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.

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.

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.

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.

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.

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.

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.

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.

Impact of Heated Humidified High Flow Air via Nasal Cannula on Respiratory Effort in Patients with Chronic Obstructive Pulmonary Disease.

Background: High flow nasal cannula therapy (HFNC) has been widely adopted for respiratory distress, and evidence suggests that purging dead space of the upper airway improves gas fractions in the lung. This study tests the hypothesis that HFNC with room air could be as effective as low flow oxygen in chronic obstructive pulmonary disease (COPD). Methods: Thirty-two COPD patients prescribed 1 - 2 L/min of oxygen were studied. The conditions tested consisted of a control (CTRL; no therapy), then in random order HFNC and prescribed low flow oxygen (LFO). HFNC was the highest flow tolerated up to 35 L/min without supplemental oxygen. Arterial blood gases (ABGs), respiratory rate (RR), heart rate (HR) and tidal volume (VT) were measured at the end of each condition. Results: Arterial oxygen (PaO2) was greater (p < 0.001) for LFO than both HFNC and CTRL (CTRL=57.4±6.1mmHg, HFNC=58.6±8.3mmHg, LFO=72.6±10.2mmHg). HFNC reduced RR by 11% (p<0.05) from CTRL and LFO (CTRL=20.2±3.8br/min, HFNC=17.9±3.3br/min, LFO=20.2±3.7br/min) with no differences in VT. There were no differences between arterial carbon dioxide (PaCO2) (CTRL=45.5±4.9mmHg, HFNC=45.0±5.3mmHg, LFO=46.0±3.9mmHg). Conclusions: HFNC resulted in a clinically relevant reduction in ventilatory effort with no change in ABG indicating a gas equilibrium effect of purging anatomical dead space. Clinical Trial Registration: ClinicalTrials.gov ID: NCT00990210.

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

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.

Comparison Study of Airway Reactivity Outcomes due to a Pharmacologic Challenge Test: Impulse Oscillometry versus Least Mean Squared Analysis Techniques.

The technique of measuring transpulmonary pressure and respiratory airflow with manometry and pneumotachography using the least mean squared analysis (LMS) has been used broadly in both preclinical and clinical settings for the evaluation of neonatal respiratory function during tidal volume breathing for lung tissue and airway frictional mechanical properties measurements. Whereas the technique of measuring respiratory function using the impulse oscillation technique (IOS) involves the assessment of the relationship between pressure and flow using an impulse signal with a range of frequencies, requires less cooperation and provides more information on total respiratory system resistance (chest wall, lung tissue, and airways). The present study represents a preclinical animal study to determine whether these respiratory function techniques (LMS and IOS) are comparable in detecting changes in respiratory resistance derived from a direct pharmacological challenge.

Brief mechanical ventilation impacts airway cartilage properties in neonatal lambs.

Ultrasound imaging allows in vivo assessment of tracheal kinetics and cartilage structure. To date, the impact of mechanical ventilation (MV) on extracellular matrix (ECM) in airway cartilage is unclear, but an indication of its functional and structural change may support the development of protective therapies. The objective of this study was to characterize changes in mechanical properties of the neonatal airway during MV with alterations in cartilage ECM. Trachea segments were isolated in a neonatal lamb model; ultrasound dimensions and pressure-volume relationships were measured on sham (no MV; n = 6) and MV (n = 7) airways for 4 hr. Tracheal cross-sections were harvested at 4 hr, tissues were fixed and stained, and Fourier transform infrared imaging spectroscopy (FT-IRIS) was performed. Over 4 hr of MV, bulk modulus (28%) and elastic modulus (282%) increased. The MV tracheae showed higher collagen, proteoglycan content, and collagen integrity (new tissue formation); whereas no changes were seen in the controls. These data are clinically relevant in that airway properties can be correlated with MV and changes in cartilage ECM. MV increases the in vivo dimensions of the trachea and is associated with evidence of airway tissue remodeling. Injury to the neonatal airway from MV may have relevance for the development of tracheomalacia. We demonstrated active airway tissue remodeling during MV using an FT-IRIS technique which identifies changes in ECM.

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.

High-flow nasal cannula: impact on oxygenation and ventilation in an acute lung injury model.

INTRODUCTION: High-flow nasal cannula therapy (HFNC) has been shown to be more effective than continuous positive airway pressure (CPAP) in reducing intubations and ventilator days. HFNC likely provides mechanisms to support respiratory efficiency beyond application of distending pressure. We reason that HFNC washout of nasopharyngeal dead space impacts CO(2) removal along with oxygenation. The aim of this study was to demonstrate the flow dependence of CO(2) reduction and improved oxygenation during HFNC and the dependence on leak around the nasal prongs. MATERIALS AND METHODS: Neonatal piglets (n=13; 2-6 kg) were injured with IV oleic acid and supported with HFNC at 2 through 8 L/min. High and low leak around the nasal prongs was accomplished by using single and double prong cannulae, respectively. Measurement of hemodynamic, respiratory and blood gas parameters were made at each setting following 10 min for physiologic equilibration. Tracheal pressures were recorded by transmural catheters. RESULTS: With HFNC, CO(2) trended downward in a flow-dependent manner independent of leak. Oxygenation and tracheal pressures increased in a flow-dependent manner with the greatest effect during double prong. At 8 L/min, tracheal pressures did not exceed 6 ± 1 cmH(2) O. CONCLUSIONS: HFNC improves gas exchange in a flow-dependent manner; double prong had greater impact on O(2;) single prong had greater impact on CO(2) elimination.

Skeletal dysplasias: evaluation with impulse oscillometry and thoracoabdominal motion analysis.

BACKGROUND: Children with skeletal dysplasia (SD) often have pulmonary disease, which can be life threatening. In clinical practice, chest wall and formal respiratory function tests are difficult to perform owing to the small size and cooperation. The objective of this study was to demonstrate distinct thoracopulmonary function patterns in children with SD. METHODS: We conducted a retrospective study reviewing pulmonary function tests from 17 patients with the diagnosis of SD. Three subgroups were studied: Morquio syndrome (MS), metatropic-spondylocostal dysplasia (MSD), and unspecified skeletal dysplasias (SDU). Rib cage contribution to tidal volume excursions (%RC), phase angle (Phtheta), phase relation during total breath (PhRTB), respiratory resistance (Rrs(5-35) Hz), respiratory reactance (Xrs(5-35) Hz), resonant frequency, and their frequency-dependency were analyzed. Values were age-matched and height-matched to reference values of healthy subjects. RESULTS: There was a decrease in %RC and an increase in PhRTB (P < 0.05) in the SD group. %RC differed between subgroups [MS: 46.4 +/- 1.8% SE, MSD: 18.4 +/- 2.6% SE, SDU: 27.5 +/- 5.2% SE (P < 0.05)]; Phtheta was within reference values only in MS, which exhibited a decrease in Xrs at 5 Hz (P < 0.05) and an increase in Rrs independent of the frequency. SDU showed a decrease in Xrs at 35 Hz (P < 0.05), no differences were found in Rrs. In MS, a correlation was found between RC and Rrs at all frequencies (r = -0.98, P < 0.01) and between Xrs(5-10) and Phtheta (r = -0.93, P < 0.05). CONCLUSIONS: Thoracoabdominal dysfunction was associated with altered chest wall reactance at high frequencies in a subgroup of SD patients with abnormal lung reactance and central airway involvement in MS.

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.

Research in high flow therapy: mechanisms of action.

Recently, heater/humidifier devices that use novel methods to condition breathing gases from an external source have been introduced. The addition of sufficient warmth and high levels of humidification to breathing gas has allowed for higher flow rates from nasal cannula devices to be applied to patients (i.e., high flow therapy). This article provides a review of the proposed mechanisms behind the efficacy of high flow therapy via nasal cannula, which include washout of nasopharyngeal dead space, attenuation of the inspiratory resistance associated with the nasopharynx, improvement in conductance and pulmonary compliance, mild distending pressure and reduction in energy expenditure for gas conditioning.