Evaluation of a novel endotracheal tube suctioning system incorporating an inflatable sweeper.

INTRODUCTION: Accumulation of secretions in an endotracheal tube can increase the resistance to flow resulting in an increased patient work of breathing when the patient is interacting with the ventilator. Retained secretions can also serve as an infection risk. Standard suction catheters are limited in their ability to keep the lumen of the endotracheal tube clear. A novel closed-suction catheter has been introduced that incorporates a balloon at its distal end that, when inflated, physically scrapes secretions out of the endotracheal tube (CleanSweep catheter (CSC), Teleflex, Morrisville NC). We hypothesized that the CSC would be more efficient at removing secretions from inside the endotracheal tube than a standard suction catheter (SSC). METHODS: We performed a bench study examining resistive pressures across different sizes of endotracheal tubes when cleaned by the CSC as compared with an SSC. This study was followed by a prospective crossover study again comparing the CSC with an SSC in intubated intensive care unit patients receiving mechanical ventilation and requiring frequent suctioning. RESULTS: For the bench study the CSC was significantly better in reducing airway resistive pressures (P < 0.001). In the prospective crossover study the CSC over 2 h also removed significantly more secretions than the SSC (P < 0.05). CONCLUSION: Both our bench and crossover clinical study demonstrated improved clearance of secretions with the CSC vs an SSC. Further research is needed to ascertain the clinical outcome benefits of enhanced secretion removal.

Impact of a Formal Research Committee on Respiratory Therapists' Publications.

BACKGROUND: Presenting research at national and international meetings is an important aspect of the practice of respiratory care. Our department regularly presented abstracts but few projects were written up as manuscripts. We also noted that we did not have a centralized strategy to evaluate individual projects and provide mentorship. To address these challenges, we formed a Research Committee that meets monthly. We hypothesized that the formation of this committee would be associated with an increase in published manuscripts. METHODS: We evaluated all original research abstracts authored or co-authored by Duke respiratory therapists presented at the AARC Open Forum between 2009 and 2019. Abstracts were grouped into two time periods; 1) 2009-2013 (before the formation of the research committee) and 2) 2014-2019 (after the formation of the research committee). Abstracts were evaluated based on authors, type of study, patient population, and whether the abstract resulted in a manuscript. Primary outcome was the percentage of abstracts published as manuscripts. RESULTS: A total of 56 abstracts were presented by 23 different lead authors, with 16 (29%) published as manuscripts. After formation of the committee, fewer abstracts per year were presented, but these abstracts were more likely to be published as manuscripts (53% vs 18%, P = .02). For abstracts published as manuscripts, there was a significant difference in the type of study before and after committee formation (P = .042), but there were no differences in lead author credentials, senior author credentials, author gender, or patient population. CONCLUSIONS: The formation of a research committee was associated with an increase in the percentage of abstracts published as manuscripts.

Dephosphorylation of the Proneural Transcription Factor ASCL1 Re-Engages a Latent Post-Mitotic Differentiation Program in Neuroblastoma.

Pediatric cancers often resemble trapped developmental intermediate states that fail to engage the normal differentiation program, typified by high-risk neuroblastoma arising from the developing sympathetic nervous system. Neuroblastoma cells resemble arrested neuroblasts trapped by a stable but aberrant epigenetic program controlled by sustained expression of a core transcriptional circuit of developmental regulators in conjunction with elevated MYCN or MYC (MYC). The transcription factor ASCL1 is a key master regulator in neuroblastoma and has oncogenic and tumor-suppressive activities in several other tumor types. Using functional mutational approaches, we find that preventing CDK-dependent phosphorylation of ASCL1 in neuroblastoma cells drives coordinated suppression of the MYC-driven core circuit supporting neuroblast identity and proliferation, while simultaneously activating an enduring gene program driving mitotic exit and neuronal differentiation. IMPLICATIONS: These findings indicate that targeting phosphorylation of ASCL1 may offer a new approach to development of differentiation therapies in neuroblastoma. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/18/12/1759/F1.large.jpg.

2018 Year in Review: Noninvasive Respiratory Support.

Noninvasive respiratory support refers to strategies aimed at providing oxygenation and/or ventilation without the use of an artificial airway. These strategies include the use of standard oxygen delivery devices (face masks, low-flow nasal cannulas), noninvasive ventilation, and high-flow nasal cannula. Considerable interest has been generated recently as to which therapy provides the optimum noninvasive support. This review examined the important literature related to noninvasive respiratory support published in 2018.

Noninvasive Respiratory Support at the End of Life.

Noninvasive respiratory support at the end of life is controversial, although it is becoming increasingly common. Supplemental oxygen is widely prescribed for palliative care and may help with hypoxemic respiratory failure. Noninvasive ventilation has a well-established evidence-based role in the management of respiratory failure due to exacerbations of COPD and cardiogenic pulmonary edema. However, its role during palliative care is unclear, and evidence of support is limited. High-flow nasal cannula oxygen therapy is a new strategy for which there is evidence to support its use for hypoxemic respiratory failure. However, any benefit of the use of high-flow nasal cannula oxygen therapy in the palliative setting is unknown at this time. This review examined evidence relating to the use of noninvasive respiratory support at the end of life.

Multi-site phosphorylation controls the neurogenic and myogenic activity of E47.

The superfamily of basic-Helix-Loop-Helix (bHLH) transcription factors influence cell fate in all three embryonic germ layers, and the tissue-specific class II factors have received prominent attention for their potent ability to direct differentiation during development and in cellular reprogramming. The activity of many class II bHLH proteins driving differentiation, and the inhibitory class VI bHLH factor Hes1, is controlled by phosphorylation on multiple sites by Cyclin-dependent kinases (Cdks). As class II proteins are generally thought to be active through hetero-dimerisation with the ubiquitously expressed class I E proteins, regulation of class I transcription factors such as E47 may influence the activity of multiple tissue-specific bHLH proteins. Using differentiation of nerve and muscle in Xenopus frog embryos as a model system, we set out to explore whether with the ubiquitously expressed class I E protein E47 that hetero-dimerises with Class II bHLHs to control their activity, is also regulated by multi-site phosphorylation. We demonstrate that E47 can be readily phosphorylated by Cdks on multiple sites in vitro, while ectopically-expressed E47 exists in multiple phosphorylated forms in Xenopus embryos. Preventing multi-site phosphorylation using a phospho-mutant version of E47 enhances the neurogenic and myogenic activity of three different class II bHLH reprogramming factors, and also when E47 acts in hetero-dimerisation with endogenous proteins. Mechanistically, unlike phospho-regulation of class II bHLH factors, we find that preventing phosphorylation of E47 increases the amount of chromatin-bound E47 protein but without affecting its overall protein stability. Thus, multi-site phosphorylation is a conserved regulatory mechanism across the bHLH superfamily that can be manipulated to enhance cellular differentiation.

A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a prevalent disease with significant mortality for which no effective pharmacologic therapy exists. Low-dose inhaled carbon monoxide (iCO) confers cytoprotection in preclinical models of sepsis and ARDS. METHODS: We conducted a phase I dose escalation trial to assess feasibility and safety of low-dose iCO administration in patients with sepsis-induced ARDS. Twelve participants were randomized to iCO or placebo air 2:1 in two cohorts. Four subjects each were administered iCO (100 ppm in cohort 1 or 200 ppm in cohort 2) or placebo for 90 minutes for up to 5 consecutive days. Primary outcomes included the incidence of carboxyhemoglobin (COHb) level ≥10%, prespecified administration-associated adverse events (AEs), and severe adverse events (SAEs). Secondary endpoints included the accuracy of the Coburn-Forster-Kane (CFK) equation to predict COHb levels, biomarker levels, and clinical outcomes. RESULTS: No participants exceeded a COHb level of 10%, and there were no administration-associated AEs or study-related SAEs. CO-treated participants had a significant increase in COHb (3.48% ± 0.7% [cohort 1]; 4.9% ± 0.28% [cohort 2]) compared with placebo-treated subjects (1.97% ± 0.39%). The CFK equation was highly accurate at predicting COHb levels, particularly in cohort 2 (R2 = 0.9205; P < 0.0001). Circulating mitochondrial DNA levels were reduced in iCO-treated participants compared with placebo-treated subjects. CONCLUSION: Precise administration of low-dose iCO is feasible, well-tolerated, and appears to be safe in patients with sepsis-induced ARDS. Excellent agreement between predicted and observed COHb should ensure that COHb levels remain in the target range during future efficacy trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT02425579. FUNDING: NIH grants P01HL108801, KL2TR002385, K08HL130557, and K08GM102695.

Subcellular localisation modulates ubiquitylation and degradation of Ascl1.

The proneural transcription factor Ascl1 is a master regulator of neurogenesis, coordinating proliferation and differentiation in the central nervous system. While its expression is well characterised, post-translational regulation is much less well understood. Here we demonstrate that a population of chromatin-bound Ascl1 can be found associated with short chains of ubiquitin while cytoplasmic Ascl1 harbours much longer ubiquitin chains. Only cytoplasmic ubiquitylation targets Ascl1 for destruction, which occurs by conjugation of ubiquitin to lysines in the basic helix-loop-helix domain of Ascl1 and requires the E3 ligase Huwe1. In contrast, chromatin-bound Ascl1 associated with short ubiquitin-chains, which can occur on lysines within the N-terminal region or the bHLH domain and is not mediated by Huwe1, is not targeted for ubiquitin-mediated destruction. We therefore offer further insights into post-translational regulation of Ascl1, highlighting complex regulation of ubiquitylation and degradation in the cytoplasm and on chromatin.

First and Second Step Characteristics of Amputee and Able-Bodied Sprinters.

CONTEXT: In sprint events, the first 2 steps are used to accelerate the center of mass horizontally and vertically. Amputee athletes cannot actively generate energy with their running-specific prosthesis. It is likely that sprint acceleration mechanics, including step asymmetry, are altered compared with able-bodied athletes. PURPOSE: To investigate spatiotemporal and kinetic variables of amputee compared with able-bodied sprinters. METHODS: Kinematic and kinetic data of the first and second stance were collected from 15 able-bodied and 7 amputee sprinters (2 unilateral transfemoral, 4 unilateral transtibial, and 1 bilateral transtibial) with a motion-capture system (250 Hz) and 2 force plates (1000 Hz). In addition, bilateral asymmetry was quantified and compared between groups. RESULTS: Compared with able-bodied athletes, amputee athletes demonstrated significantly lower performance values for 5- and 10-m times. Step length, step velocity, and step frequency were decreased and contact times increased. Peak horizontal force and relative change of horizontal velocity were decreased in both stances. Peak vertical force and relative change of vertical velocity were lower for the amputee than the able-bodied group during the first stance but significantly higher during the second stance. During the first stance, able-bodied and amputee sprinters displayed a similar orientation of the ground-reaction-force vector, which became more vertically orientated in the amputee group during second stance. Amputee sprinters showed significantly greater asymmetry magnitudes for vertical force kinetics compared with able-bodietd athletes. CONCLUSION: A running-specific prosthesis does not replicate the function of the biological limb well in the early acceleration phase.

Clinical Management Strategies for Airway Pressure Release Ventilation: A Survey of Clinical Practice.

BACKGROUND: Airway pressure release ventilation (APRV) is a commonly used mode of ventilation designed to increase mean airway pressure and thus oxygenation. Different strategies for clinical management have been described in the literature but are largely based on physiologic concepts, animal data, and small clinical trials. The purpose of this study was to determine how APRV is currently managed by surveying practicing respiratory therapists with experience using APRV. METHODS: A 15-item survey was developed by the authors and posted on the AARConnect online media platform in January 2016 after being declared exempt by our institution's institutional review board. Survey questions were derived from a literature review of recommended APRV settings. Responses were limited to one per institution. RESULTS: The survey was completed by 60 respondents who used APRV. Of the 4 key initial APRV settings (P high, P low, T high, and T low), there was good agreement among survey responders and published guidelines for setting initial T high (4-6 s) and initial P low (0 cm H2O). There was some disagreement regarding initial P high, with 48% of responders matching P high to conventional ventilation plateau pressures but another 31% using conventional ventilation mean airway pressure plus 2-5 cm H2O. The most disagreement was with the T low setting, with only 47% of survey responders agreeing with published guidelines about using the expiratory flow signal to set T low. There was good agreement among survey responders and published guidelines for what changes to make when gas exchange was outside of the targeted range. A substantial number of respondents accepted P high and APRV release volumes that may exceed lung-protective limits. CONCLUSIONS: There is only limited consensus among practitioners for initial APRV settings, probably reflecting the paucity of good clinical outcome data and confusion surrounding the physiology of this mode.

MyoD phosphorylation on multiple C terminal sites regulates myogenic conversion activity.

MyoD is a master regulator of myogenesis with a potent ability to redirect the cell fate of even terminally differentiated cells. Hence, enhancing the activity of MyoD is an important step to maximising its potential utility for in vitro disease modelling and cell replacement therapies. We have previously shown that the reprogramming activity of several neurogenic bHLH proteins can be substantially enhanced by inhibiting their multi-site phosphorylation by proline-directed kinases. Here we have used Xenopus embryos as an in vivo developmental and reprogramming system to investigate the multi-site phospho-regulation of MyoD during muscle differentiation. We show that, in addition to modification of a previously well-characterised site, Serine 200, MyoD is phosphorylated on multiple additional serine/threonine sites during primary myogenesis. Through mutational analysis, we derive an optimally active phospho-mutant form of MyoD that has a dramatically enhanced ability to drive myogenic reprogramming in vivo. Mechanistically, this is achieved through increased protein stability and enhanced chromatin association. Therefore, multi-site phospho-regulation of class II bHLH proteins is conserved across cell lineages and germ layers, and manipulation of phosphorylation of these key regulators may have further potential for enhancing mammalian cell reprogramming.

Should A Tidal Volume of 6 mL/kg Be Used in All Patients?

It has been shown that mechanical ventilation by itself can cause lung injury and affect outcomes. Ventilator-induced lung injury is associated with high tidal volumes in lungs afflicted with ARDS. However, the question is: Do high tidal volumes have this same effect in normal lungs or lungs that have respiratory compromise stemming from something other than ARDS? Many clinicians believe that a tidal volume strategy of 6 mL/kg predicted body weight should be standard practice in all patients receiving mechanical ventilation. There is a growing body of evidence related to this issue, and this is the debate that will be tackled in this paper from both pro and con perspectives.

Should a Portable Ventilator Be Used in All In-Hospital Transports?

Movement of the mechanically ventilated patient may be for a routine procedure or medical emergency. The risks of transport seem manageable, but the memory of a respiratory-related catastrophe still gives many practitioners pause. The risk/benefit ratio of transport must be assessed before movement. During transport of the ventilated patients, should we always use a transport ventilator? What is the risk of using manual ventilation? How are PEEP and FIO2 altered? Is there an impact on the ability to trigger during manual ventilation? Is hyperventilation and hypoventilation a common problem? Does hyperventilation or hypoventilation result in complications? Are portable ventilators worth the cost? What about the function of portable ventilators? Can these devices faithfully reproduce ICU ventilator function? The following pro and con discussion will attempt to address many of these issues by reviewing the current evidence on transport ventilation.

Prolonged postoperative respiratory support after proximal thoracic aortic surgery: Is deep hypothermic circulatory arrest a risk factor?

PURPOSE: In addition to the pulmonary risks associated with cardiopulmonary bypass, thoracic aortic surgery using deep hypothermic circulatory arrest (DHCA) may subject the lungs to further injury. However, this topic has received little investigation to date. MATERIALS AND METHODS: A prospective cohort review was performed on all patients undergoing proximal thoracic aortic surgery with (n = 478) and without (n = 135) DHCA between July 2005 and February 2013 at a single institution. The primary outcome was prolonged postoperative respiratory support (PPRS), defined as any of the following: >1 day of mechanical ventilation at either fraction of inspired oxygen >0.4 and/or positive end-expiratory pressure >5 mm Hg, >2 days of supplemental O2 requirement of at least 2.5 L/min, or discharge with new O2 requirement. Independent risk factors for PPRS were identified using multivariable logistic regression. RESULTS: Postoperative respiratory support was required in 100 patients (20.9%) with and 30 patients (22.2%) without DHCA (P = .74). Independent predictors of PPRS after proximal aortic surgery included the following: age, diabetes, history of stroke, preoperative creatinine, American Society of Anesthesiologists class 4, redo-sternotomy, total arch replacement, and transfusion requirement. Use of DHCA was not an independent risk factor for PPRS in the entire cohort. Subanalysis of only DHCA patients revealed that longer DHCA times were independently associated with PPRS. CONCLUSIONS: Prolonged postoperative respiratory support is common after proximal aortic surgery. The use of DHCA was not associated with this complication in the overall cohort, although longer DHCA times were predictive when only the subset of patients undergoing DHCA was analyzed. Knowledge of the risk factors for PPRS after proximal aortic surgery should improve preoperative risk stratification and postoperative management of these patients.

Effects of inhaled CO administration on acute lung injury in baboons with pneumococcal pneumonia.

Inhaled carbon monoxide (CO) gas has therapeutic potential for patients with acute respiratory distress syndrome if a safe, evidence-based dosing strategy and a ventilator-compatible CO delivery system can be developed. In this study, we used a clinically relevant baboon model of Streptococcus pneumoniae pneumonia to 1) test a novel, ventilator-compatible CO delivery system; 2) establish a safe and effective CO dosing regimen; and 3) investigate the local and systemic effects of CO therapy on inflammation and acute lung injury (ALI). Animals were inoculated with S. pneumoniae (10(8)-10(9) CFU) (n = 14) or saline vehicle (n = 5); in a subset with pneumonia (n = 5), we administered low-dose, inhaled CO gas (100-300 ppm × 60-90 min) at 0, 6, 24, and/or 48 h postinoculation and serially measured blood carboxyhemoglobin (COHb) levels. We found that CO inhalation at 200 ppm for 60 min is well tolerated and achieves a COHb of 6-8% with ambient CO levels ≤ 1 ppm. The COHb level measured at 20 min predicted the 60-min COHb level by the Coburn-Forster-Kane equation with high accuracy. Animals given inhaled CO + antibiotics displayed significantly less ALI at 8 days postinoculation compared with antibiotics alone. Inhaled CO was associated with activation of mitochondrial biogenesis in the lung and with augmentation of renal antioxidative programs. These data support the feasibility of safely delivering inhaled CO gas during mechanical ventilation and provide preliminary evidence that CO may accelerate the resolution of ALI in a clinically relevant nonhuman primate pneumonia model.