Derek W. Russell

A Multicenter, Randomized Trial of Ramped Position vs Sniffing Position During Endotracheal Intubation of Critically Ill Adults

BACKGROUND: Hypoxemia is the most common complication during endotracheal intubation of critically ill adults. Intubation in the ramped position has been hypothesized to prevent hypoxemia by increasing functional residual capacity and decreasing the duration of intubation, but has never been studied outside of the operating room. METHODS: Multicenter, randomized trial comparing the ramped position (head of the bed elevated to 25°) with the sniffing position (torso supine, neck flexed, and head extended) among 260 adults undergoing endotracheal intubation by pulmonary and critical care medicine fellows in four ICUs between July 22, 2015, and July 19, 2016. The primary outcome was lowest arterial oxygen saturation between induction and 2 minutes after intubation. Secondary outcomes included Cormack‐Lehane grade of glottic view, difficulty of intubation, and number of laryngoscopy attempts. RESULTS: The median lowest arterial oxygen saturation was 93% (interquartile range [IQR], 84%‐99%) with the ramped position vs 92% (IQR, 79%‐98%) with the sniffing position (P = .27). The ramped position appeared to increase the incidence of grade III or IV view (25.4% vs 11.5%, P = .01), increase the incidence of difficult intubation (12.3% vs 4.6%, P = .04), and decrease the rate of intubation on the first attempt (76.2% vs 85.4%, P = .02), respectively. CONCLUSIONS: In this multicenter trial, the ramped position did not improve oxygenation during endotracheal intubation of critically ill adults compared with the sniffing position. The ramped position may worsen glottic view and increase the number of laryngoscopy attempts required for successful intubation. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02497729; URL: www.clinicaltrials.gov

Disease phenotyping in chronic obstructive pulmonary disease: the neutrophilic endotype.

Purpose of review Despite decades of scientific attention, chronic obstructive pulmonary disease (COPD) remains a major cause of both morbidity and mortality worldwide with strikingly few effective drug classes available. This may be in part because COPD is actually a syndrome composed of distinct diseases with varying pathophysiology (endotypes), and therapies have not been designed to target the causal pathological processes specific to an endotype. Recent findings Recent work has begun to clarify the nature of these endotypes and characterize them. One promising field focuses on the central role of the neutrophil and the tripeptide matrikine proline-glycine-proline (PGP) in a subset of COPD patients. Two drugs with mechanisms of action novel to the COPD therapeutic arena (azithromycin and roflumilast) have been shown to reduce acute exacerbations of COPD. Intriguingly, recent evidence has linked both of these agents to modulation of the PGP/neutrophil pathway in concert with this exacerbation reduction, suggesting that a neutrophilic endotype is present and amenable to pharmacological targeting. Summary Further work characterizing COPD endotypes, including this neutrophilic endotype, will be important as we strive to understand the mechanistic roots of this disease in the hope of creating more effective therapies.

Novel Method for Noninvasive Sampling of the Distal Airspace in Acute Respiratory Distress Syndrome

Rationale: A major barrier to a more complete understanding of acute respiratory distress syndrome (ARDS) pathophysiology is the inability to sample the distal airspace of patients with ARDS. The heat moisture exchanger (HME) filter is an inline bacteriostatic sponge that collects exhaled moisture from the lungs of mechanically ventilated patients. Objectives: To test the hypothesis that HME filter fluid (HMEF) represents the distal airspace fluid in patients with ARDS. Methods: Samples of HMEF were collected from 37 patients with acute pulmonary edema (either from ARDS or hydrostatic causes [HYDRO; control subjects]). Concurrent undiluted pulmonary edema fluid (EF) and HMEF were collected from six patients. HMEF from 11 patients (8 ARDS and 3 HYDRO) were analyzed by liquid chromatography‐coupled tandem mass spectometry. Total protein (bicinchoninic acid assay), MMP‐9 (matrix metalloproteinase‐9), and MPO (myeloperoxidase) (ELISA) were measured in 29 subjects with ARDS and 5 subjects with HYDRO. SP‐D (surfactant protein‐D), RAGE (receptor for advanced glycation end‐products) (ELISA), and cytokines (IL‐1&bgr;, IL‐6, IL‐8, and tumor necrosis factor‐&agr;) (electrochemiluminescent assays) were measured in six concurrent HMEF and EF samples. Measurements and Main Results: Liquid chromatography‐coupled tandem mass spectrometry on concurrent EF and HMEF samples from four patients revealed similar base peak intensities and m/z values indicating similar protein composition. There were 21 significantly elevated proteins in HMEF from patients with ARDS versus HYDRO. Eight proteins measured in concurrent EF and HMEF from six patients were highly correlated. In HMEF, total protein and MMP‐9 were significantly higher in ARDS than in HYDRO. Conclusions: These data suggest that HMEF is a novel, noninvasive method to accurately sample the distal airspace in patients with ARDS.

Neutrophil Fates in Bronchiectasis and Alpha-1 Antitrypsin Deficiency

The neutrophil is a powerful cellular defender of the vulnerable interface between the environment and pulmonary tissues. This cells potent weapons are carefully calibrated in the healthy state to maximize effectiveness in fighting pathogens while minimizing tissue damage and allowing for repair of what damage does occur. The three related chronic airway disorders of cystic fibrosis, non-cystic fibrosis bronchiectasis, and alpha-1 antitrypsin deficiency all demonstrate significant derangements of this homeostatic system that result in their respective pathologies. An important shared feature among them is the inefficient resolution of chronic inflammation that serves as a central means for neutrophil-driven lung damage resulting in disease progression. Examining the commonalities and divergences between these diseases in the light of their immunopathology is informative and may help guide us toward future therapeutics designed to modulate the neutrophils interplay with the pulmonary environment.

Exosomal microRNA predicts and protects against severe bronchopulmonary dysplasia in extremely premature infants

Premature infants are at high risk for developing bronchopulmonary dysplasia (BPD), characterized by chronic inflammation and inhibition of lung development, which we have recently identified as being modulated by microRNAs (miRNAs) and alterations in the airway microbiome. Exosomes and exosomal miRNAs may regulate cell differentiation and tissue and organ development. We discovered that tracheal aspirates from infants with severe BPD had increased numbers of, but smaller, exosomes compared with term controls. Similarly, bronchoalveolar lavage fluid from hyperoxia-exposed mice (an animal model of BPD) and supernatants from hyperoxia-exposed human bronchial epithelial cells (in vitro model of BPD) had increased exosomes compared with air controls. Next, in a prospective cohort study of tracheal aspirates obtained at birth from extremely preterm infants, utilizing independent discovery and validation cohorts, we identified unbiased exosomal miRNA signatures predictive of severe BPD. The strongest signal of reduced miR-876-3p in BPD-susceptible compared with BPD-resistant infants was confirmed in the animal model and in vitro models of BPD. In addition, based on our recent discovery of increased Proteobacteria in the airway microbiome being associated with BPD, we developed potentially novel in vivo and in vitro models for BPD combining Proteobacterial LPS and hyperoxia exposure. Addition of LPS led to a larger reduction in exosomal miR 876-3p in both hyperoxia and normoxia compared with hyperoxia alone, thus indicating a potential mechanism by which alterations in microbiota can suppress miR 876-3p. Gain of function of miR 876-3p improved the alveolar architecture in the in vivo BPD model, demonstrating a causal link between miR 876-3p and BPD. In summary, we provide evidence for the strong predictive biomarker potential of miR 876-3p in severe BPD. We also provide insights on the pathogenesis of neonatal lung disease, as modulated by hyperoxia and microbial product-induced changes in exosomal miRNA 876-3p, which could be targeted for future therapeutic development.

Fibroblast growth factor 23 and Klotho contribute to airway inflammation

Circulating levels of fibroblast growth factor (FGF)23 are associated with systemic inflammation and increased mortality in chronic kidney disease. α-Klotho, a co-receptor for FGF23, is downregulated in chronic obstructive pulmonary disease (COPD). However, whether FGF23 and Klotho-mediated FGF receptor (FGFR) activation delineates a pathophysiological mechanism in COPD remains unclear. We hypothesised that FGF23 can potentiate airway inflammation via Klotho-independent FGFR4 activation. FGF23 and its effect were studied using plasma and transbronchial biopsies from COPD and control patients, and primary human bronchial epithelial cells isolated from COPD patients as well as a murine COPD model. Plasma FGF23 levels were significantly elevated in COPD patients. Exposure of airway epithelial cells to cigarette smoke and FGF23 led to a significant increase in interleukin-1β release via Klotho-independent FGFR4-mediated activation of phospholipase Cγ/nuclear factor of activated T-cells signalling. In addition, Klotho knockout mice developed COPD and showed airway inflammation and elevated FGFR4 expression in their lungs, whereas overexpression of Klotho led to an attenuation of airway inflammation. Cigarette smoke induces airway inflammation by downregulation of Klotho and activation of FGFR4 in the airway epithelium in COPD. Inhibition of FGF23 or FGFR4 might serve as a novel anti-inflammatory strategy in COPD. Fibroblast growth factor 23 and cigarette smoke-induced FGFR4 signalling lead to the development of airway inflammation and emphysema http://ow.ly/j4tZ30jWyGF

COPD ground zero: small airways rather than alveoli as the initial site of injury

Chronic obstructive pulmonary disease (COPD) has long been perceived as a dichotomy—an overlapping spectrum of remodelling in the large airways (chronic bronchitis) and alveoli (emphysema). However, as our understanding of COPD grows in sophistication, the anatomical intersection between these spectra—namely, terminal bronchioles and transitional bronchioles, hereafter termed small bronchioles—is increasingly implicated as a likely so-called ground zero of COPD pathogenesis. It has long been appreciated that small bronchioles, which do not resist airflow much in the healthy state because of their abundance and parallel configuration, contribute heavily to expiratory resistance in COPD. Further evidence that these small bronchioles might be key in COPD pathogenesis has accrued slowly, with progress being hampered both by the complex anatomical and physiological interdependence of the bronchioles and alveoli as well as by technical factors related to their size and low attenuation. Previous work showed that patients with very severe COPD (Global Diagnosis of Chronic Obstructive Lung Disease [GOLD] stage 4) had a substantially reduced number of terminal bronchioles, supporting the centrality of small airways to the disease. However, the exclusion of patients with less severe disease from this analysis left unanswered the question of whether small bronchiole pruning was a feature of only advanced COPD. The present work by Hyun-Kyoung Koo and colleagues in The Lancet Respiratory Medicine addresses this question. This study is a major step towards answering the more fundamental question of whether the pathological pruning of terminal and transitional airways is a primary process or secondary to alveolar disruption and emphysema. Lung specimens were obtained from a much broader cohort of patients (including patients with GOLD 1, GOLD 2, and GOLD 4 COPD, as well as non-obstructed smokers who were controls) than that used in previous studies, and the investigators used an elegant combination of techniques, hybridising ultrahigh-resolution micro-CT imaging with careful imagepaired histological study. This approach allowed airways to be localised, quantified, and qualitatively categorised. Collectively, this fascinating analysis provides a first in kind systematic survey of the small bronchiolar tissue of a fairly broad range of patients with COPD. Compared with the control group, the authors observed a significant decrease of 40% in terminal bronchioles per mL of lung in patients with GOLD 1 COPD (p=0·014) and 43% in patients with GOLD 2 COPD (p=0·036), and a significant decrease of 56% in transitional bronchioles per mL of lung in patients with GOLD 1 COPD (p=0·0001) and 59% in patients with GOLD 2 COPD (p=0·0001). The authors found that, in addition to a numerical reduction in terminal and transitional bronchioles, the remaining small airways were qualitatively unhealthy, as characterised by airway wall thickening and luminal obstruction. Perhaps most importantly, they also conclusively showed that much of the reduction in small airways occurs in areas of the lung unaffected by histologically defined emphysema. These findings support the intriguing concept that the remodelling of COPD originates and centres around the small bronchioles. If this finding is confirmed, it would represent a considerable shift in current understanding of this disease. However, it must be noted that certain limitations preclude conclusive proof of this paradigm. Because this was a cross-sectional cohort study, temporality and causality could not be shown. For example, reduced pulmonary function early in life (congenital or acquired) is thought to be a risk factor for COPD, which could account for some observed differences between the GOLD 1, 2, and control groups. Because the control cohort was a subset of smokers without obstruction, development of an above average number of small bronchioles early in life could have protected against COPD. The retrospective nature of the inquiry, reliant on patients who underwent lobectomy or pneumonectomy for cancer, introduces possible biases into the findings. Furthermore, although this study does show that airway loss can occur in the absence of emphysema, it does not rule out the hypothesis that alveolar elastance impairment sufficient to cause secondary small bronchiolar collapse from untethered radial elastic fibres occurs even before alveolar septae are lost. Nevertheless, these findings do importantly confirm that small bronchiole loss is a dominant feature of Lancet Respir Med 2018

Manual ventilation to prevent hypoxaemia during endotracheal intubation of critically ill adults: protocol and statistical analysis plan for a multicentre randomised trial

Introduction Hypoxaemia is the most common complication during endotracheal intubation of critically ill adults, and it increases the risk of cardiac arrest and death. Manual ventilation between induction and intubation has been hypothesised to decrease the incidence of hypoxaemia, but efficacy and safety data are lacking. Methods and analysis The Preventing Hypoxemia with Manual Ventilation during Endotracheal Intubation trial is a prospective, multicentre, non-blinded randomised clinical trial being conducted in seven intensive care units in the USA. A total of 400 critically ill adults undergoing endotracheal intubation will be randomised 1:1 to receive prophylactic manual ventilation between induction and endotracheal intubation using a bag-valve-mask device or no prophylactic ventilation. The primary outcome is the lowest arterial oxygen saturation between induction and 2 min after successful endotracheal intubation, which will be analysed as an unadjusted, intention-to-treat comparison of patients randomised to prophylactic ventilation versus patients randomised to no prophylactic ventilation. The secondary outcome is the incidence of severe hypoxaemia, defined as any arterial oxygen saturation of less than 80% between induction and 2 min after endotracheal intubation. Enrolment began on 2 February 2017 and is expected to be complete in May 2018. Ethics and dissemination The trial was approved by the institutional review boards or designees of all participating centres. The results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences. Trial registration number NCT03026322; Pre-results.

Risk Factors for and Prediction of Hypoxemia during Tracheal Intubation of Critically Ill Adults

Rationale: Hypoxemia is a common complication during tracheal intubation of critically ill adults and is a frequently used endpoint in airway management research. Identifying patients likely to experience low oxygen saturations during tracheal intubation may be useful for clinical practice and clinical trials. Objectives: To identify risk factors for lower oxygen saturations and severe hypoxemia during tracheal intubation of critically ill adults and develop prediction models for lowest oxygen saturation and hypoxemia. Methods: Using data on 433 intubations from two randomized trials, we developed linear and logistic regression models to identify preprocedural risk factors for lower arterial oxygen saturations and severe hypoxemia between induction and 2 minutes after intubation. Penalized regression was used to develop prediction models for lowest oxygen saturation after induction and severe hypoxemia. A simplified six‐point score was derived to predict severe hypoxemia. Results: Among the 433 intubations, 426 had complete data and were included in the model. The mean (standard deviation) lowest oxygen saturation was 88% (14%); median (interquartile range) was 93% (83‐98%). Independent predictors of severe hypoxemia included hypoxemic respiratory failure as the indication for intubation (odds ratio [OR], 2.70; 95% confidence interval [CI], 1.58‐4.60), lower oxygen saturation at induction (OR, 0.92 per 1% increase; 95% CI, 0.89‐0.96 per 1% increase), younger age (OR, 0.97 per 1‐year increase; 95% CI, 0.95‐0.99 per 1‐year increase), higher body mass index (OR, 1.03 per 1 kg/m2; 95% CI, 1.00‐1.06 per 1 kg/m2), race (OR, 4.58 for white vs. black; 95% CI, 1.97‐10.67; OR, 4.47 for other vs. black; 95% CI, 1.19‐16.84), and operator with fewer than 100 prior intubations (OR, 2.83; 95% CI, 1.37‐5.85). A six‐point score using the identified risk factors predicted severe hypoxemia with an area under the receiver operating curve of 0.714 (95% CI, 0.653 to 0.778). Conclusions: Lowest oxygen saturation and severe hypoxemia during tracheal intubation in the intensive care unit can be accurately predicted using routinely available preprocedure clinical data, with saturation at induction and hypoxemic respiratory failure being the strongest predictors. A simple bedside score may identify patients at risk for hypoxemia during intubation to help target preventative interventions and facilitate enrichment in clinical trials.

Early exposure to hyperoxia and mortality in critically ill patients with severe traumatic injuries

BackgroundHyperoxia is common early in the course of resuscitation of critically ill patients. It has been associated with mortality in some, but not all, studies of cardiac arrest patients and other critically ill cohorts. Reasons for the inconsistency are unclear and may depend on unmeasured patient confounders, the timing and duration of hyperoxia, population characteristics, or the way that hyperoxia is defined and measured. We sought to determine whether, in a prospectively collected cohort of mechanically ventilated patients with traumatic injuries with and without head trauma, higher maximum partial pressure of arterial oxygen (PaO2) within 24 hours of admission would be associated with increased risk of in-hospital mortality.MethodsCritically ill patients with traumatic injuries undergoing invasive mechanical ventilation enrolled in the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study were included in this study. All arterial blood gases (ABGs) from the first 24 hours of admission were recorded. Primary analysis was comparison of the highest PaO2 between hospital survivors and non-survivors.ResultsA total of 653 patients were evaluated for inclusion. Of these, 182 were not mechanically ventilated or did not have an ABG measured in the first 24 hours, leaving 471 patients in the primary analysis. In survivors, the maximum PaO2 was 141 mmHg (median, interquartile range 103 - 212) compared to 148 mmHg (IQR 105 - 209) in non-survivors (p = 0.82). In the subgroup with head trauma (n = 266), the maximum PaO2 was 133 mmHg (IQR 97 - 187) among survivors and 152 mmHg (108 - 229) among nonsurvivors (p = 0.19). After controlling for age, injury severity score, number of arterial blood gases, and fraction of inspired oxygen, maximum PaO2 was not associated with increased mortality (OR 1.27 for every fold increase of PaO2 (95% CI 0.72 - 2.25).ConclusionsIn mechanically ventilated patients with severe traumatic injuries, hyperoxia in the first 24 hours of admission was not associated with increased risk of death or worsened neurological outcomes in a setting without brain tissue oxygenation monitoring.