Muscle loss phenotype in COPD is associated with adverse outcomes in the UK Biobank.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder with systemic consequences that can cause a muscle loss phenotype (MLP), which is characterized by the loss of muscle mass, muscle strength, or loss of both muscle and fat mass. There are limited data comparing the individual traits of MLP with clinical outcomes in a large unbiased cohort of COPD patients. Our aim was to determine the proportion of patients who met criteria for MLP in an unbiased sample of COPD patients at the population-level. We also determined if specific MLP features were associated with all-cause and COPD-related mortality. METHODS: A retrospective population-based cohort analysis of the UK Biobank was performed. COPD was defined by a FEV1/FVC ratio < 0.7, physician established diagnosis of COPD, or those with a COPD-related hospitalization before baseline assessment. MLP included one or more of the following: 1) Low fat-free mass index (FFMI) on bioelectric impedance analysis (BIA) or 2) Appendicular skeletal muscle index (ASMI) on BIA, 3) Low muscle strength defined by handgrip strength (HGS), or 4) Low muscle and fat mass based on body mass index (BMI). Cox regression was used to determine the association between MLP and all-cause or COPD-related mortality. All models were adjusted for sex, age at assessment, ethnicity, BMI, alcohol use, smoking status, prior cancer diagnosis and FEV1/FVC ratio. RESULTS: There were 55,782 subjects (56% male) with COPD followed for a median of 70.1 months with a mean(± SD) age at assessment of 59 ± 7.5 years, and FEV1% of 79.2 ± 18.5. Most subjects had mild (50.4%) or moderate (42.8%) COPD. Many patients had evidence of a MLP, which was present in 53.4% of COPD patients (34% by ASMI, 26% by HGS). Of the 5,608 deaths in patients diagnosed with COPD, 907 were COPD-related. After multivariate adjustment, COPD subjects with MLP had a 30% higher hazard-ratio for all-cause death and 70% higher hazard-ratio for COPD-related death. CONCLUSIONS: Evidence of MLP is common in a large population-based cohort of COPD and is associated with higher risk for all-cause and COPD-related mortality.

A Taxonomy for Noninvasive Modes Provided by Portable Ventilators.

The purpose of this article is to identify (by brand name) and then classify the modes available on contemporary portable ventilators used for noninvasive ventilation in the United States. We propose a formal taxonomy that identifies the modes by their control variable, breath sequence, and targeting scheme, therefore describing what the mode does. Use of this taxonomy should be helpful in finding modes with comparable functionality that cater to the specific goal of mechanical ventilation and effective ventilatory strategies for each disease state.

Budget impact analysis of a digital monitoring platform for COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive debilitating condition with frequent exacerbations that have a high burden for patients and society. Digital tools may help to reduce the economic burden for patients and payers by improving outcomes. The Propeller platform is a digital self-management tool that facilitates passive monitoring of inhaler medication utilization, potentially assisting the healthcare team to identify patients at risk of a COPD exacerbation who may require further intervention. This study estimated the budget impact of Propeller from commercial payer and Medicare fee-for-service payer perspectives. METHODS: An Excel-based model was used to estimate the budget impact of Propeller for COPD patients in commercial and Medicare population sizes of 5 million members. Data on prevalence, baseline healthcare resource utilization (HCRU), and baseline use of rescue and controller inhaler medications with unit costs (adjusted to 2020 US dollars) were obtained from peer-reviewed literature. Data on reductions in HCRU during Propeller usage were based on direct evidence. Estimates for costs of remote monitoring were obtained from publicly available information. All patients were assumed to have insurance claims related to ongoing remote monitoring. RESULTS: The estimated number of annual eligible COPD patients for commercial and Medicare was 212,200 and 606,600, respectively. Propeller decreased costs by an estimated $2,475 (commercial) and $915 (Medicare) per enrolled patient. The greatest increase in expenditure was for remote monitoring related expenses. After accounting for estimated reductions in hospitalizations, emergency department visits and short-acting beta-agonist use, total net savings were approximately $1.60 and $1.70 per-member per-month for commercial and Medicare payers, respectively. CONCLUSION: Propeller is projected to be cost saving from both the commercial and Medicare payer perspectives.

Bedside Assessment of Lung Recruitability: Making Sense of the Recruitment-to-Inflation Ratio.

Determination of optimum PEEP levels remains an elusive goal. One factor is the recruitability of the lung, yet this is another difficult determination. Recently, a simple bedside technique, called the recruitment-to-inflation ratio, has been described and validated by comparison to the dual pressure-volume curve method. We describe the prior research and concepts of lung mechanics leading up to this metric and develop some background mathematics that help clinicians understand its meaning.

Bench Assessment of Work of Breathing During a Spontaneous Breathing Trial on Zero Pressure Support and Zero PEEP Compared to T-Piece.

BACKGROUND: Analysis of observational data suggests that both a T-piece and zero pressure support ventilation (PSV) and zero PEEP impose work of breathing (WOB) during a spontaneous breathing trial (SBT) similar to what a patient experiences after extubation. The aim of our study was to compare the WOB imposed by the T-piece with zero PSV and zero PEEP. We also compared the difference in WOB when using zero PSV and zero PEEP on 3 different ventilators. METHODS: This study was conducted by using a breathing simulator that simulated 3 lung models (ie, normal, moderate ARDS, and COPD). Three ventilators were used and set to zero PSV and zero PEEP. The outcome variable was WOB expressed as mJ/L of tidal volume. RESULTS: An analysis of variance showed that WOB was statistically different between the T-piece and zero PSV and zero PEEP on all the ventilators (Servo-i, Servo-u, and Carescape R860). The absolute difference was lowest for the Carescape R860, which increased WOB by 5-6%, whereas the highest for Servo-u, which reduced the WOB by 15-21%. CONCLUSIONS: Work may be imposed or reduced during spontaneous breathing on zero PSV and zero PEEP when compared to T-piece. The unpredictable nature of how zero PSV and zero PEEP behaves on different ventilators makes it an imprecise SBT modality in the context of assessing extubation readiness.

Gene polymorphisms associated with heterogeneity and senescence characteristics of sarcopenia in chronic obstructive pulmonary disease.

BACKGROUND: Sarcopenia, or loss of skeletal muscle mass and decreased contractile strength, contributes to morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). The severity of sarcopenia in COPD is variable, and there are limited data to explain phenotype heterogeneity. Others have shown that COPD patients with sarcopenia have several hallmarks of cellular senescence, a potential mechanism of primary (age-related) sarcopenia. We tested if genetic contributors explain the variability in sarcopenic phenotype and accelerated senescence in COPD. METHODS: To identify gene variants [single nucleotide polymorphisms (SNPs)] associated with sarcopenia in COPD, we performed a genome-wide association study (GWAS) of fat free mass index (FFMI) in 32 426 non-Hispanic White (NHW) UK Biobank participants with COPD. Several SNPs within the fat mass and obesity-associated (FTO) gene were associated with sarcopenia that were validated in an independent COPDGene cohort (n = 3656). Leucocyte telomere length quantified in the UK Biobank cohort was used as a marker of senescence. Experimental validation was done by genetic depletion of FTO in murine skeletal myotubes exposed to prolonged intermittent hypoxia or chronic hypoxia because hypoxia contributes to sarcopenia in COPD. Molecular biomarkers for senescence were also quantified with FTO depletion in murine myotubes. RESULTS: Multiple SNPs located in the FTO gene were associated with sarcopenia in addition to novel SNPs both within and in proximity to the gene AC090771.2, which transcribes long non-coding RNA (lncRNA). To replicate our findings, we performed a GWAS of FFMI in NHW subjects from COPDGene. The SNP most significantly associated with FFMI was on chromosome (chr) 16, rs1558902A > T in the FTO gene (ß = 0.151, SE = 0.021, P = 1.40 × 10-12 for UK Biobank |ß= 0.220, SE = 0.041, P = 9.99 × 10-8 for COPDGene) and chr 18 SNP rs11664369C > T nearest to the AC090771.2 gene (ß = 0.129, SE = 0.024, P = 4.64 × 10-8 for UK Biobank |ß = 0.203, SE = 0.045, P = 6.38 × 10-6 for COPDGene). Lower handgrip strength, a measure of muscle strength, but not FFMI was associated with reduced telomere length in the UK Biobank. Experimentally, in vitro knockdown of FTO lowered myotube diameter and induced a senescence-associated molecular phenotype, which was worsened by prolonged intermittent hypoxia and chronic hypoxia. CONCLUSIONS: Genetic polymorphisms of FTO and AC090771.2 were associated with sarcopenia in COPD in independent cohorts. Knockdown of FTO in murine myotubes caused a molecular phenotype consistent with senescence that was exacerbated by hypoxia, a common condition in COPD. Genetic variation may interact with hypoxia and contribute to variable severity of sarcopenia and skeletal muscle molecular senescence phenotype in COPD.

Noninvasive positive pressure in acute exacerbations of chronic obstructive pulmonary disease.

PURPOSE OF REVIEW: Noninvasive positive pressure ventilation (NIV) is standard of care for patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). We review the most current evidence and highlight areas of uncertainty and ongoing research. We highlight key concepts for the clinician caring for patients with AECOPD which require NIV. RECENT FINDINGS: Implementation of NIV in AECOPD is not uniform in spite of the evidence and guidelines. Initiation of NIV should be done early and following protocols. Low-intensity NIV remains the standard of care, although research and guidelines are evaluating higher intensity NIV. Scores to predict NIV failure continue to be refined to allow early identification and interventions. Several areas of uncertainty remain, among them are interventions to improve tolerance, length of support and titration and nutritional support during NIV. SUMMARY: The use of NIV in AECOPD is the standard of care as it has demonstrated benefits in several patient-centered outcomes. Current developments and research is related to the implementation and adjustment of NIV.

Diabetes associated with higher health care utilization and poor outcomes after COPD-related hospitalizations.

OBJECTIVES: Readmissions after hospitalizations for acute exacerbation of chronic obstructive pulmonary disease (COPD) have a high socioeconomic burden. Comorbidities such as diabetes increase the risk for hospital readmissions, but the impact of diabetes on hospital outcomes remains unknown. The aim of this study was to evaluate the effect of complicated or uncomplicated diabetes on outcomes and health care costs related to admissions and readmissions in patients 35 years and older with an index admission for COPD. STUDY DESIGN: This was a retrospective longitudinal data analysis. We analyzed data from the Healthcare Cost and Utilization Project (HCUP) Nationwide Readmissions Database. METHODS: We analyzed the 2012-2015 HCUP Nationwide Readmissions Database and used multivariable weighted regression analyses to adjust for confounding factors. Individuals with any chronic pulmonary disease other than COPD were excluded. RESULTS: Of 1,728,931 patients hospitalized for COPD, 522,020 (30.2%) had a diagnosis of diabetes. Risk of all-cause 30-day readmission was higher among patients with complicated diabetes (adjusted odds ratio [OR], 1.15; 95% CI, 1.11-1.18) and uncomplicated diabetes (adjusted OR, 1.10; 95% CI, 1.08-1.12) compared with patients without diabetes. Diabetes was associated with longer length of stay, higher rates of hospital complications during index hospitalizations and 30-day readmissions, and a higher health care cost. Although diabetes was not associated with higher hospital mortality, routine hospital discharges were less common and the need for home health care upon discharge was higher among those with diabetes. CONCLUSIONS: Patients hospitalized for COPD and coexisting diabetes have worse clinical outcomes and higher 30-day readmissions compared with patients hospitalized for COPD without diabetes. Optimizing medical therapies and targeted interventions for both diseases is needed to alleviate disease burden to individuals and to society.

Impact of Esophageal Pressure Measurement on Pulmonary Hypertension Diagnosis in Patients With Obesity.

BACKGROUND: Elevated intrathoracic pressure could affect pulmonary vascular pressure measurements and influence pulmonary hypertension (PH) diagnosis and classification. Esophageal pressure (Pes) measurement adjusts for the increase in intrathoracic pressure, better reflecting the pulmonary hemodynamics in patients with obesity. RESEARCH QUESTION: In individuals with obesity, what is the impact of adjusting pulmonary hemodynamic determinations for Pes on PH diagnosis and classification? Can Pes be estimated by positional or respiratory hemodynamic changes? STUDY DESIGN AND METHODS: In this prospective cohort study, we included patients with obesity who underwent right heart catheterization and demonstrated elevated pulmonary artery wedge pressure (PAWP; ≥ 12 mm Hg). After placement of an esophageal balloon, we performed pressure determination using an air-filled transducer connected to a regular hemodynamic monitor. We measured pulmonary pressures changes when sitting and the variations during the respiratory cycle. RESULTS: We included 53 patients (mean ± SD age, 59 ± 12 years; mean ± SD BMI, 44.4 ± 10.2 kg/m2). Supine end-expiratory pressures revealed a mean pulmonary artery pressure of > 20 mm Hg in all patients and a PAWP of >15 mm Hg in most patients (n = 50). The Pes adjustment led to a significant decrease in percentage of patients with postcapillary PH (from 60% to 8%) and combined precapillary and postcapillary PH (from 34% to 11%), at the expense of an increase in percentage of patients with no PH (0% to 23%), isolated precapillary PH (2% to 25%), and undifferentiated PH (4% to 34%). INTERPRETATION: Adjusting pulmonary hemodynamics for Pes in patients with obesity leads to a pronounced reduction in the number of patients who receive a diagnosis of postcapillary PH. Measuring Pes should be considered in patients with obesity, particularly those with elevated PAWP.

A 21-Year-Old Man With Dyspnea, Wheezing, and Cough.

CASE PRESENTATION: A 21-year-old male college student presented for a second opinion with low alpha-1 antitrypsin (AAT) levels and complaints of episodic dyspnea with wheezing and cough. He was a never smoker with a medical history of frequent respiratory tract infections in early childhood and allergy to dander, dust mites, peanuts, and eggs. There was no travel history outside of the continental United States. His mother had asthma. His symptoms were not controlled on inhaled corticosteroids and bronchodilators. His AAT genotype was found to be PI∗SZ, and augmentation therapy (with pooled human-plasma derived AAT) was recommended locally.

Chronic hypercapnic respiratory failure and non-invasive ventilation in people with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) should no longer be seen as a condition for which little can be done. Novel pharmacotherapeutic interventions, surgical and procedural advances, and respiratory assist devices have provided numerous ways to help patients with COPD and treatable traits. For nearly 30 years, non-invasive ventilation, the application of positive pressure through a mask interface placed outside of the airway, has been the cornerstone for treatment of acute hypercapnic respiratory failure due to COPD exacerbation. Clinical trials indicate that this intervention could benefit patients with COPD and chronic hypercapnic respiratory failure in a stable state. This narrative review aims to provide the necessary background for internists to consider this therapeutic option for their COPD patients. We discuss the mechanism of action and implementation, and provide a glimpse into the future of this promising intervention.

Surge capacity and capability of intensive care units across a large healthcare system: An operational blueprint for regional integration.

OBJECTIVE: Many hospitals were unprepared for the surge of patients associated with the spread of coronavirus disease 2019 (COVID-19) pandemic. We describe the processes to develop and implement a surge plan framework for resource allocation, staffing, and standardized management in response to the COVID-19 pandemic across a large integrated regional healthcare system. SETTING: A large academic medical center in the Cleveland metropolitan area, with a network of 10 regional hospitals throughout Northeastern Ohio with a daily capacity of more than 500 intensive care unit (ICU) beds. RESULTS: At the beginning of the pandemic, an equitable delivery of healthcare services across the healthcare system was developed. This distribution of resources was implemented with the potential needs and resources of the individual ICUs in mind, and epidemiologic predictions of virus transmissibility. We describe the processes to develop and implement a surge plan framework for resource allocation, staffing, and standardized management in response to the COVID-19 pandemic across a large integrated regional healthcare system. We also describe an additional level of surge capacity, which is available to well-integrated institutions called "extension of capacity." This refers to the ability to immediately have access to the beds and resources within a hospital system with minimal administrative burden. CONCLUSIONS: Large integrated hospital systems may have an advantage over individual hospitals because they can shift supplies among regional partners, which may lead to faster mobilization of resources, rather than depending on local and national governments. The pandemic response of our healthcare system highlights these benefits.

Duration of noninvasive ventilation is not a predictor of clinical outcomes in patients with acute exacerbation of COPD and respiratory failure.

PURPOSE: Acute exacerbation of chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity. Noninvasive ventilation (NIV) is proven to be effective in the majority of patients with acute exacerbation COPD (AECOPD) complicated with respiratory failure. NIV could be lifesaving but also can delay mechanical ventilation if its efficacy is not assessed in a timely manner. In this study, we analyzed potential predictors of NIV failure in AECOPD in a tertiary medical intensive care unit (MICU). In particular, we wondered whether duration of NIV among those who eventually failed was associated with poor outcomes. METHODS: A retrospective review of consecutive patients with a primary diagnosis of AECOPD requiring NIV admitted to the MICU was conducted for the period between 2012 and 2017. Baseline data included demographics, APACHE III score, albumin level, blood lactate, and blood gas elements. Additional chart review was performed to collect NIV setting parameters on presentation to the MICU. Clinical outcome variables collected included outcome and duration of NIV, duration of invasive mechanical ventilation, MICU length of stay, hospital length of stay, and in-hospital mortality. Multivariate regression analysis was performed to determine independent variables associated with clinical outcomes. RESULTS: There were 370 patients who met the inclusion criteria; 53.2% were male. Mean age was 64.7 ± 11.2 years old. Mean baseline FEV1 was 34 ±17% of predicted. Patients had mean pH of 7.20 ± 0.54 and PaCO2 of 70.3 ± 28.7 on presentation; 323 patients (87.3%) were successfully weaned off NIV; 47 patients (12.7%) failed NIV and required invasive mechanical ventilation. APACHE III score was higher among patients who failed NIV (68.3±18.9 versus 48.8± 15.2, P < 0.001). In the subset of 47 patients who failed NIV requiring intubation, duration of NIV was 25.0 ± 58.8 h. Multivariate regression analysis yielded a model consisting of APACHE III score and body mass index as predictive variables for NIV failure (C-statistic = 0.809). Duration of NIV was not associated with worse clinical outcomes among patients who failed NIV. CONCLUSIONS: NIV is successful in preventing invasive mechanical ventilation in majority of patients with acute respiratory failure due to COPD. Patients with worse clinical status at presentation are more likely to fail NIV and require mechanical ventilation. In the subgroup of patients who failed NIV, duration of NIV prior to intubation was not associated with poor clinical outcomes.

Evaluation of High-Frequency Oscillatory Ventilation as a Rescue Strategy in Respiratory Failure.

BACKGROUND: The use of high-frequency oscillatory ventilation (HFOV) is backed by sound physiologic rationale, but clinical data on the elective use of HFOV have been largely disappointing. Nonetheless, HFOV is still occasionally used as a rescue mode in patients with severe hypoxemia. The evidence that supports this practice is sparse. METHODS: This was a retrospective single-center analysis that involved subjects admitted to the medical ICU at Cleveland Clinic, Cleveland, Ohio. We included all adult patients (ages > 18 y) who received rescue HFOV between January 1, 2010, and December 31, 2018, and analyzed their clinical outcomes. RESULTS: A total of 48 subjects were included in the analysis. The most common primary diagnosis was pneumonia (n = 33 [68.8%]), followed by aspiration (n = 6 [12.5%]) and diffuse alveolar hemorrhage (n = 2 [4.2%]). Switching to HFOV improved oxygenation but also increased vasopressor requirements at 3 h. The mortality rate of the study population was 92% (44/48). CONCLUSIONS: Our study did not support utilization of HFOV as a "last-ditch" rescue measure in subjects with respiratory failure. The delayed timing of HFOV initiation and its detrimental hemodynamic effects are among the potential reasons for the high mortality rate.

Inhaled corticosteroids do not adversely impact outcomes in COVID-19 positive patients with COPD: An analysis of Cleveland Clinic's COVID-19 registry.

Inhaled Corticosteroids (ICS) are commonly prescribed to patients with severe COPD and recurrent exacerbations. It is not known what impact ICS cause in terms of COVID-19 positivity or disease severity in COPD. This study examined 27,810 patients with COPD from the Cleveland Clinic COVID-19 registry between March 8th and September 16th, 2020. Electronic health records were used to determine diagnosis of COPD, ICS use, and clinical outcomes. Multivariate logistic regression was used to adjust for demographics, month of COVID-19 testing, and comorbidities known to be associated with increased risk for severe COVID-19 disease. Amongst the COPD patients who were tested for COVID-19, 44.1% of those taking an ICS-containing inhaler tested positive for COVID-19 versus 47.2% who tested negative for COVID-19 (p = 0.033). Of those who tested positive for COVID-19 (n = 1288), 371 (28.8%) required hospitalization. In-hospital outcomes were not significantly different when comparing ICS versus no ICS in terms of ICU admission (36.8% [74/201] vs 31.2% [53/170], p = 0.30), endotracheal intubation (21.9% [44/201] vs 16.5% [28/170], p = 0.24), or mortality (18.4% [37/201] vs 20.0% [34/170], p = 0.80). Multivariate logistic regression demonstrated no significant differences in hospitalization (adj OR 1.12, CI: 0.90-1.38), ICU admission (adj OR: 1.31, CI: 0.82-2.10), need for mechanical ventilation (adj OR 1.65, CI: 0.69-4.02), or mortality (OR: 0.80, CI: 0.43-1.49). In conclusion, ICS therapy did not increase COVID-19 related healthcare utilization or mortality outcome in patients with COPD followed at the Cleveland Clinic health system. These findings should encourage clinicians to continue ICS therapy for COPD patients during the COVID-19 pandemic.

Multiplex Ventilation: Solutions for Four Main Safety Problems.

BACKGROUND: The COVID-19 pandemic has led to an increased demand for mechanical ventilators and concerns of a ventilator shortage. Several groups have advocated for 1 ventilator to ventilate 2 or more patients in the event of such a shortage. However, differences in patient lung mechanics could make sharing a ventilator detrimental to both patients. Our previous study indicated failure to ventilate in 67% of simulations. The safety problems that must be solved include individual control of tidal volume (VT), individual measurement of VT, individualization of PEEP settings, and individual PEEP measurement. The purpose of this study was to evaluate potential solutions developed at our institution. METHODS: Two separate lung simulators were ventilated with a modified multiplex circuit using pressure control ventilation. Parameters of the lung models used for simulations (resistance and compliance) were evidence-based from published studies. Individual circuit-modification devices were first evaluated for accuracy. Devices were an adjustable flow diverter valve, a prototype dual volume display, a PEEP valve, and a disposable PEEP display. Then the full modified multiplex circuit was assessed by ventilating 6 pairs of simulated patients with different lung models and attempting to equalize ventilation. Ventilation was considered equalized when VT and end-expiratory lung volume were within 10% for each simulation. RESULTS: The adjustable flow diverter valve allowed volume adjustment to 1 patient without affecting the other. The average error of the dual volume display was -17%. The PEEP valves individualized PEEP, but the PEEP gauge error ranged from 17% to 41%. Using the multiplex circuit, ventilation was equalized regardless of differences in resistance or compliance, reversing the "failure modes" of our previous study. CONCLUSIONS: The results of this simulation-based study indicate that devices for individual control and display of VT and PEEP are effective in extending the usability and potential patient safety of multiplex ventilation.