The epidemiology of apnoea of prematurity.

WHAT IS KNOWN AND OBJECTIVE: Many premature infants less than 37 weeks gestational age (GA), and almost all infants less than 28 weeks GA, will experience apnoea of prematurity (AOP)-a cessation of respiration for 20 or more seconds (or less than 20 s if accompanied by other signs). Because the treatment options for AOP are so limited, we explore its epidemiology, with the ultimate hope of learning how to decrease its incidence. COMMENT: Although AOP usually resolves with maturation of the respiratory system, many short- and long-term negative effects are correlated statistically with AOP (although direct causality has not been established). The primary risk factor for AOP is preterm birth, but delivery technique, genetics, socioeconomic status, racial disparities and other influences are suspected to be involved. Anaemia, asthma and gastric reflux have also been associated with preterm birth, but the relationship with AOP is unclear. The postulated associations and the strength of the evidence are briefly reviewed and discussed. WHAT IS NEW AND CONCLUSION: Attempts to elucidate the epidemiology of apnoea of prematurity have been challenging. Studies of AOP are hampered in part by challenges in monitoring the condition, the interplay of multiple comorbidities in preterm neonates and lack of expert consensus definitions. However, since the primary risk factor is preterm birth, efforts to decrease the prevalence of preterm birth would have a positive secondary effect on the prevalence of AOP. Until then, better pharmacotherapeutic options are needed.

The limited management options for apnoea of prematurity.

WHAT IS KNOWN AND OBJECTIVE: About 10% of all infants are born prematurely. Almost all of those of gestational age less than about 30 weeks, and about half of those of gestational age up to about 35 weeks, are subject to unpredictable interruptions of breathing-known as "apnoea of prematurity" (AOP). We present a synopsis of the problem and point out the limited management options. COMMENT: A basal rate for spontaneous breathing is normally maintained by integrated action of generator cells in the brainstem and feedback from central and peripheral chemosensors. In AOP, there are intermittent periods (seconds) lacking spontaneous firing, which results in hypoxia and hypercapnia. The long-term consequences of these interruptions in oxygen supply to tissues are not known. Although many treatment modalities are used, including drug therapy, nonpharmacologic care and mechanical intervention, there is no universally effective first-line management for AOP. Caffeine citrate is generally the most frequently used pharmacotherapeutic agent, but its side effect profile narrows with higher doses and the upper limit is still being investigated to discern the greatest benefit-to-risk ratio; thus, most infants do not achieve complete resolution of apnoeas. WHAT IS NEW AND CONCLUSION: Given the widespread and serious nature of the problem of AOP, there is a surprising lack of treatment options. A more consistent and effective treatment, alone or as adjunct, would be welcome.

HVNI vs NIPPV in the treatment of acute decompensated heart failure: Subgroup analysis of a multi-center trial in the ED.

BACKGROUND AND OBJECTIVE: Managing respiratory failure (RF) secondary to acute decompensated heart failure (ADHF) with non-invasive positive-pressure ventilation (NIPPV) has been shown to significantly improve morbidity and mortality in patients presenting to the emergency department (ED). This subgroup analysis compares high-velocity nasal insufflation (HVNI), a form of high-flow nasal cannula, with NIPPV in the treatment of RF secondary to ADHF with respect to therapy failure, as indicated by the requirement for intubation or all-cause arm failure including subjective crossover to the alternate therapy. METHODS: The subgroup analysis is from a larger randomized control trial of adults presenting to the ED with RF requiring NIPPV support. Patients were randomly selected to therapy, and subgroup selection was established a priori in the original study as a discharge diagnosis. The primary outcome was therapy failure at 72 h after enrolment. RESULTS: Subgroup analysis included a total of 22 HVNI and 20 NIPPV patients which fit discharge diagnosis ADHF. Baseline patient characteristics were not statistically significant. Primary outcomes were not statistically significant: intubation rate (p = 1.000), therapy success (p = 1.000). Repeated measures (vitals, dyspnea, blood gases) showed comparable differences over initial 4 h. Physicians scored HVNI superior on patient comfort/tolerance (p < 0.001), ease of use (p = 0.004), and monitoring (p = 0.036). Limitations were technical inability to blind the clinician team and lack of power of the subgroup analysis. CONCLUSION: In conclusion, this subgroup analysis suggests HVNI may be non-inferior to NIPPV in patients with respiratory failure secondary to ADHF that do not need emergent intubation.

High-Velocity Nasal Insufflation in the Treatment of Respiratory Failure: A Randomized Clinical Trial.

STUDY OBJECTIVE: We compare high-velocity nasal insufflation, a form of high-flow nasal cannula, with noninvasive positive-pressure ventilation in the treatment of undifferentiated respiratory failure with respect to therapy failure, as indicated by requirement for endotracheal intubation or cross over to the alternative therapy. METHODS: This was a multicenter, randomized trial of adults presenting to the emergency department (ED) with respiratory failure requiring noninvasive positive-pressure ventilation. Patients were randomly assigned to high-velocity nasal insufflation (initial flow 35 L/min; temperature 35°C (95°F) to 37°C (98.6°F); FiO2 1.0) or noninvasive positive-pressure ventilation using an oronasal mask (inspiratory positive airway pressure 10 cm H2O; expiratory positive airway pressure 5 cm H2O). The primary outcome was therapy failure at 72 hours after enrollment. A subjective outcome of crossover was allowed as a risk mitigation to support deferment of informed consent. Noninferiority margins were set at 15 and 20 percentage points, respectively. RESULTS: A total of 204 patients were enrolled and included in the analysis, randomized to high-velocity nasal insufflation (104) and noninvasive positive-pressure ventilation (100). The intubation rate (high-velocity nasal insufflation=7%; noninvasive positive-pressure ventilation=13%; risk difference=-6%; 95% confidence interval -14% to 2%) and any failure of the assigned arm (high-velocity nasal insufflation=26%; noninvasive positive-pressure ventilation=17%; risk difference 9%; confidence interval -2% to 20%) at 72 hours met noninferiority. The effect on PCO2 over time was similar in the entire study population and in patients with baseline hypercapnia. Vital signs and blood gas analyses improved similarly over time. The primary limitation was the technical inability to blind the clinical team. CONCLUSION: High-velocity nasal insufflation is noninferior to noninvasive positive-pressure ventilation for the treatment of undifferentiated respiratory failure in adult patients presenting to the ED.

AOA Critical Issues Symposium: The Dynamic Environment of Health Care.

ABSTRACT: The dynamic health-care environment continues to undergo disruptive change. As the health-care system emerges from the pandemic, underlying issues have progressively become critical. Private equity acquisition is dramatically increasing, and consolidation in the entire health-care system limits choice and access. Challenges in the workforce and supply chain persist, adding pressure on already strained health-care organizations. Innovative solutions are required to provide equitable value-based access to orthopaedic care.

A Single Ascending-Dose Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Respiratory Stimulant ENA-001.

Background ENA-001 (formerly known as GAL-021) is a novel, first-in-class respiratory stimulant. Pharmacokinetic and pharmacodynamic properties, plus safety and tolerability, were assessed in a randomized, single-center study of healthy volunteers. Methodology This four-period study was designed to test continuous two-hour intravenous infusion regimens of ENA-001 at doses of 0.96, 1.44, and 1.92 mg/kg/hour versus placebo. Each participant received four infusions with a seven-day minimum washout between them: one infusion each of the three doses of ENA-001 and one placebo. Pharmacokinetic and pharmacodynamic parameters were assessed and adverse events were recorded. Results A total of 17 participants completed the study. ENA-001 was generally safe and well tolerated over the dose range studied (0.96 to 1.92 mg/kg/hour). ENA-001 was able to drive hyperventilation in a dose-dependent manner in healthy participants. Increases in ventilation due to ENA-001 were not associated with like-magnitude blood pressure response. ENA-001-stimulated decreases in ETCO2 were associated with small, statistically significant, increases in SpO2 levels. Hyperventilation occurred in two participants at the highest dose level, leading to study discontinuation. The terminal half-life of ENA-001 was 6.33 hours. Conclusions The respiratory stimulant ENA-001 demonstrated well-behaved pharmacokinetics following the two-hour infusion. Mean peak plasma concentrations and the mean total systemic exposure values were approximately dose-proportional in the dose range studied.

Noninvasive Point of Care Device for Assessing Cardiac Response to Acute Volume Changes.

Purpose: The change in the amplitude of a peripheral pulse in response to a Valsalva maneuver has diagnostic utility for assessing volume status at the bedside. We have developed a device to automatically quantify the Valsalva pulse response (VPR) to a standardized Valsalva maneuver that the device guides a user to perform. In this study, we sought to determine whether VPR by the device, Indicor, is sensitive enough to detect the acute increase in central pressure and volume load that occurs with a passive leg raise (PLR) in healthy volunteers. Methods: Healthy volunteers were tested semirecumbently at 45 degrees, then again after being leaned back on a pivoted wedge with legs raised at 45 degrees and torso and head flat, and then again in the semirecumbent position. The device recorded a finger photoplethysmography (PPG) signal during a 10-second expiratory effort of 20 mmHg as guided by the device. VPR was automatically calculated as the ratio of the end-Valsalva pulse amplitude to the baseline pulse amplitude. Results: In the 30 participants who completed testing, VPR increased from baseline to PLR in every participant, from 0.34 ± 0.13 to 0.60 ± 0.14 (p < 0.0001). Back upright, VPR decreased back to 0.33 ± 0.10 (p < 0.0001 versus PLR; NS versus baseline position). Conclusion: In this proof-of-concept study of healthy participants, the Indicor device, a noninvasive, convenient device that automatically calculates VPR from a finger photoplethysmography signal during a standardized Valsalva maneuver, was sensitive enough to detect the increase in VPR that occurred with an acute central volume load from a PLR. Future studies should examine whether VPR responds differently to a PLR in heart failure patients with abnormal cardiac performance and/or congestion.

The New Stealth Drug on the Street: A Narrative Review of Xylazine as a Street Drug.

Xylazine is an alpha-adrenergic receptor agonist approved for use only in animals with a prescription from a veterinarian. It is a powerful sedative that is slowly infiltrating the recreational street drug scene and is often used by polysubstance abusers. Known as "tranq," it can be fatal, and xylazine-induced toxicity cannot be reversed with naloxone or nalmefene. Due to its vasoconstrictive effects, chronic use of xylazine is associated with necrotic skin lesions and general deterioration of health. Since xylazine is not approved for human use and is not scheduled as a controlled substance, there are no human studies to provide evidence of drug-drug interactions, lethal doses, or reversal protocols. Xylazine is available online without a prescription. Street drug users may take xylazine knowingly or unknowingly, as it is often combined with other illicit substances such as fentanyl. There are no rapid tests for xylazine, although there are specialty tests that can be ordered. Xylazine represents a major threat to street drug users and another challenge to emergency healthcare workers, first responders, and others who care for those who have taken this "new" street drug.

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.

Airway injury resulting from repeated endotracheal intubation: Possible prevention strategies.

OBJECTIVE: To characterize physical and inflammatory injury that may result from repeated intubation, independent of positive-pressure ventilation; and to determine whether corticosteroids can attenuate injury and or inflammation that may result from repeated intubation. DESIGN: A 4-hr animal protocol. SETTING: All work was done in the animal laboratory at the Alfred I. DuPont Hospital for Children. SUBJECTS: Neonatal piglets (2-8 days old; 2.5 ± 0.4 kg) were intubated and randomized to four groups (n = 8 each) to be followed over 4 hrs. Groups were control (not reintubated), injured (reintubated every 0.5 hr), intratracheal pretreatment with 1 mg of nebulized budesonide (intratracheal pretreated), or intravenous pretreatment with 0.3 mg/kg of dexamethasone (intravenous pretreated). INTERVENTION: Each pig was sedated for the duration of study and had a 3.5F catheter inserted in the femoral artery for blood sampling and blood pressure measurement every hour. After 4 hrs, each pig was killed, and tissue was harvested for histology and interleukin-6 assays. MEASUREMENTS AND MAIN RESULTS: Laryngeal tissue interleukin-6 content was greater in the injured group compared with the control group (p < .05). In the intratracheal pretreated group, the interleukin-6 content of laryngeal tissue was greater compared with the control group (p < .05), whereas the intravenous pretreated group was not different from the control group. The reintubation injury resulted in plasma interleukin-6 levels that, compared with control, were greater in the injured and intratracheal pretreated groups (p < .05). Quantitative histology showed that the degree of tracheal injury was higher in injured and intratracheal pretreated groups compared with the control group (p < .05). CONCLUSIONS: Repeated intubation alone results in significant tracheal trauma and systemic inflammation. Intravenous but not inhaled steroids attenuated the injury.

Protective ventilation to reduce inflammatory injury from one lung ventilation in a piglet model.

OBJECTIVES: To test the hypothesis that protective ventilation strategy (PVS) as defined by the use of low stretch ventilation (tidal volume of 5 ml x kg(-1) and employing 5 cm of positive end expiratory pressure (PEEP) during one lung ventilation (OLV) in piglets would result in reduced injury compared to a control group of piglets who received the conventional ventilation (tidal volume of 10 ml x kg(-1) and no PEEP). BACKGROUND: PVS has been found to be beneficial in adults to minimize injury from OLV. We designed the current study to test the beneficial effects of PVS in a piglet model of OLV. METHODS: Ten piglets each were assigned to either 'Control' group (tidal volume of 10 ml x kg(-1) and no PEEP) or 'PVS' group (tidal volume of 5 ml x kg(-1) during the OLV phase and PEEP of 5 cm of H2O throughout the study). Experiment consisted of 30 min of baseline ventilation, 3 h of OLV, and again 30 min of bilateral ventilation. Respiratory parameters and proinflammatory markers were measured as outcome. RESULTS: There was no difference in PaO2 between groups. PaCO2 (P < 0.01) and ventilatory rate (P < 0.01) were higher at 1.5 h OLV and at the end point in the PVS group. Peak inflating pressure (PIP) and pulmonary resistance were higher (P < 0.05) in the control group at 1.5 h OLV. tumor necrosis factor-alpha (P < 0.04) and IL-8 were less (P < 0.001) in the plasma from the PVS group, while IL-6 and IL-8 were less (P < 0.04) in the lung tissue from ventilated lungs in the PVS group. CONCLUSIONS: Based on this model, PVS decreases inflammatory injury both systemically and in the lung tissue with no adverse effect on oxygenation, ventilation, or lung function.

The ventilatory effect of high velocity nasal insufflation compared to non-invasive positive-pressure ventilation in the treatment of hypercapneic respiratory failure: A subgroup analysis.

PURPOSE: Oxygen delivery by high flow nasal cannula (HFNC) is effective in providing respiratory support. HFNC has utility in clearing the extra-thoracic dead space, making it potentially beneficial in the treatment of hypercapnic respiratory failure. This study compares high velocity nasal insufflation (HVNI), a form of HFNC, to non-invasive positive pressure ventilation (NIPPV) in their abilities to provide ventilatory support for patients with hypercapnic respiratory failure. METHODS: This is a pre-defined subgroup analysis from a larger randomized clinical trial of Emergency Department (ED) patients with respiratory failure requiring NIPPV support. Patients were randomized to HVNI or NIPPV. Subgroup selection was done for patients with discharge diagnoses of acute hypercapnic respiratory failure or acute exacerbation of chronic obstructive pulmonary disease. The primary outcomes were change in pCO2 and pH over time. Secondary outcomes were treatment failure and intubation rate. RESULTS: 65 patients with hypercapnic respiratory failure were compared. 34 were randomized to HVNI and 31 to NIPPV. The therapeutic impact on PCO2 and pH over time was similar in each group. The intubation rate was 5.9% in the HVNI group and 16.1% in the NIPPV group (p = 0.244). The rate of treatment failure was 23.5% in the HVNI group and 25.8% in the NIPPV group (p = 1.0). CONCLUSION: HVNI may provide ventilatory support similar to NIPPV in patients presenting with acute hypercapnic respiratory failure, but further study is needed to corroborate these findings.

Heat shock protein 70 secretion by neonatal tracheal tissue during mechanical ventilation: association with indices of tissue function and modeling.

Mechanical ventilation (MV) of the neonatal airway alters mechanical properties and activates tissue-modeling pathways. Heat shock protein (HSP70) is a marker of tissue injury and modulates inflammation, which may influence subsequent pulmonary tissue modeling by matrix metalloproteinases (MMPs). HSP70 secretion is up-regulated in MV airway tissues and associated with changes in airway elasticity and secretion of MMPs. Proximal tracheal segments were isolated in 13 newborn lambs and were either MV for 4 h or SHAM. At baseline and hourly, tracheal segments were flushed and tracheal elasticity was determined. Tracheal wash fluid was assayed for HSP70 by ELISA and for MMPs by substrate zymography. HSP70 secretion increased from baseline to a peak at 1 h in both groups (p < 0.01), greater in the MV group (p < 0.05), and returned to baseline values by 2 h. This response was in contrast to the progressive decrease in tracheal elasticity (p < 0.05). The HSP70 elevation pattern was noted in MMP-2, but beyond 1 h, MMP-2 returned to baseline values in MV group but remained elevated in SHAM (p < 0.05). HSP70 secretion is associated with the degree of biophysical tracheal injury as well as the time course of MMP-2 secretion by tracheal tissues.

Randomised cross-over study of automated oxygen control for preterm infants receiving nasal high flow.

OBJECTIVE: To evaluate a prototype automated controller (IntellO2) of the inspired fraction of oxygen (FiO2) in maintaining a target range of oxygen saturation (SpO2) in preterm babies receiving nasal high flow (HF) via the Vapotherm Precision Flow. DESIGN: Prospective two-centre order-randomised cross-over study. SETTING: Neonatal intensive care units. PATIENTS: Preterm infants receiving HF with FiO2 ≥25%. INTERVENTION: Automated versus manual control of FiO2 to maintain a target SpO2 range of 90%-95% (or 90%-100% if FiO2=21%). MAIN OUTCOME MEASURES: The primary outcome measure was per cent of time spent within target SpO2 range. Secondary outcomes included the overall proportion and durations of SpO2 within specified hyperoxic and hypoxic ranges and the number of in-range episodes per hour. RESULTS: Data were analysed from 30 preterm infants with median (IQR) gestation at birth of 26 (24-27) weeks, study age of 29 (18-53) days and study weight 1080 (959-1443) g. The target SpO2 range was achieved 80% of the time on automated (IntellO2) control (IQR 70%-87%) compared with 49% under manual control (IQR 40%-57%; p<0.0001). There were fewer episodes of SpO2 below 80% lasting at least 60 s under automated control (0 (IQR 0-1.25)) compared with manual control (5 (IQR 2.75-14)). There were no differences in the number of episodes per hour of SpO2 above 98% (4.5 (IQR 1.8-8.5) vs 5.5 (IQR 1.9-14); p=0.572) between the study arms. CONCLUSIONS: The IntellO2 automated oxygen controller maintained patients in the target SpO2 range significantly better than manual adjustments in preterm babies receiving HF. TRIAL REGISTRATION NUMBER: NCT02074774.

Effects of oxygen concentration and exposure time on cultured human airway epithelial cells.

OBJECTIVES: To distinguish the direct effects of oxygen dose and exposure time on human airway epithelial cells. We hypothesized that progressive oxygen exposure would induce cell dysfunction and inflammation in a dose-dependent manner. DESIGN: Interventional laboratory study. SETTING: An academic medical research facility in the northeastern United States. SUBJECTS: Calu-3 human airway epithelial cell culture. INTERVENTIONS: Cells were cultured at a gas-liquid interface with the cells fed basolaterally with medium and grown to full confluence. The apical surfaces were then exposed to gas containing 21%, 40%, 60%, or 80% oxygen, 5% CO2, and balance nitrogen for 24 or 72 hrs. MEASUREMENTS AND MAIN RESULTS: The effects of oxygen concentration and time-induced cellular change were examined by measuring transepithelial resistance of monolayers, cell viability by trypan blue exclusion, basolateral lactate concentration, histology of monolayer cross-sections, and cytospin slides, plus interleukin (IL)-6 and IL-8 secretion in apical surface fluid. Transepithelial resistance decreased in a dose- and time-dependent manner (p < .001), whereas cell viability was reduced only at 72 hrs and in all hyperoxic groups (p < .05). IL-6 secretion was elevated in all hyperoxic groups at 24 hrs (p < .001), and both IL-6 and IL-8 levels were greater in the 40% FiO2 group compared with all other groups at 72 hrs (p < .01). CONCLUSIONS: In this model, airway epithelial cells demonstrate profound concentration and time-dependent responses to hyperoxic exposure with respect to cell physiology, viability, histology, and secretion of inflammatory mediators. This model might be a valuable tool for preliminary analysis of potentially protective therapies against hyperoxia-induced airway epithelial injury.

Low dose methylprednisolone prophylaxis to reduce inflammation during one-lung ventilation.

BACKGROUND: The specific aim of this study was to examine the efficacy of a low dose of methylprednisolone in minimizing inflammatory response in juvenile piglets when given 45-60 min prior to onset of one-lung ventilation. METHODS: Twenty piglets aged 3 weeks were assigned to either the control group (n = 10) or methylprednisolone group (n = 10). The animals were anesthetized and after 30 min of ventilation, they had their left lung blocked. Ventilation was continued via right lung for 3 h. The left lung was then unblocked. Following another 30 min of bilateral ventilation, the animals were euthanized and both lungs were harvested. The methylprednisolone group had a single dose (2 mg x kg(-1)) of methylprednisolone given i.v. 45-60 min prior to onset of one-lung ventilation. Physiological parameters (PaO2, resistance, and compliance) and markers of inflammation (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, IL-6, and IL-8) were measured at baseline and every 30 min thereafter. Lung tissue homogenates from both collapsed and ventilated lungs were analyzed for TNF-alpha, IL-1beta, IL-6, and IL-8. RESULTS: The methylprednisolone group had higher partial pressure of oxygen (P = 0.01), lower plasma levels of TNF-alpha (P = 0.03) and IL-6 (P = 0.001) when compared with control group. Lung tissue homogenate in the methylprednisolone group had lower levels of TNF-alpha (P < 0.05), IL-1beta (P < 0.05), and IL-8 (P < 0.05) in both the collapsed and the ventilated lungs. CONCLUSIONS: In a piglet model of one-lung ventilation, use of prophylactic methylprednisolone prior to collapse of the lung improves lung function and decreases systemic pro-inflammatory response. In addition, in the piglets who received methylprednisolone, there were reduced levels of inflammatory mediators in both the collapsed and ventilated lungs.

Dissociation between the effects of oxygen and pressure on matrix metalloproteinase-2, -7, and -9 expression in human airway epithelial cells.

We tested the hypothesis that hyperoxia or pressure exposure differentially activates expression of cytokines and/or matrix modeling proteins in human airway epithelial cells. Calu-3 epithelial cell monolayers were cultured on transwell plates with the apical surface exposed to gas. Following establishment of baseline, plates were placed in a chamber and exposed to: control (21% O (2); atm), hyperoxia (60% O (2); atm), pressure (21% O (2); 40 cm H (2)O), and combination (60% O (2); 40 cm H (2)O). At 72 hour of exposure, monolayers were assessed for integrity, viability, and expression of interleukin (IL)-6, IL-8 and matrix metalloproteinases (MMPs) -2, -7, and -9. Compared with controls, hyperoxia had lower transepithelial resistance ( P < 0.001) and greater IL-6 secretion ( P < 0.01), and pressure had lower cell viability ( P < 0.001) and greater IL-8 secretion ( P < 0.001). Hyperoxia resulted in more latent MMP-2 ( P < 0.05) and MMP-7 ( P < 0.001). Pressure was associated with a rise in MMPs independent of oxygen exposure ( P < 0.05). Hyperoxia and pressure differentially affected MMP activities in Calu-3 cells and may lead to the different functional and structural abnormalities observed in these in vitro studies.

Recombinant human Clara cell secretory protein treatment increases lung mRNA expression of surfactant proteins and vascular endothelial growth factor in a premature lamb model of respiratory distress syndrome.

Infant respiratory distress syndrome (IRDS) can lead to impaired alveolarization and dysmorphic vascularization of bronchopulmonary dysplasia. Clara cell secretory protein (CC10) has anti-inflammatory properties but is deficient in the premature infant. Because surfactant and vascular endothelial growth factor (VEGF) profiles are impaired by inflammation and CC10 inhibits lung inflammation, we hypothesized that CC10 may up-regulate surfactant protein (SP) and VEGF expression. Preterm lambs ( N = 24; 126 +/- 3 days [standard error] gestation) with IRDS were randomized to receive 100 mg/kg surfactant, 100 mg/kg surfactant followed by intratracheal 0.5, 1.5, or 5 mg/kg rhCC10 and studied for 4 hours. Gas exchange and lung mechanics were monitored; surfactant protein and VEGF mRNA profiles in lung were assessed. There was a significant rhCC10 dose-dependent increase in respiratory compliance and ventilation efficiency index; both parameters were significantly greater in animals treated with 5 mg/kg rhCC10 than those treated with surfactant alone. Similarly, there was a significant rhCC10 dose and protein-dependent increase in surfactant protein (SP-B > SP-C > SP-A) and dose- and isoform-dependent increase in VEGF (VEGF189 > VEGF165 > VEGF121). These data demonstrate that early intervention with rhCC10 up-regulates surfactant protein and VEGF expression, supporting the role of CC10 to protect against hyperoxia and mechanical ventilation in the immature lung.

Sequential alterations of tracheal mechanical properties in the neonatal lamb: effect of mechanical ventilation.

UNLABELLED: Alterations in neonatal airway mechanics resulting from ventilatory therapies are implicated in airway collapse and chronic disease. Quantifying the functional impact of mechanical ventilation (MV) on the neonatal airway and elucidating the time course of these changes will support development of protective therapies. The objective of this study was to test the hypothesis that conventional MV would result in decreased static and dynamic elastance of an isolated tracheal segment and thinning of the muscle (trachealis) region of the tracheal wall in a time dependent manner. Tracheal segments were isolated in newborn lambs spontaneously breathing through the distal trachea; segments were MV (n = 7; PIP/PEEP = 35/5 cmH2O; 40 breaths/min) or instrumented, non-ventilated (SHAM; n = 7; PIP/PEEP = 0/0 cmH2O) for 4 hr. At baseline and hourly, tracheal segments were filled with saline, and static pressure-volume curves were constructed as the pressure response to stepwise volume infusions. Then, cross-sectional ultrasound images were captured at 0 cmH2O on SHAM, and at 0 cmH2O, peak inspiratory pressure (PIP) and positive end expiratory pressure (PEEP), on MV tracheae for subsequent dimensional analysis. Tracheal elasticity indices were derived from static pressure-volume data, and during dynamic ventilation using ultrasound images to calculate the stress-strain relationships. Over 4 hr of MV, tracheal internal diameter (ID) increased (14%; P < 0.05). Markers of tracheal mechanical properties indicated a decrease in elasticity under both static (bulk modulus; 28%; P < 0.05) and dynamic (elastic modulus; 282 %; P < 0.05) conditions, indicating a significant alteration in elastic components. No time dependent changes were identified in dimensions or mechanical properties in the SHAM group. CONCLUSIONS: MV results in dimensional alterations that increased anatomical dead space and reduced static and dynamic elastance of the neonatal trachea.

An ultrasound imaging method for in vivo tracheal bulk and Young's moduli of elasticity.

Alterations in neonatal airway mechanical properties resulting from ventilatory therapies such as mechanical ventilation have been implicated in airway collapse and chronic disease. Advances in ultrasound (US) technology allow for real-time imaging and accurate measurement of tracheal dimensions in vivo; thus, changes in mechanical properties can be tracked longitudinally. In this report we introduce an adaptation of engineering concepts using US imaging data to study airway mechanics in vivo. In this protocol, tracheal segments are isolated in a spontaneously breathing newborn lamb model and the segments are exposed to time-cycled, pressure-limited mechanical ventilation. Serially, tracheal segments are filled with saline and pressure-volume relationships are recorded with stepwise volume infusions. US dimensional measurements of the segments are made while static (no distending pressure) and at pressure limits during dynamic ventilator cycling. US measurements are used to normalize pressure-volume data for resting volume, calculation of bulk modulus, stress-strain relationships and the adapted Young's modulus associated with tangential wall stress. Temporal changes in bulk and Young's moduli demonstrate the time dependence of alterations in conducting airway mechanical properties in vivo during the course of mechanical ventilation. This methodology will provide a means to evaluate respiratory therapies with respect to airway mechanics.