Publications by authors named "Thomas H Shaffer"

109 Publications

Effect of positive end-expiratory pressure on additional passive ventilation generated by CPR compressions in a porcine model.

Intensive Care Med Exp 2021 Jul 26;9(1):37. Epub 2021 Jul 26.

Department of Pediatrics, Sidney Kimmel Medical School of Thomas Jefferson University, Philadelphia, PA, USA.

Background: Compressions given during cardiopulmonary resuscitation generate small, ineffective passive ventilations through oscillating waves. Positive end-expiratory pressure increases the volume of these passive ventilations; however, its effect on passive ventilation is unknown. Our objective was to determine if increasing positive end-expiratory pressure during cardiopulmonary resuscitation increases passive ventilation generated by compressions to a clinically significant point. This study was conducted on 13 Landrace-Yorkshire pigs. After inducing cardiac arrest with bupivacaine, cardiopulmonary resuscitation was performed with a LUCAS 3.1. During cardiopulmonary resuscitation, pigs were ventilated at a positive end-expiratory pressure of 0, 5, 10, 15, 20 cmHO (randomly determined) for 9 min. Using the NM3 respiratory monitoring device, expired minute ventilation and volumetric capnography were measured. Arterial blood gas was obtained for each positive end-expiratory pressure level to compare the effects of positive end-expiratory pressure on carbon dioxide.

Results: Increasing positive end-expiratory pressure from 0 to 20 cmHO increased the mean (SEM) expired minute ventilation from 6.33 (0.04) to 7.33 (0.04) mL/min. With the 5-cmHO incremental increases in positive end-expiratory pressure from 0 to 20 cmHO, volumetric capnography increased from a mean (SEM) of 94.19 (0.78) to 115.18 (0.8) mL/min, except for 15 cmHO, which showed greater carbon dioxide exhalation with volumetric capnography compared with 20 cmHO. PCO declined significantly as positive end-expiratory pressure was increased from 0 to 20 cmHO.

Conclusions: When increasing positive end-expiratory pressure from 0 to 20, the contribution to overall ventilation from gas oscillations generated by the compressions became more significant, and may even lead to hypocapnia, especially when using positive end-expiratory pressures between 15 and 20.
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http://dx.doi.org/10.1186/s40635-021-00401-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310691PMC
July 2021

Automated Assessment of Thoracic-Abdominal Asynchrony in Patients with Morquio Syndrome.

Diagnostics (Basel) 2021 May 15;11(5). Epub 2021 May 15.

Nemours Biomedical Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.

Morquio syndrome is a rare disease caused by a disorder in the storage of mucopolysaccharides that affects multiple organs, including musculoskeletal, respiratory, cardiovascular, and digestive systems. Respiratory failure is one of the leading causes of mortality in Morquio patients; thus, respiratory function testing is vital to the management of the disease. An automated respiratory assessment methodology using the RIP device and a machine-learning algorithm was developed. RIP is a noninvasive approach that uses differences between thoracic and abdominal movements (thoracic-abdominal asynchrony) during respiration to assess respiratory status. The technique was evaluated on 17 patients with Morquio (9 females and 8 males) between the ages of 2 and 57 years. The results of the automated technique agreed with the clinical assessment in 16 out of the 17 patients. It was found that the inverse cumulative percentage representation of the time delay between the thorax and abdomen was the most critical variable for accurate evaluation. It was demonstrated that the technique could be successfully used on patients with Morquio who have difficulty breathing with 100% compliance. This technique is highly accurate, portable, noninvasive, and easy to administer, making it suitable for a variety of settings, such as outpatient clinics, at home, and emergency rooms.
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http://dx.doi.org/10.3390/diagnostics11050880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156300PMC
May 2021

Adjustment of high flow nasal cannula rates using real-time work of breathing indices in premature infants with respiratory insufficiency.

J Perinatol 2021 Jul 4;41(7):1711-1717. Epub 2021 Mar 4.

Department of Pediatrics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States.

Objective: To assess the feasibility of real-time monitoring of work of breathing (WOB) indices and the impact of adjusting HFNC flow on breathing synchrony and oxygen stability in premature infants.

Study Design: A prospective, observational study of infants stable on HFNC. The flow adjusted per predetermined algorithm. Respiratory inductive plethysmography (RIP) noninvasively measured WOB. A high-resolution pulse oximeter collected oxygen saturation and heart rate data. Summary statistics and mixed linear models were used.

Results: Baseline data for 32 infants, final analysis of 21 infants. Eighty-one percent with abnormal WOB. Sixty-two percent demonstrated 20% improvement in WOB. For infants with gestational age <28 weeks, an incremental increase in HFNC flow rate decreased WOB (p < 0.001) and improved oxygen saturation and stability (p < 0.01).

Conclusions: Premature infants do not receive optimal support on HFNC. The use of a real-time feedback system to adjust HFNC is feasible and improves WOB, oxygen saturation, and oxygen stability. This technology may improve the utility of HFNC in premature infants.
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http://dx.doi.org/10.1038/s41372-021-00977-zDOI Listing
July 2021

Pulmonary immune cell transcriptome changes in double-hit model of BPD induced by chorioamnionitis and postnatal hyperoxia.

Pediatr Res 2021 Jan 14. Epub 2021 Jan 14.

Department of Pediatrics, Nemours AI duPont Hospital for Children, Wilmington, DE, USA.

Background: Preterm infants with bronchopulmonary dysplasia (BPD) have lifelong increased risk of respiratory morbidities associated with environmental pathogen exposure and underlying mechanisms are poorly understood. The resident immune cells of the lung play vital roles in host defense. However, the effect of perinatal events associated with BPD on pulmonary-specific immune cells is not well understood.

Methods: We used a double-hit model of BPD induced by prenatal chorioamnionitis followed by postnatal hyperoxia, and performed a global transcriptome analysis of all resident pulmonary immune cells.

Results: We show significant up-regulation of genes involved in chemokine-mediated signaling and immune cell chemotaxis, and down-regulation of genes involved in multiple T lymphocyte functions. Multiple genes involved in T cell receptor signaling are downregulated and Cd8a gene expression remains downregulated at 2 months of age in spite of recovery in normoxia for 6 weeks. Furthermore, the proportion of CD8a+CD3+ pulmonary immune cells is decreased.

Conclusions: Our study has highlighted that perinatal lung inflammation in a double-hit model of BPD results in short- and long-term dysregulation of genes associated with the pulmonary T cell receptor signaling pathway, which may contribute to increased environmental pathogen-associated respiratory morbidities seen in children and adults with BPD.

Impact: In a translationally relevant double-hit model of BPD induced by chorioamnionitis and postnatal hyperoxia, we identified pulmonary immune cell-specific transcriptomic changes and showed that T cell receptor signaling genes are downregulated in short term and long term. This is the first comprehensive report delineating transcriptomic changes in resident immune cells of the lung in a translationally relevant double-hit model of BPD. Our study identifies novel resident pulmonary immune cell-specific targets for potential therapeutic modulation to improve short- and long-term respiratory health of preterm infants with BPD.
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http://dx.doi.org/10.1038/s41390-020-01319-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808307PMC
January 2021

A novel noninvasive approach for evaluating work of breathing indices in a developmental rat model using respiratory inductance plethysmography.

Sci Rep 2020 11 26;10(1):20730. Epub 2020 Nov 26.

Department of Biomedical Research and Center for Pediatric Lung Research, Nemours/Alfred I. duPont Hospital for Children, P.O. Box 269, Wilmington, DE, 19803, USA.

Pulmonary function testing (PFT) is an important component for evaluating the outcome of experimental rodent models of respiratory diseases. Respiratory inductance plethysmography (RIP) provides a noninvasive method of PFT requiring minimal cooperation. RIP measures work of breathing (WOB) indices including phase angle (Ф), percent rib cage (RC %), breaths per minute (BPM), and labored breathing index (LBI) on an iPad. The aim of this study was to evaluate the utility of a recently developed research instrument, pneuRIP, for evaluation of WOB indices in a developmental rat model. Sprague Dawley rats (2 months old) were commercially acquired and anaesthetised with isoflurane. The pneuRIP system uses two elastic bands: one band (RC) placed around the rib cage under the upper armpit and another band (AB) around the abdomen. The typical thoracoabdominal motion (TAM) plot showed the abdomen and rib cage motion in synchrony. The plots of phase angle and LBI as a function of data point number showed that values were within the range. The distribution for phase angle and LBI was within a narrow range. pneuRIP testing provided instantaneous PFT results. This study demonstrated the utility of RIP as a rapid, noninvasive approach for evaluating treatment interventions in the rodent model.
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http://dx.doi.org/10.1038/s41598-020-77731-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691344PMC
November 2020

DNA Methylation Profile in Human Cord Blood Mononuclear Leukocytes From Term Neonates: Effects of Histological Chorioamnionitis.

Front Pediatr 2020 4;8:437. Epub 2020 Aug 4.

Neonatology, Thomas Jefferson University/Nemours, Philadelphia, PA, United States.

Histological chorioamnionitis (HCA) is an infection/inflammation of fetal membranes and complicates 5.2-28.5% of all live births. Exposure to HCA can have long-term consequences including abnormal neurodevelopment and an increased risk for allergic disorders and asthma later in childhood. HCA may incite epigenetic changes, which have the potential to modulate both the immune and neurological systems as well as increase the risk of related disorders later in life. However, there is limited data on the impact of HCA on epigenetics, in particular DNA methylation, and changes to immune and neurological systems in full-term human neonates. To determine differential DNA methylation in cord blood mononuclear leukocytes from neonates exposed to HCA. Cord blood was collected from 10 term neonates (5 with HCA and 5 controls without HCA) and mononuclear leukocytes were isolated. Genome-wide DNA methylation screening was performed on Genomic DNA extracted from mononuclear leukocytes. Mononuclear leukocytes from cord blood of HCA-exposed neonates showed differential DNA methylation of 68 probe sets compared to the control group (44 hypermethylated, 24 hypomethylated) with a ≤ 0.0001. Several genes involved in immune modulation and nervous system development were found to be differentially methylated. Important canonical pathways as revealed by Ingenuity Pathway Analysis (IPA) were CREB Signaling in Neurons, FcγRIIB Signaling in B Lymphocytes, Cell Cycle: G1/S Checkpoint Regulation, Interleukin-1, 2, 3, 6, 8, 10, 17, and 17A signaling, p53 signaling, dopamine degradation, and serotonin degradation. The diseases and disorders picked up by IPA were nervous system development and function, neurological disease, respiratory disease, immune cell trafficking, inflammatory response, and immunological disease. HCA induces differential DNA methylation in cord blood mononuclear leukocytes. The differentially methylated genes may contribute to inflammatory, immunological and neurodevelopmental disorders in neonates exposed to HCA.
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http://dx.doi.org/10.3389/fped.2020.00437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417608PMC
August 2020

Machine learning for automatic identification of thoracoabdominal asynchrony in children.

Pediatr Res 2021 Apr 3;89(5):1232-1238. Epub 2020 Jul 3.

Biomedical Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.

Background: The current methods for assessment of thoracoabdominal asynchrony (TAA) require offline analysis on the part of physicians (respiratory inductance plethysmography (RIP)) or require experts for interpretation of the data (sleep apnea detection).

Methods: To assess synchrony between the thorax and abdomen, the movements of the two compartments during quiet breathing were measured using pneuRIP. Fifty-one recordings were obtained: 20 were used to train a machine-learning (ML) model with elastic-net regularization, and 31 were used to test the model's performance. Two feature sets were explored: (1) phase difference (ɸ) between the thoracic and abdominal signals and (2) inverse cumulative percentage (ICP), which is an alternate measure of data distribution. To compute accuracy of training, the model outcomes were compared with five experts' assessments.

Results: Accuracies of 61.3% and 90.3% were obtained using ɸ and ICP features, respectively. The inter-rater reliability (i.r.r.) of the assessments of experts was 0.402 and 0.684 when they used ɸ and ICP to identify TAA, respectively.

Conclusions: With this pilot study, we show the efficacy of the ICP feature and ML in developing an accurate automated approach to identifying TAA that reduces time and effort for diagnosis. ICP also helped improve consensus among experts.

Impact: Our article presents an automated approach to identifying thoracic abdominal asynchrony using machine learning and the pneuRIP device. It also shows how a modified statistical measure of cumulative frequency can be used to visualize the progression of the pulmonary functionality along time. The pulmonary testing method we developed gives patients and doctors a noninvasive and easy to administer and diagnose approach. It can be administered remotely, and alerts can be transmitted to the physician. Further, the test can also be used to monitor and assess pulmonary function continuously for prolonged periods, if needed.
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http://dx.doi.org/10.1038/s41390-020-1032-1DOI Listing
April 2021

Perfluorochemical-facilitated plasminogen activator delivery to the airways: A novel treatment for inhalational smoke-induced acute lung injury.

Clin Transl Med 2020 Jan;10(1):258-274

Department of Thoracic Medicine & Surgery, Physiology & Pediatrics, and Temple Lung Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA.

Background: Effective clinical management of airway clot and fibrinous cast formation of severe inhalational smoke-induced acute lung injury (ISALI) is lacking. Aerosolized delivery of tissue plasminogen activator (tPA) is confounded by airway bleeding; single-chain urokinase plasminogen activator (scuPA) moderated this adverse effect and supported transient improvement in gas exchange and lung mechanics. However, neither aerosolized plasminogen activator (PA) yielded durable improvements in physiologic responses or reduction in cast burden. Here, we hypothesized that perfluorochemical (PFC) liquids would facilitate PA distribution and sustain improvements in physiologic outcomes in ISALI.

Methods: Spontaneously breathing adult sheep (n = 36) received anesthesia and analgesia and were instrumented, exposed to cotton smoke inhalation, and supported by mechanical ventilation for 48 h. Groups (n = 6/group) were studied without supplemental treatment, or, starting 4 h post injury, they received intratracheal low volume (8 mL) PFC liquid alone or a dose range of tPA/PFC or scuPA/PFC suspensions (4 or 8 mg in 8 mL PFC) every 8 h. Outcomes were evaluated by sequential measurements of cardiopulmonary parameters, lung histomorphology, and biochemical analyses of bronchoalveolar lavage fluid.

Results: Dose-response and PA-type comparisons of outcomes demonstrated sustained superiority with low-volume PFC suspensions of scuPA over tPA or PFC alone, favoring the highest dose of scuPA/PFC suspension over lower doses, without airway bleeding.

Conclusions: We propose that this improved profile over previously reported aerosolized delivery is likely related to improved dose distribution. Sustained salutary responses to scuPA/PFC suspension delivery in this translational model are encouraging and support the possibility that the observed outcomes could be of clinical importance.
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http://dx.doi.org/10.1002/ctm2.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240845PMC
January 2020

Diagnostic differences in respiratory breathing patterns and work of breathing indices in children with Duchenne muscular dystrophy.

PLoS One 2020 10;15(1):e0226980. Epub 2020 Jan 10.

Department of Biomedical Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America.

Rationale: Pulmonary function testing (PFT) provides diagnostic information regarding respiratory physiology. However, many forms of PFT are time-intensive and require patient cooperation. Respiratory inductance plethysmography (RIP) provides thoracoabdominal asynchrony (TAA) and work of breathing (WOB) data. pneuRIPTM is a noninvasive, wireless analyzer that provides real-time assessment of RIP via an iPad. In this study, we show that pneuRIPTM can be used in a hospital clinic setting to differentiate WOB indices and breathing patterns in children with DMD as compared to age-matched healthy subjects.

Methods: RIP using the pneuRIPTM was conducted on 9 healthy volunteers and 7 DMD participants (ages 5-18) recruited from the neuromuscular clinic, under normal resting conditions over 3-5 min during routine outpatient visits. The tests were completed in less than 10 minutes and did not add excessive time to the clinic visit. Variables recorded included labored-breathing index (LBI), phase angle (Φ) between abdomen and rib cage, respiratory rate (RR), percentage of rib cage input (RC%), and heart rate (HR). The data were displayed in histogram plots to identify distribution patterns within the normal ranges. The percentages of data within the ranges (0≤ Φ ≤30 deg.; median RC %±10%; median RR±5%; 1≤LBI≤1.1) were compared. Unpaired t-tests determined significance of the data between groups.

Results: 100% patient compliance demonstrates the feasibility of such testing in clinical settings. DMD patients showed a significant elevation in Φ, LBI, and HR averages (P<0.006, P<0.002, P<0.046, respectively). Healthy subjects and DMD patients had similar BPM and RC% averages. All DMD data distributions were statistically different from healthy subjects based on analysis of histograms. The DMD patients showed significantly less data within the normal ranges, with only 49.7% Φ, 48.0% RC%, 69.2% RR, and 50.7% LBI.

Conclusion: In this study, noninvasive pneuRIPTM testing provided instantaneous PFT diagnostic results. As compared to healthy subjects, patients with DMD showed abnormal results with increased markers of TAA, WOB indices, and different breathing patterns. These results are similar to previous studies evaluating RIP in preterm infants. Further studies are needed to compare these results to other pulmonary testing methods. The pneuRIPTM testing approach provides immediate diagnostic information in outpatient settings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226980PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953871PMC
April 2020

Histological Chorioamnionitis Induces Differential Gene Expression in Human Cord Blood Mononuclear Leukocytes from Term Neonates.

Sci Rep 2019 04 10;9(1):5862. Epub 2019 Apr 10.

Neonatology, Thomas Jefferson University/Nemours, Philadelphia, PA, USA.

Histological chorioamnionitis (HCA) is an infection of fetal membranes and complicates 5.2% to 28.5% of all live births. HCA is associated with increased mortality and morbidity in both premature and term neonates. Exposure to HCA may have long-term consequences, including an increased risk for allergic disorders and asthma later in childhood, the mechanism(s) of which are still not yet well understood. The objective of this study was to determine the mRNA transcriptome of cord blood mononuclear leukocytes from term neonates to identify key genes and pathways involved in HCA. We found 366 differentially expressed probe IDs with exposure to HCA (198 upregulated, 168 downregulated). These transcriptomes included novel genes and pathways associated with exposure to HCA. The differential gene expression included key genes regulating inflammatory, immune, respiratory and neurological pathways, which may contribute to disorders in those pathways in neonates exposed to HCA. Our data may lead to understanding of the role of key genes and pathways identified on the long-term sequelae related to exposure to HCA, as well as to identifying potential markers and therapies to prevent HCA-associated complications.
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http://dx.doi.org/10.1038/s41598-019-42205-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458165PMC
April 2019

Age-related ranges of respiratory inductance plethysmography (RIP) reference values for infants and children.

Paediatr Respir Rev 2019 Feb 19;29:60-67. Epub 2018 May 19.

Department of Biomedical Research and Center for Pediatric Lung Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA. Electronic address:

The current noninvasive method for respiratory monitoring is respiratory inductance plethysmography (RIP); two bands are connected, one each to the chest and the abdomen, to measure the breathing pattern. RIP requires post hoc analysis to calculate indices such as respiratory rate, phase angle, labored breathing index, and percent of rib cage contribution to breathing. Clinical studies have provided patient RIP values and age-matched normal values, but they lack global evaluation of normative data for a wide age range of pediatric subjects. Herein, we compiled normative RIP indices from numerous studies for a large range of pediatric ages. From these data, we derived regression equations useful for computing normal RIP parameters as a function of age. The presented review will provide caregivers the ability to compare RIP data of pediatric patients against the regression analysis. This comparison will help identify patients with pulmonary complications and aid in guiding respiratory therapy.
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http://dx.doi.org/10.1016/j.prrv.2018.03.010DOI Listing
February 2019

Nebulization of Single-Chain Tissue-Type and Single-Chain Urokinase Plasminogen Activator for Treatment of Inhalational Smoke-Induced Acute Lung Injury.

J Drug Deliv Sci Technol 2018 Aug 30;48:19-27. Epub 2018 Apr 30.

The University of Texas at Austin, College of Pharmacy, Division of Molecular Pharmaceutics and Drug Delivery, Austin, TX, USA.

Single-chain tissue-type plasminogen activator (sctPA) and single-chain urokinase plasminogen activator (scuPA) have attracted interest as enzymes for the treatment of inhalational smoke-induced acute lung injury (ISALI). In this study, the pulmonary delivery of commercial human sctPA and lyophilized scuPA and their reconstituted solution forms were demonstrated using vibrating mesh nebulizers (Aeroneb® Pro (active) and EZ Breathe® (passive)). Both the Aeroneb® Pro and EZ Breathe® vibrating mesh nebulizers produced atomized droplets of protein solution of similar size of less than about 5 μm, which is appropriate for pulmonary delivery. Enzymatic activities of scuPA and of sctPA were determined after nebulization and both remained stable (88.0% and 93.9%). Additionally, the enzymatic activities of sctPA and tcuPA were not significantly affected by excipients, lyophilization or reconstitution conditions. The results of these studies support further development of inhaled formulations of fibrinolysins for delivery to the lungs following smoke-induced acute pulmonary injury.
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http://dx.doi.org/10.1016/j.jddst.2018.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095669PMC
August 2018

Impact of endotracheal tube biofilm and respiratory secretions on airway resistance and mechanics of breathing in a neonatal lung model.

J Appl Physiol (1985) 2018 07 26. Epub 2018 Jul 26.

Pediatrics/Neonatology, Christiana Care Health System, United States.

Endotracheal tube (ETT) obstruction from biofilm formation is a theoretical risk for intubated preterm neonates. The objective of this study is to determine the impact of ETT biofilm on ETT resistance and minute ventilation in a neonatal respiratory model. Post-extubation 2.5 and 3.0mm ETTs from ventilated preterm infants were matched with unused control ETTs. The pressure gradient across the ETT was measured at set flow rates and converted to airway resistance. Spontaneous breathing tests (SBT) were performed using a virtual patient model and were considered "passed" if minute ventilation of patient ETTs was greater than 60% of controls. Twenty-four 2.5mm ETTs and sixteen 3.0mm ETTs were analyzed. In patient and control ETTs, as flow rate increases, the pressure gradient across the ETT also increases in a linear fashion. Resistance to flow in patient ETTs was statistically different from matched control ETTs (p < 0.001), and patient ETTs had 19.9cmH2O/L/sec greater resistance than control ETTs. Spontaneous breathing tests (SBT) were performed in 27 of 40 ETTs. Twenty-six ETTs "passed" a SBT. In one obstructed 3.0mm ETT, SBT measurements were unobtainable. The clinical impact of endotracheal tube biofilm as measured by a SBT appears to be minimal for the majority of patients in our study group. In one out of 27 ETTs, the presence of a biofilm significantly altered resistance to airflow and resulted in a failed SBT. Gas flow rate and ETT size had a greater impact on resistance to airflow and minute ventilation than ETT biofilm in this study sample.
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http://dx.doi.org/10.1152/japplphysiol.00083.2018DOI Listing
July 2018

Measures of respiratory inductance plethysmography (RIP) in children with neuromuscular disease.

Pediatr Pulmonol 2018 09 12;53(9):1260-1268. Epub 2018 Jul 12.

Department of Biomedical Research and Center for Pediatric Lung Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware.

Background: Pulmonary function testing (PFT) is essential for the clinical assessment of respiratory problems. Respiratory inductance plethysmography (RIP) is a non-invasive method of PFT requiring minimal patient cooperation. RIP measures the volumetric change in the ribcage and abdomen, from which work of breathing (WOB) indices are derived. WOB indices include: phase angle (Ф), percent ribcage (RC%), respiratory rate (RR), and labored breathing index (LBI). Heart rate (HR) is collected separately.

Aim: The goal of this study was to assess the utility of a newly developed RIP system, the pneuRIP, in an outpatient clinic setting in children with neuromuscular (NM) disease.

Method: The pneuRIP system measures and displays the WOB indices in real-time on an iPad display. Forty-three subjects, 22 NM patients and 21 healthy children (ages: 5-18 years) were enrolled.

Results: Patients' means showed an increase of 119.8% for Ф, 15.7% for LBI, and 19.9% for HR compared with healthy subjects, when adjusted for age and gender. The study found significant differences between the mean values of the healthy subjects and patients in Ф (P = 0.000), LBI (P = 0.001), and HR (P = 0.001). No differences were noted for RC% and RR between groups. Data for Ф in NM patients were diffusely distributed as compared with healthy subjects based on analysis of histograms.

Conclusion: Non-invasive pneuRIP testing provided instantaneous PFT results. As compared to healthy subjects, NM patients showed abnormal results with increased markers of thoracoabdominal asynchrony, WOB indices, and biphasic breathing patterns likely resulting from NM weakness.
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http://dx.doi.org/10.1002/ppul.24134DOI Listing
September 2018

Quantitative Analysis of Thoracoabdominal Asynchrony in Pediatric Polysomnography.

J Clin Sleep Med 2018 07 15;14(7):1169-1176. Epub 2018 Jul 15.

Division of Pulmonology, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware.

Study Objectives: Objective measurements of thoracoabdominal asynchrony (TAA), such as average phase angle (θavg), can quantify airway obstruction. This study demonstrates and evaluates use of θavg for predicting obstructive sleep apnea (OSA) in pediatric polysomnography (PSG).

Methods: This prospective observational study recruited otherwise healthy 3- to 8-year-old children presenting for PSG due to snoring, behavioral problems, difficulty sleeping, and/or enlarged tonsils. Respiratory inductance plethysmography (RIP) was directly monitored and data were collected during each PSG. θavg and average labored breathing index (LBIavg) were calculated for earliest acceptable 5-minute periods of stage N3 sleep and stage R sleep. Associations between θavg and obstructive apnea index (OAI) and obstructive apnea-hypopnea index (OAHI), as well as between LBIavg and OAI and OAHI, were examined.

Results: Forty patients undergoing PSG were analyzed. Thirty percent of patients had OSA, 57.5% had enlarged tonsils, and 17.5% were obese. θavg during stage N3 sleep and stage R sleep had significant positive correlations with OAI (Spearman = .35 [ = .03] and .40 [ = .01], respectively) and θavg during stage N3 sleep with OAHI ( = .35 [ = .03]). LBIavg showed lower correlations. Median θavg during stage R sleep (33.1) was significantly greater than during stage N3 sleep (13.7, = .0005).

Conclusions: Association of θavg with OAI and OAHI shows that θavg reflects airway obstruction and has potential use as a quantitative indicator of OSA. RIP provides valuable information that is readily available in PSG. The significant difference between θavg in stage N3 sleep and stage R sleep confirms the clinical observation that there is more asynchrony during rapid eye movement sleep than non-rapid eye movement sleep.
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http://dx.doi.org/10.5664/jcsm.7218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040800PMC
July 2018

Lack of durable protection against cotton smoke-induced acute lung injury in sheep by nebulized single chain urokinase plasminogen activator or tissue plasminogen activator.

Clin Transl Med 2018 Jun 18;7(1):17. Epub 2018 Jun 18.

The Department of Cellular and Molecular Biology and the Texas Lung Institute, The University of Texas Health Science Center at Tyler, 11927 US HWY 271, Tyler, TX, 75708, USA.

Background: Airway fibrin casts are clinically important complications of severe inhalational smoke-induced acute lung injury (ISIALI) for which reliable evidence-based therapy is lacking. Nebulized anticoagulants or a tissue plasminogen activator; tPA, has been advocated, but airway bleeding is a known and lethal potential complication. We posited that nebulized delivery of single chain urokinase plasminogen activator, scuPA, is well-tolerated and improves physiologic outcomes in ISIALI. To test this hypothesis, we nebulized scuPA or tPA and delivered these agents every 4 h to sheep with cotton smoke induced ISIALI that were ventilated by either adaptive pressure ventilation/controlled mandatory ventilation (APVcmv; Group 1, n = 14) or synchronized controlled mandatory ventilation (SCMV)/limited suctioning; Group 2, n = 32). Physiologic readouts of acute lung injury included arterial blood gas analyses, PaO/FiO ratios, peak and plateau airway pressures, lung resistance and static lung compliance. Lung injury was further assessed by histologic scoring. Biochemical analyses included determination of antigenic and enzymographic uPA and tPA levels, plasminogen activator and plasminogen activator inhibitor-1 activities and D-dimer in bronchoalveolar lavage (BAL). Plasma levels of uPA, tPA antigens, D-dimers and α-macroglobulin-uPA complex levels were also assessed.

Results: In Group 1, tPA at the 2 mg dose was ineffective, but at 4 mg tPA or scuPA, the PaO/FiO ratios, peak/plateau pressures improved during evolving injury (p < 0.01) without significant differences at 48 h. To improve delivery of the interventions, the experiments were repeated in Group 2 with limited suctioning/SCMV, which generally increased PAs in (BAL). In Group 2, tPA was ineffective, but scuPA (4 or 8 mg) improved physiologic outcomes (p < 0.01) and plateau pressures remained lower at 48 h. Airway bleeding occurred at 8 mg tPA. BAL plasminogen activator (PA) levels positively correlated with physiologic outcomes at 48 h.

Conclusions: Physiologic outcomes improved in sheep in which better delivery of the PAs occurred. The benefits of nebulized scuPA were achieved without airway bleeding associated with tPA, but were transient and largely abrogated at 48 h, in part attributable to the progression and severity of ISIALI.
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http://dx.doi.org/10.1186/s40169-018-0196-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006005PMC
June 2018

Skeletal dysplasia: Respiratory management during infancy.

Respir Med 2017 10 1;131:18-26. Epub 2017 Aug 1.

Center for Pediatric Lung Research, Nemours, Alfred I. DuPont Hospital for Children, Wilmington, DE, United States; Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States; Temple University School of Medicine, Philadelphia, PA, United States.

Background: Skeletal dysplasia encompasses a variety of developmental disorders of the bone and cartilage that manifest as disproportionate shortening of limbs and trunk in the neonate. Many types of skeletal dysplasia are complicated by respiratory failure at or soon after birth and require intensive care and prolonged hospitalization. Respiratory complications in these infants are complex and are characterized by airway anomalies, restrictive lung disease due to a narrow and abnormally compliant chest wall, pulmonary hypoplasia, and central apnea. Appropriate management of these unique patients requires a clear understanding of the pathophysiology and use of pulmonary function tests for early recognition and management of complications.

Conclusion: This review provides an overview of the underlying respiratory pathology and a practical guide to the newborn care provider for the diagnosis and management of respiratory complications in infants with skeletal dysplasia.
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http://dx.doi.org/10.1016/j.rmed.2017.07.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659738PMC
October 2017

Lung Rest During Extracorporeal Membrane Oxygenation for Neonatal Respiratory Failure-Practice Variations and Outcomes.

Pediatr Crit Care Med 2017 Jul;18(7):667-674

1Department of Pediatrics, Nemours, Alfred I. duPont Hospital for Children, Wilmington, DE. 2Center for Pediatric Lung Research, Nemours, Alfred I. duPont Hospital for Children, Wilmington, DE. 3Department of Pediatrics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA. 4Biostatistics Core, Nemours, Alfred I. duPont Hospital for Children, Wilmington, DE. 5Temple University School of Medicine, Philadelphia, PA.

Objective: Describe practice variations in ventilator strategies used for lung rest during extracorporeal membrane oxygenation for respiratory failure in neonates, and assess the potential impact of various lung rest strategies on the duration of extracorporeal membrane oxygenation and the duration of mechanical ventilation after decannulation.

Data Sources: Retrospective cohort analysis from the Extracorporeal Life Support Organization registry database during the years 2008-2013.

Study Selection: All extracorporeal membrane oxygenation runs for infants less than or equal to 30 days of life for pulmonary reasons were included.

Data Extraction: Ventilator type and ventilator settings used for lung rest at 24 hours after extracorporeal membrane oxygenation initiation were obtained.

Data Synthesis: A total of 3,040 cases met inclusion criteria. Conventional mechanical ventilation was used for lung rest in 88% of cases and high frequency ventilation was used in 12%. In the conventional mechanical ventilation group, 32% used positive end-expiratory pressure strategy of 4-6 cm H2O (low), 22% used 7-9 cm H2O (mid), and 43% used 10-12 cm H2O (high). High frequency ventilation was associated with an increased mean (SEM) hours of extracorporeal membrane oxygenation (150.2 [0.05] vs 125 [0.02]; p < 0.001) and an increased mean (SEM) hours of mechanical ventilation after decannulation (135 [0.09] vs 100.2 [0.03]; p = 0.002), compared with conventional mechanical ventilation among survivors. Within the conventional mechanical ventilation group, use of higher positive end-expiratory pressure was associated with a decreased mean (SEM) hours of extracorporeal membrane oxygenation (high vs low: 136 [1.06] vs 156 [1.06], p = 0.001; mid vs low: 141 [1.06] vs 156 [1.06]; p = 0.04) but increased duration of mechanical ventilation after decannulation in the high positive end-expiratory pressure group compared with low positive end-expiratory pressure (p = 0.04) among survivors.

Conclusions: Wide practice variation exists with regard to ventilator settings used for lung rest during neonatal respiratory extracorporeal membrane oxygenation. Use of high frequency ventilation when compared with conventional mechanical ventilation and use of low positive end-expiratory pressure strategy when compared with mid positive end-expiratory pressure and high positive end-expiratory pressure strategy is associated with longer duration of extracorporeal membrane oxygenation. Further research to provide evidence to drive optimization of pulmonary management during neonatal respiratory extracorporeal membrane oxygenation is warranted.
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http://dx.doi.org/10.1097/PCC.0000000000001171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503755PMC
July 2017

RIP: A Novel Respiratory Inductance Plethysmography Monitor.

J Med Device 2017 Mar 24;11(1):0110101-110106. Epub 2017 Jan 24.

Department of Biomedical Research and Center for Pediatric Lung Research, Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, DE 19803 e-mail: 

Objective pulmonary function (PF) evaluation is essential for the diagnosis, monitoring, and management of many pediatric respiratory diseases as seen in the emergency room, intensive care, and outpatient settings. In this paper, the development and testing of a new noninvasive PF instrument, pneuRIP, which utilizes respiratory inductance plethysmography (RIP) are discussed. The pneuRIP hardware includes a small circuit board that connects to the RIP bands and measures and wirelessly transmits the band inductance data to any designated wirelessly connected tablet. The software provides indices of respiratory work presented instantaneously in a user-friendly graphical user interface on the tablet. The system was tested with ten normal children and compared with an existing system, Respitrace (Sensormedics, Yorba Linda, CA), under normal and loaded breathing conditions. Under normal breathing, the percentage differences between the two systems were 2.9% for labored breathing index (LBI), 31.8% for phase angle (Φ), 4.8% for percentage rib cage (RC%), and 26.7% for respiratory rate (BPM). Under loaded breathing, the percentage differences between the two systems were 1.6% for LBI, 4.1% for Φ, 8.5% for RC%, and 52.7% for BPM. For LBI, Φ, and RC%, the two systems were in general agreement. For BPM the pneuRIP is shown to be more accurate than the respitrace when compared to manually counting the breaths: 13.2% versus 36.4% accuracy for normal breathing and 16.9% versus 60.7% accuracy for breathing under load, respectively.
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http://dx.doi.org/10.1115/1.4035546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318692PMC
March 2017

Non-invasive pulmonary function test on Morquio patients.

J Rare Dis Res Treat 2017 ;2(2):55-62

Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.

Morquio patients, in many cases, present with severe tracheal narrowing and restrictive lung problems making them susceptible to high mortality arising from sleep apnea and related complications. Tracheal obstruction with growth imbalance, short neck, adeno and tonsillar hypertrophy, large mandible, and/or pectus carinatum also contributes to the challenges in managing the airway with intubation and extubation due to factors intrinsic to Morquio syndrome. Taken together, these issues lead to serious respiratory distress and life-threatening complications during anesthetic procedures. Furthermore, patients with Morquio syndrome frequently cannot perform standard pulmonary function tests as a result of their distinctive skeletal dysplasia and chest deformity, thus making diagnosis of incipient pulmonary disease difficult. In many cases, conventional spirometry is too difficult for patients to complete, deriving from issues with cooperation or clinical circumstance. Therefore, it is an unmet challenge to assess pulmonary insufficiency with standard pulmonary function test (PFT) with minimal effort. Non-invasive PFT such as respiratory inductance plethysmography, impulse oscillometry system, and pneumotachography were described in Morquio patients as compared with spirometry. Findings from our previous study indicate that these non-invasive tests are a reliable approach to evaluate lung function in a larger range of patients, and provide valuable clinical information otherwise unobtainable from invasive tests. In conclusion, the present study describes the utility of non-invasive (PFT) to accommodate a broad range of patients including intolerance to effort-dependent PFT.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171363PMC
January 2017

A translational cellular model to study the impact of high-frequency oscillatory ventilation on human epithelial cell function.

J Appl Physiol (1985) 2017 01 10;122(1):198-205. Epub 2016 Nov 10.

Nemours Research Lung Center, Alfred I. duPont Children's Hospital, Wilmington, Delaware.

High-frequency oscillatory ventilation (HFOV) has been proposed as gentle ventilation strategy to prevent lung injury in the preterm infant. High-frequency jet ventilation leads to dimensional and mechanical airway deformation in animal airway models, which is consistent with translational studies demonstrating the impact of oxygen and biophysical stresses on normal airway cellular function. There is an overall paucity of clinical and cellular data on the impact of HFOV on the conducting airway. We developed an innovative method to test the impact of the clinical HFO Ventilator (SensorMedics 3100A) on human epithelial cell function. In this translational model, we were able to study the differential effects of biophysical stress due to HFOV independently and in combination with hyperoxia on a direct cellular level of the conducting airway system. Additionally, we could demonstrate that hyperoxia and pressure by HFOV independently resulted in significant cell dysfunction and inflammation, while the combination of HFOV and hyperoxia had a synergistic effect, resulting in greater cell death.

New & Noteworthy: Traditionally, large-animal models are used to analyze the impact of clinical ventilators on lung cellular function. In our dual-chamber model, we interface high-frequency oscillatory ventilation (HFOV) directly with airway cells to study the effects of HFOV independently and combined with hyperoxia. Therefore, it is possible to study the preclinical impact of interventional factors without the high cost of animal models, thus reducing staff, time, as well as animal sparing.
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http://dx.doi.org/10.1152/japplphysiol.00400.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283848PMC
January 2017

Management of Supplemental Oxygen for Infants with Persistent Pulmonary Hypertension of Newborn: A Survey.

Am J Perinatol 2017 Feb 4;34(3):276-282. Epub 2016 Aug 4.

Department of Pediatrics, Nemours, Alfred I. duPont Hospital for Children, Wilmington, Delaware.

 To evaluate practice variations amongst neonatologists regarding oxygen management in neonates with persistent pulmonary hypertension of newborn (PPHN).  An online survey was administered to neonatologists to assess goal oxygenation targets and oxygen titration practices in PPHN. Response variations were assessed and intergroup comparisons performed.  Thirty-three percent (492) of neonatologists completed the survey. Twenty-eight percent reported using specific oxygen titration guidelines. Majority of respondents used a combination of oxygen saturation (SpO) and arterial oxygen tension (PaO) initially to titrate oxygen. Seventy percent of the respondents used higher goal SpO > 95% or 95 to 98% and thirty-eight percent of the respondents used PaO > 80 mm Hg. Physicians with extracorporeal membrane oxygenation experience and those with greater than ten years neonatal intensive care unit experience inclined toward use of SpO alone for oxygen titration and aimed for lower range of SpO and PaO targets. Greater proportion of neonatologists who employed specific oxygen titration guidelines used lower SpO targets.  Wide practice variations exist amongst neonatologists regarding optimal SpO and PaO targets and oxygen titration practices in the management of PPHN.
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http://dx.doi.org/10.1055/s-0036-1586754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646216PMC
February 2017

Activity of daily living for Morquio A syndrome.

Mol Genet Metab 2016 06 25;118(2):111-22. Epub 2016 Apr 25.

Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA; Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan. Electronic address:

The aim of this study was to evaluate the activity of daily living (ADL) and surgical interventions in patients with mucopolysaccharidosis IVA (MPS IVA). The factor(s) that affect ADL are age, clinical phenotypes, surgical interventions, therapeutic effect, and body mass index. The ADL questionnaire comprises three domains: "Movement," "Movement with cognition," and "Cognition." Each domain has four subcategories rated on a 5-point scale based on the level of assistance. The questionnaire was collected from 145 healthy controls and 82 patients with MPS IVA. The patient cohort consisted of 63 severe and 17 attenuated phenotypes (2 were undefined); 4 patients treated with hematopoietic stem cell transplantation (HSCT), 33 patients treated with enzyme replacement therapy (ERT) for more than a year, and 45 untreated patients. MPS IVA patients show a decline in ADL scores after 10years of age. Patients with a severe phenotype have a lower ADL score than healthy control subjects, and lower scores than patients with an attenuated phenotype in domains of "Movement" and "Movement with cognition." Patients, who underwent HSCT and were followed up for over 10years, had higher ADL scores and fewer surgical interventions than untreated patients. ADL scores for ERT patients (2.5years follow-up on average) were similar with the-age-matched controls below 10years of age, but declined in older patients. Surgical frequency was higher for severe phenotypic patients than attenuated ones. Surgical frequency for patients treated with ERT was not decreased compared to untreated patients. In conclusion, we have shown the utility of the proposed ADL questionnaire and frequency of surgical interventions in patients with MPS IVA to evaluate the clinical severity and therapeutic efficacy compared with age-matched controls.
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http://dx.doi.org/10.1016/j.ymgme.2016.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016714PMC
June 2016

Parental preferences regarding administration of an animal-derived versus a synthetic medication to newborn infants.

J Neonatal Perinatal Med 2016 ;9(1):7-14

Center for Pediatric Lung Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.

Aim: We examined the perceptions of parents with regard to animal-derived versus synthetic medications of comparable efficacy. We hypothesized that this issue is a concern in neonatal care and that the perceptions of parents from one geographical location would be similar to those of another.

Methods: A survey was distributed to parents of neonates admitted to a neonatal intensive care unit of a southeastern hospital.

Results: Of 153 parents surveyed, 150 (98%) responded. More mothers than fathers completed the surveys (113 vs. 34). Fifty-six percent of participants indicated a college or higher education; 40% had an income of $51,000/yr or higher. Thirty-four percent of parents had concerns about animal-derived medications, 41% preferred a synthetic medication of equivalent efficacy, and 69% would like to be informed if a medication was animal-derived.

Conclusion: Parents have concerns about exposing neonates to animal-derived medication and wish to be informed if an animal-derived medication is being considered.
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http://dx.doi.org/10.3233/NPM-16915062DOI Listing
May 2017

Safety and Long Term Outcomes with High Flow Nasal Cannula Therapy in Neonatology: A Large Retrospective Cohort Study.

J Pulm Respir Med 2014 Dec;4(6)

Vapotherm, Inc., Stevensville, USA ; Department of Pediatrics, Jefferson Medical College, Philadelphia, PA, USA.

Objective: High flow nasal cannula therapy (HFT) has been shown to be similar to nasal continuous positive airway pressure (nCPAP) in neonates with respect to avoiding intubation. The objective of the current study is to determine if there are trends for adverse safety and long-term respiratory outcomes in very low birth weight infants (<1500 g) from centers using HFT as their primary mode of non-invasive respiratory support compared to data from the largest neonatal outcomes database (Vermont Oxford Network; VON).

Methods: A multicenter, retrospective analysis of pulmonary outcomes data was performed for the calendar years 2009, 2010 and 2011. Performance of five HFT centers was compared with population outcomes from the VON database. The five HFT centers routinely use flow rates between 4-8 L/min as described by the mechanistic literature. Weighted average percentages from the five HFT centers were calculated, along with the 95% confidence intervals (CI) to allow for comparison to the VON means.

Results: Patient characteristics between the HFT centers and the VON were not different in any meaningful way, despite the HFT having a greater percentage of smaller infants. The average VON center primarily used nCPAP (69% of all infants) whereas the HFT centers primarily used HFT (73%). A lesser percentage of VLBW infants in the HFT cohort experienced mortality and nosocomial infection. Compared to VON data, an appreciably lesser percent of the HFT cohort were receiving oxygen at 36 weeks and less went home on oxygen.

Conclusions: Considering there was no trend for adverse events, and there was a trend for better outcomes pertaining to long-term oxygen use, these data support claims of safety for HFT as a routine respiratory management strategy in the NICU.
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http://dx.doi.org/10.4172/2161-105X.1000216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497790PMC
December 2014

Non-invasive pulmonary function test on Morquio patients.

Mol Genet Metab 2015 Aug 23;115(4):186-92. Epub 2015 Jun 23.

Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA; Center for Pediatric Lung Research, Nemours/Alfred I. DuPont Hospital for Children, Wilmington, DE, USA. Electronic address:

In clinical practice, respiratory function tests are difficult to perform in Morquio syndrome patients due to their characteristic skeletal dysplasia, small body size and lack of cooperation of young patients, where in some cases, conventional spirometry for pulmonary function is too challenging. To establish feasible clinical pulmonary endpoints and determine whether age impacts lung function in Morquio patients non-invasive pulmonary tests and conventional spirometry were evaluated. The non-invasive pulmonary tests: impulse oscillometry system, pneumotachography, and respiratory inductance plethysmography in conjunction with conventional spirometry were evaluated in twenty-two Morquio patients (18 Morquio A and 4 Morquio B) (7 males), ranging from 3 to 40 years of age. Twenty-two patients were compliant with non-invasive tests (100%) with the exception of IOS (81.8%-18 patients). Seventeen patients (77.3%) were compliant with spirometry testing. All subjects had normal vital signs at rest including >95% oxygen saturation, end tidal CO2 (38-44 mmHg), and age-appropriate heart rate (mean=98.3, standard deviation=19) (two patients were deviated). All patients preserved normal values in the impulse oscillometry system, pneumotachography, and respiratory inductance plethysmography, although predicted forced expiratory total (72.8±6.9 SE%) decreased with age and was below normal; phase angle (35.5±16.5°), %rib cage (41.6±12.7%), resonant frequency, and forced expiratory volume in 1 s/forced expiratory volume total (110.0±3.2 SE%) were normal and not significantly impacted by age. The proposed non-invasive pulmonary function tests are able to cover a greater number of patients (young patients and/or wheel-chair bound), thus providing a new diagnostic approach for the assessment of lung function in Morquio syndrome which in many cases may be difficult to evaluate. Morquio patients studied herein demonstrated no clinical or functional signs of restrictive and/or obstructive lung disease.
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http://dx.doi.org/10.1016/j.ymgme.2015.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706533PMC
August 2015

Prophylactic methylprednisolone to reduce inflammation and improve outcomes from one lung ventilation in children: a randomized clinical trial.

Paediatr Anaesth 2015 Jun 2;25(6):587-94. Epub 2015 Jan 2.

Department of Anesthesiology and Critical Care Medicine, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA; Department of Anesthesiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA; Department of Pediatrics, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA.

Background: One lung ventilation (OLV) results in inflammatory and mechanical injury, leading to intraoperative and postoperative complications in children. No interventions have been studied in children to minimize such injury.

Objective: We hypothesized that a single 2-mg·kg(-1) dose of methylprednisolone given 45-60 min prior to lung collapse would minimize injury from OLV and improve physiological stability.

Methods: Twenty-eight children scheduled to undergo OLV were randomly assigned to receive 2 mg·kg(-1) methylprednisolone (MP) or normal saline (placebo group) prior to OLV. Anesthetic management was standardized, and data were collected for physiological stability (bronchospasm, respiratory resistance, and compliance). Plasma was assayed for inflammatory markers related to lung injury at timed intervals related to administration of methylprednisolone.

Results: Three children in the placebo group experienced clinically significant intraoperative and postoperative respiratory complications. Respiratory resistance was lower (P = 0.04) in the methylprednisolone group. Pro-inflammatory cytokine IL-6 was lower (P = 0.01), and anti-inflammatory cytokine IL-10 was higher (P = 0.001) in the methylprednisolone group. Tryptase, measured before and after OLV, was lower (P = 0.03) in the methylprednisolone group while increased levels of tryptase were seen in placebo group after OLV (did not achieve significance). There were no side effects observed that could be attributed to methylprednisolone in this study.

Conclusions: Methylprednisolone at 2 mg·kg(-1) given as a single dose prior to OLV provides physiological stability to children undergoing OLV. In addition, methylprednisolone results in lower pro-inflammatory markers and higher anti-inflammatory markers in the children's plasma.
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http://dx.doi.org/10.1111/pan.12601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414674PMC
June 2015

Piecewise Mixed Effects Model to Compare the Weight-gain Patter ns Before and After Diagnosis of Asthma in Children Younger than 5 Years.

J Biom Biostat 2015 Jan;6(4):248

Department of Biomedical Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.

Asthma and obesity are two significant public health problems that both originate in early childhood and have shared risk factors and manifestations. Studies suggest a strong association between asthma development and subsequent accelerated weight gain. Children are diagnosed with asthma in early childhood and are often exposed to factors associated with rapid weight gain. This article intends to demonstrate an innovative application of the piecewise mixed effects model to characterize the difference in the temporal rate of change in BMIz, the standardized scores of body mass index and weight-for-length that measure weight status, before and after asthma diagnosis in children younger than 5 years. The data consist of unique sequences from 1194 children's clinic visits during the first 5 years of life. We used a knot at the time of diagnosis and detected a differential weight-gain pattern before and after asthma diagnosis. The pre- and post-asthma-diagnosis weight-gain patterns further differ by sex and race-ethnicity. After asthma diagnosis, female children showed a higher increase in the rate of change in BMIz than males. Non-Hispanic African Americans and Hispanics had higher post-diagnosis rates of change in BMIz than Caucasians. The differential weight-gain patterns between male and female children were mainly contributed by Caucasian children. These findings could have important implications in the clinical care of children after asthma diagnosis.
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http://dx.doi.org/10.4172/2155-6180.1000248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772666PMC
January 2015

Plp1 gene duplication inhibits airway responsiveness and induces lung inflammation.

Pulm Pharmacol Ther 2015 Feb 4;30:22-31. Epub 2014 Nov 4.

Alfred I. duPont Hospital for Children, Nemours Lung Center, Wilmington, DE 19803, USA; Alfred I. duPont Hospital for Children, Nemours Biomedical Research, Wilmington, DE 19803, USA.

Mice with Plp1 gene duplication model the most common form of Pelizaeus-Merzbacher disease (PMD), a CNS disease in which patients may suffer respiratory complications. We hypothesized that affected mice would lack airway responsiveness compared to wild-type and carrier mice during methacholine challenge. Wild-type (n = 10), carrier female (n = 6) and affected male (n = 8) mice were anesthetized-paralyzed, tracheostomized and ventilated. Respiratory mechanics were recorded at baseline and during escalating doses of nebulized methacholine followed by albuterol. Lung resistance (RL) was the primary endpoint. Lung tissues were assayed for inflammatory and histological differences. At baseline, phase angles were higher in carrier and affected mice than wild-type. Dose-response RL curves in affected and carrier mice indicated a lack of methacholine response. Albuterol reduced RL in wild-type and carrier, but not affected mice. Affected mice exhibited lower interleukin (IL)-6 tissue levels and alveolar inflammatory infiltrates. Affected and carrier mice, compared to wild-type, lacked airway reactivity during methacholine challenge, but only affected mice exhibited decreased lung tissue levels of IL-6 and inflammation.
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http://dx.doi.org/10.1016/j.pupt.2014.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874309PMC
February 2015

The orl rat is more responsive to methacholine challenge than wild type.

Pulm Pharmacol Ther 2014 Dec 16;29(2):199-208. Epub 2014 Sep 16.

Alfred I. duPont Hospital for Children, Nemours Lung Center, Wilmington, DE 19803, United States; Temple University School of Medicine, Department of Physiology, Philadelphia, PA 19140, United States; Temple University School of Medicine, Department of Pediatrics, Philadelphia, PA 19140, United States.

Background: This study presents an animal model of native airway hyperresponsiveness (AHR). AHR is a fundamental aspect of asthma and reflects an abnormal response characterized by airway narrowing following exposure to a wide variety of non-immunological stimuli. Undescended testis (UDT) is one of the most common male congenital anomalies. The orl rat is a Long Evans substrain with inherited UDT. Since boys born with congenital UDT are more likely to manifest asthma symptoms, the main aim of this study was to investigate the alternative hypothesis that orl rats have greater AHR to a methacholine aerosol challenge than wild type rats.

Methods: Long Evans wild type (n = 9) and orl (n = 13) rats were anesthetized, tracheostomized, and mechanically ventilated at 4 weeks of age. Escalating concentrations of inhaled methacholine were delivered. The methacholine potency and efficacy in the strains were measured. Respiratory resistance was the primary endpoint. After the final methacholine aerosol challenge, the short-acting β2-adrenoceptor agonist albuterol was administered as an aerosol and lung/diaphragm tissues were assayed for interleukin (IL)-4, IL-6, and tumor necrosis factor (TNF)-α. Histological and histomorphometrical analyses were performed.

Results: The methacholine concentration-response curve in the orl group indicated increased sensitivity, hyperreactivity, and exaggerated maximal response in comparison with the wild type group, indicating that orl rats had abnormally greater AHR responses to methacholine. Histological findings in orl rats showed the presence of eosinophils, unlike wild type rats. β2-Adrenoceptor agonist intervention resulted in up-regulation of IL-4 diaphragmatic levels and down-regulation of IL-4 and IL-6 in the lungs of orl rats.

Conclusion: orl rats had greater AHR than wild type rats during methacholine challenge, with higher IL-4 levels in diaphragmatic tissue homogenates. Positive immunostaining for IL-4 was detected in lung and diaphragmatic tissue in both strains. This model offers advantages over other pre-clinical murine models for studying potential mechanistic links between cryptorchidism and asthma. This animal model may be useful for further testing of compounds/therapeutics options for treating AHR.
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http://dx.doi.org/10.1016/j.pupt.2014.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323580PMC
December 2014
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