% O2) hyperoxia from birth until postnatal day 7 (P7d). The mice were killed at either P7d (immediate effects) or lived in air until adulthood (P56d, persistent effects). We enumerated macrophages in lung tissue at P7d and immune cells in bronchoalveolar lavage fluid (BALF) at P56d. At P7d and P56d, we assessed pulmonary oxidative stress [heme oxygenase-1 (HO-1) and nitrotyrosine staining] and lung architecture. The data were interrogated for sex differences. At P7d, HO-1 gene expression was greater in the 65% O2 group than in the 21% O2 group. At P56d, the area of nitrotyrosine staining and number of immune cells were greater in the 40% O2 and 65% O2 groups relative to the 21% O2 group. Exposure to 65% O2, but not 40% O2, led to larger alveoli and lower tissue fraction in the short term and to persistently fewer bronchiolar-alveolar attachments. Exposure to 40% O2 or 65% O2 causes persistent increases in pulmonary oxidative stress and immune cells, suggesting chronic inflammation within the adult lung. Unlike 65% O2, 40% O2 does not affect lung architecture.

Exhaled Carbon Dioxide and Neonatal Breathing Patterns in Preterm Infants after Birth.

OBJECTIVES: To examine the amount of exhaled carbon dioxide (ECO2) with different breathing patterns in spontaneously breathing preterm infants after birth. STUDY DESIGN: Preterm infants had a facemask attached to a combined carbon dioxide/flow sensor placed over their mouth and nose to record ECO2 and gas flow. A breath-by-breath analysis of the first 5 minutes of the recording was performed. RESULTS: Thirty spontaneously breathing preterm infants, gestational age (mean ± SD) 30 ± 2 weeks and birth weight 1635 ± 499 g were studied. ECO2 from normal breaths and slow expirations was significantly larger than with other breathing patterns (P < .001). ECO2 per breath also increased with gestational age P < .001. The expiratory hold pattern was the most prevalent breathing pattern both during the first minute of recording and overall. Breathing pattern proportions also varied by gestational age. Finally, ECO2 from the fifth minute of recording was significantly greater than that produced during the first 4 minutes of recording (P ≤ .029). CONCLUSIONS: ECO2 varies with different breathing patterns and increases with gestational age and over time. ECO2 may be an indicator of lung aeration and that postnatal ECO2 monitoring may be useful in preterm infants in the delivery room.

Spontaneously Breathing Preterm Infants Change in Tidal Volume to Improve Lung Aeration Immediately after Birth.

OBJECTIVE: To examine the temporal course of lung aeration at birth in preterm infants <33 weeks gestation. STUDY DESIGN: The research team attended deliveries of preterm infants <33 weeks gestation at the Royal Alexandra Hospital. Infants who received only continuous positive airway pressure were eligible for inclusion. A combined carbon dioxide (CO2) and flow-sensor was placed between the mask and the ventilation device. To analyze lung aeration patterns during spontaneous breathing, tidal volume (VT), and exhaled CO2 (ECO2) were recorded for the first 100 breaths. RESULTS: Thirty preterm infants were included with a total of 1512 breaths with mask leak <30%. Mean (SD) gestational age and birth weight was 30 (1) weeks and 1478 (430) g. Initial VT and ECO2 for the first 30 breaths was 5-6 mL/kg and 15-22 mm Hg, respectively. VT and ECO2 increased over the next 20 breaths to 7-8 mL/kg and 25-32 mm Hg, respectively. For the remaining observation period VT decreased to 4-6 mL/kg and ECO2 continued to increase to 35-37 mm Hg. CONCLUSIONS: Preterm infants begin taking deeper breaths approximately 30 breaths after initiating spontaneous breathing to inflate their lungs. Concurrent CO2 removal rises as alveoli are recruited. Lung aeration occurs in 2 phases: initially, large volume breaths with poor alveolar aeration followed by smaller breaths with elimination of CO2 as a consequence of adequate aeration.