PET Imaging of Neurofibromatosis Type 1 with a Fluorine-18 Labeled Tryptophan Radiotracer.

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder. Plexiform neurofibromas (PNFs) are benign tumors commonly formed in patients with NF1. PNFs have a high incidence of developing into malignant peripheral nerve sheath tumors (MPNSTs) with a 5-year survival rate of only 30%. Therefore, the accurate diagnosis and differentiation of MPNSTs from benign PNFs are critical to patient management. We studied a fluorine-18 labeled tryptophan positron emission tomography (PET) radiotracer, 1-(2-[18F]fluoroethyl)-L-tryptophan (L-[18F]FETrp), to detect NF1-associated tumors in an animal model. An ex vivo biodistribution study of L-[18F]FETrp showed a similar tracer distribution and kinetics between the wild-type and triple mutant mice with the highest uptake in the pancreas. Bone uptake was stable. Brain uptake was low during the 90-min uptake period. Static PET imaging at 60 min post-injection showed L-[18F]FETrp had a comparable tumor uptake with [18F]fluorodeoxyglucose (FDG). However, L-[18F]FETrp showed a significantly higher tumor-to-brain ratio than FDG (n = 4, p < 0.05). Sixty-minute-long dynamic PET scans using the two radiotracers showed similar kidney, liver, and lung kinetics. A dysregulated tryptophan metabolism in NF1 mice was further confirmed using immunohistostaining. L-[18F]FETrp is warranted to further investigate differentiating malignant NF1 tumors from benign PNFs. The study may reveal the tryptophan-kynurenine pathway as a therapeutic target for treating NF1.

Impact of intravenous fluid administration on cardiac output and oxygenation during cardiopulmonary resuscitation.

BACKGROUND: The effect of intravenous fluid (IVF) administration during cardiopulmonary resuscitation (CPR) is an unexplored factor that may improve cardiac output (CO) during CPR. The aim of this study was to determine the effect of IVF administration on CO and oxygenation during CPR. METHODS: This experimental animal study was performed in a critical care animal laboratory. Twenty-two Landrace-Yorkshire female piglets weighing 27-37 kg were anesthetized, intubated, and placed on positive pressure ventilation. Irreversible cardiac arrest was induced with bupivacaine. CPR was performed with a LUCAS 3 mechanical compression device. Pigs were randomized into IVF or no-IVF groups. Pigs in the IVF group were given 20 mL/kg of Plasma-Lyte (Baxter International, Deerfield, IL USA), infused from 15 to 35 min of CPR. CPR was maintained for 50 min with serial measurements of CO obtained using ultrasound dilution technology and partial pressure of oxygen (PaO2). RESULTS: A mixed-effects repeated measures analysis of variance was used to compare within-group, and between-group mean changes in CO and PaO2 over time. CO and PaO2 for the piglets were measured at 10-min intervals during the 50 min of CPR. CO was greater in the IVF compared with the control group at all time points during and after the infusion of the IVF. Mean PaO2 decreased with time; however, at no time was there a significant difference in PaO2 between the IVF and control groups. CONCLUSIONS: Administration of IVF during CPR resulted in a significant increase in CO during CPR both during and after the IVF infusion. There was no statistically significant decrease in PaO2 between the IVF and control groups.

A Novel Agnostic Respiratory Stimulant as a Treatment for Apnea of Prematurity: A Proof-of-Concept Study.

AIM/OBJECTIVE: ENA-001 is a novel selective antagonist of large-conductance BK (big potassium) channels located in the carotid bodies, where they act as chemoreceptors that sense low arterial oxygen levels and establish a feedback loop to brainstem nuclei responsible for initiating spontaneous breathing and maintaining adequate oxygen to tissues. ENA-001 attenuates respiratory depression induced by a variety of chemical agents, essentially "agnostic" to the precipitating drug (e.g., opioid(s), benzodiazepine, alcohol, or propofol). But it had not been tested against respiratory depression resulting from a physiological cause, such as apnea of prematurity (AOP). This proof-of-principle study used a well-described animal model (premature lamb) to test the effectiveness of ENA-001 in the setting of an under-developed respiratory control system, similar to that in human AOP. MATERIALS AND METHODS: A set of twin lambs was delivered prematurely via caesarian section at 135 ± 2 d gestational age (GA). An arterial catheter was connected to a transducer for pressure monitoring and a venous catheter was connected to a pump for continuous infusion of 5% dextrose in water (D5W). Lambs were to receive four mechanical breaths for lung recruitment and then started on continuous positive airway pressure (CPAP). After a stabilization period of 15 minutes, the protocol called for the first lamb to be started on continuous infusion of ENA-001, with ascending dose hourly (0.4, 1.1, 2.0, 12.0 mg/kg/hr), while the second lamb was to serve as a sham (D5W) control. At least 10 representative breaths free of artifact from motion or atypical breaths were recorded using a pulmonary function system designed for neonatal research. To maintain a stable plane of anesthesia, repeat doses of fentanyl (1 µg IM) were given as needed based on blood pressure response to stimulation. RESULTS: Two male lambs were delivered. Unexpectedly, neither lamb exhibited a drive for spontaneous breathing. Each required manual ventilation, with a complete absence of spontaneous effort. Despite the poor prognosis owing to the absence of ventilatory effort, continuous infusion of the first dose of ENA-001 was started 20 minutes after birth. The test animal continued to require manual ventilation, which was continued for an additional 10 minutes. An intravenous (IV) bolus of ENA-001 was given. Nearly instantaneously following the delivery of the IV bolus, the lamb began breathing spontaneously and did not require manual intervention for the remainder of the study. The sham animal was delivered approximately an hour following the test animal. As with the test animal, the sham animal lacked spontaneous breathing efforts. A decision was made to manually ventilate for 30 minutes to match the course for the test animal. At the 30-minute time point, an IV bolus infusion of ENA-001 was delivered. Nearly instantaneously following the delivery of the IV bolus, the lamb began breathing spontaneously. After several minutes, the spontaneous breathing efforts abated, and manual ventilation was resumed. The animal was then sacrificed for tissue harvest. CONCLUSION: These results suggest that ENA-001 might be an effective therapy, alone or as a co-medication, for the treatment of AOP. They further suggest that ENA-001 might have broader applications in situations of neurological ventilatory insufficiency.

Utilising pneuRIP device in determining the adequacy of respiratory support when weaning high-flow nasal cannula in paediatric patients with acute respiratory distress: A pilot study.

AIM: Recognition of paediatric respiratory distress and timely intervention is critical, especially during the weaning phase of support in paediatric acute respiratory failure, as weaning too aggressively can lead to further setbacks in a patient's recovery. We aimed to determine if pulmonary function measurements obtained with the pneuRIP device, a noninvasive pulmonary function testing device that provides measurements of labored breathing index (LBI), phase angle and %rib cage (%RC) contribution to breathing, will provide predictive values to assess the adequacy of respiratory support while weaning from HFNC. METHODS: We reviewed patients ages 0-18 years admitted to the PICU for respiratory distress due to respiratory infections receiving HFNC. Patients with history of chronic lung disease and chronic neuromuscular disease with baseline habnormal breathing patterns were excluded. Phase angle, LBI and %RC were obtained every hour and with every wean of HFNC. Nine patients were enroled. RESULTS: Mean LBI range remained 1.27-1.68 when LBI was plotted as a function of the HFNC flow rate. Mean values of %RC contribution to breathing ranged 43.65-57.12 as a function of the HFNC flow rate. No significant deviations existed in either %RC (P = 0.16) or LBI (P = 0.16) during the weaning of HFNC. Mean phase angle for all subjects was 41.48°-74.12° for the duration of wean and showed significant deviation from baseline during the weaning process (p = 0.001). CONCLUSIONS: Measurements of LBI and %RC on the pneuRIP device effectively demonstrated tolerance of weaning HFNC during the recovery phase of acute respiratory failure from a respiratory infection.

Administration of Drugs/Gene Products to the Respiratory System: A Historical Perspective of the Use of Inert Liquids.

The present review is a historical perspective of methodology and applications using inert liquids for respiratory support and as a vehicle to deliver biological agents to the respiratory system. As such, the background of using oxygenated inert liquids (considered a drug when used in the lungs) opposed to an oxygen-nitrogen gas mixture for respiratory support is presented. The properties of these inert liquids and the mechanisms of gas exchange and lung function alterations using this technology are described. In addition, published preclinical and clinical trial results are discussed with respect to treatment modalities for respiratory diseases. Finally, this forward-looking review provides a comprehensive overview of potential methods for administration of drugs/gene products to the respiratory system and potential biomedical applications.

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

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 cmH2O (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 cmH2O increased the mean (SEM) expired minute ventilation from 6.33 (0.04) to 7.33 (0.04) mL/min. With the 5-cmH2O incremental increases in positive end-expiratory pressure from 0 to 20 cmH2O, volumetric capnography increased from a mean (SEM) of 94.19 (0.78) to 115.18 (0.8) mL/min, except for 15 cmH2O, which showed greater carbon dioxide exhalation with volumetric capnography compared with 20 cmH2O. PCO2 declined significantly as positive end-expiratory pressure was increased from 0 to 20 cmH2O. 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.

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

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 pneuRIP device and a machine-learning algorithm was developed. pneuRIP 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.

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

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.

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

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.

Machine learning for automatic identification of thoracoabdominal asynchrony in children.

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.

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

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.

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

Background: 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. Objective: To determine differential DNA methylation in cord blood mononuclear leukocytes from neonates exposed to HCA. Methods: 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. Results: 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 p ≤ 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. Conclusions: 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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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. Postextubation 2.5- and 3.0-mm 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 (SBTs) were performed using a virtual patient model and were considered "passed" if minute ventilation of patient ETTs was greater than 60% of control ETTs. Twenty-four 2.5-mm ETTs and sixteen 3.0-mm ETTs were analyzed. In both 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 19.9 cmH2O·l-1·sec-1 greater resistance than control ETTs. SBTs were performed in 27 of 40 ETTs. Twenty-six ETTs "passed" an SBT. In one obstructed 3.0-mm ETT, SBT measurements were unobtainable. The clinical impact of ETT biofilm as measured by a SBT appears to be minimal for the majority of patients in our study group. In 1 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.NEW & NOTEWORTHY This is the first study to our knowledge to characterize the impact of endotracheal tube (ETT) biofilm and respiratory secretions on resistance to airflow in a neonatal ETT using a simulation neonatal lung model. Results show that the clinical impact of ETT biofilm is minimal for the majority of patients in our study group, and ETT obstruction from biofilm is an uncommon cause of respiratory decompensation in a preterm neonate.

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

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.

Quantitative Analysis of Thoracoabdominal Asynchrony in Pediatric Polysomnography.

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 r = .35 [P = .03] and .40 [P = .01], respectively) and θavg during stage N3 sleep with OAHI (r = .35 [P = .03]). LBIavg showed lower correlations. Median θavg during stage R sleep (33.1) was significantly greater than during stage N3 sleep (13.7, P = .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.