Lowering PCO2 With Noninvasive Ventilation Is Associated With Improved Survival in Chronic Hypercapnic Respiratory Failure.

BACKGROUND: Chronic hypercapnic respiratory failure is associated with high mortality. Although previous work has demonstrated a mortality improvement with high-intensity noninvasive ventilation in COPD, it is unclear whether a PCO2 reduction strategy is associated with improved outcomes in other populations of chronic hypercapnia. METHODS: The objective of this study was to investigate the association between PCO2 reduction (by using transcutaneous PCO2 as an estimate for PaCO2 and survival in a broad population of individuals treated with noninvasive ventilation for chronic hypercapnia. We hypothesized that reductions in PCO2 would be associated with improved survival. Therefore, we performed a cohort study of all the subjects evaluated from February 2012 to January 2021 for noninvasive ventilation initiation and/or optimization due to chronic hypercapnia at a home ventilation clinic in an academic center. We used multivariable Cox proportional hazard models with time-varying coefficients and PCO2 as a time-varying covariate to test the association between PCO2 and all-cause mortality and when adjusting for known cofounders. RESULTS: The mean ± SD age of 337 subjects was 57 ± 16 years, 37% women, and 85% white. In a univariate analysis, survival probability increased with reductions in PCO2 to < 50 mm Hg after 90 d, and these remained significant after adjusting for age, sex, race, body mass index, diagnosis, Charlson comorbidity index, and baseline PCO2 . In the multivariable analysis, the subjects who had a PaCO2 < 50 mm Hg had a reduced mortality risk of 94% between 90 and 179 d (hazard ratio [HR] 0.06, 95% CI 0.01-0.50), 69% between 180 and 364 d (HR 0.31, 95% CI 0.12-0.79), and 73% for 365-730 d (HR 0.27, 95% CI 0.13-0.56). CONCLUSIONS: Reduction in PCO2 from baseline for subjects with chronic hypercapnia treated with noninvasive ventilation was associated with improved survival. Management strategies should target the greatest attainable reductions in PCO2 .

Practical Guide to Management of Long-Term Noninvasive Ventilation for Adults With Chronic Neuromuscular Disease.

Recent technological advances in respiratory support and monitoring have dramatically enhanced the utility of long-term noninvasive ventilation (NIV). Improved quality of life and prolonged survival have been demonstrated for several common chronic neuromuscular diseases. Many adults with progressive neuromuscular respiratory disease can now comfortably maintain normal ventilation at home to near total respiratory muscle paralysis without needing a tracheostomy. However, current practice in many communities falls short of that potential. Mastery of the new technology calls for detailed awareness of the respiratory cycle; expert knowledge of mechanical devices, facial interfaces, and quantitative monitoring tools for home ventilation; and a willingness to stay current in a rapidly expanding body of clinical research. The depth and breadth of the expertise required to manage home assisted ventilation has given rise to a new focused medical subspecialty in chronic respiratory failure at the interface between pulmonology, critical care, and sleep medicine. For clinicians seeking pragmatic "how to" guidance, this primer presents a comprehensive, physician-directed management approach to long-term NIV of adults with chronic neuromuscular respiratory disease. Bi-level devices, portable ventilators, ventilation modalities, terminology, and monitoring strategies are reviewed in detail. Building on that knowledge base, we present a step-by-step guide to initiation, refinement, and maintenance of home NIV tailored to patient-centered goals of therapy. The quantitative approach recommended incorporates routine monitoring of home ventilation using technologies that have only recently become widely available including cloud-based device telemonitoring and noninvasive measurements of blood gases. Strategies for troubleshooting and problem solving are included.

Nontraumatic Chylothorax and Chylopericardium: Diagnosis and Treatment Using an Algorithmic Approach Based on Novel Lymphatic Imaging.

Rationale: Outcomes of interventional lymphangiographic treatment of nontraumatic chylous pleural effusions using traditional approaches have been highly variable. Recent advances in lymphatic imaging have revealed variations in underlying pathophysiology, enabling improved targeting of therapeutic interventions. Objectives: To assess outcomes of an algorithm for management of nontraumatic chylous pleural effusions based on advanced magnetic resonance (MR) identification of various abnormalities in the thoracoabdominal lymphatic network that give rise to chylothorax. Methods: Novel lymphatic MR imaging was performed in 52 patients aged 11-89 years. Three distinct pathophysiological patterns were found: 1) abnormal pulmonary lymphatic flow from the thoracic duct only; 2) abnormal pulmonary lymphatic flow from retroperitoneal lymphatic networks with or without involvement of the thoracic duct; and 3) chylous ascites presenting as chylous pleural effusion. Lymphatic interventions were individualized to the underlying pathophysiological patterns. Results: In 41/52 (79%) patients, imaging revealed abnormal pulmonary lymphatic flow from the thoracic duct and/or retroperitoneal lymphatic networks. Thoracic duct embolization and/or interstitial embolization of retroperitoneal lymphatic resulted in resolution of chylothorax in this group in 38/41 (93%) of those patients. Five patients experienced grade 1 or 2 complications. One patient succumbed to postoperative stress-induced cardiomyopathy and pulmonary embolism. Chylous ascites was the cause of chylothorax in 11/52 (21%) patients. Eight chose to undergo interventions for chylous ascites with clinical success in 6/8 (75%). Conclusions: Application of magnetic resonance imaging-guided intervention algorithm resulted in successful control of nontraumatic chylothorax in 93% patients with abnormal pulmonary lymphatic flow. Appropriate treatment of chylous ascites presenting as a pleural effusion requires systematic evaluation and diagnosis prior to potential treatments.

Telemonitoring for Home-assisted Ventilation: A Narrative Review.

The recent advent of remote ventilator telemonitoring has the potential to revolutionize home-assisted ventilation care in the United States and elsewhere. Home ventilation machines (i.e., respiratory assist devices and portable ventilators) can now wirelessly transmit usage and performance data to cloud-based web servers for remote access by participating clinicians. In this Focused Review, we provide an update on available technology, suggest practical applications for clinical care and research, and review supporting literature. Remote monitoring permits early data review, refinement of device settings to optimize ventilatory function, and troubleshooting if a new problem arises after initial setup. Data from home spirometry and noninvasively measured blood gas tensions can complement ventilator data to reflect physiological response. Acknowledging a paucity of published outcome studies, remote telemonitoring may be a cost-effective strategy to reduce emergency room visits, urgent clinic appointments, and hospitalizations. Ongoing clinical trials in Europe aim to expand on the benefit of this rapidly evolving technology. However, several barriers may hinder widespread implementation, especially in the United States. Clinicians must familiarize themselves with each ventilator manufacturer's proprietary software to safely leverage this technology for improving care. Legal and ethical considerations threaten clinician interest. Medical insurance payers must adapt a reimbursement scheme to incentivize clinicians and durable medical equipment companies to perform this time-consuming service. Cohort-level ventilator data will facilitate multicenter clinical trials focused on improving the respiratory care of this vulnerable population.

Noninvasive Ventilation Use Is Associated with Better Survival in Amyotrophic Lateral Sclerosis.

Rationale: Noninvasive ventilation (NIV) is standard of care in amyotrophic lateral sclerosis (ALS), yet few data exist regarding its benefits.Objectives: We sought to identify whether the use of NIV was associated with survival in ALS.Methods: This was a single-center retrospective cohort study of 452 patients with ALS seen between 2006 and 2015. We matched one or more NIV subjects (prescribed NIV) to non-NIV subjects (never prescribed NIV) without replacement. The outcome was time from NIV prescription date (NIV subjects) or matched date (non-NIV subjects) until death. We performed a multivariable Cox proportional hazards model with NIV hourly usage as a time-varying covariate and stratified by matched groups.Results: After creating 180 matched groups and adjusting for age, body mass index, ALS Functional Rating Scale Revised dyspnea score, and hourly NIV use, NIV was associated with a 26% reduction in the rate of death compared with non-NIV subjects (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57-0.98; P = 0.04). Among those with limb-onset ALS, NIV subjects had a 37% lower rate of death compared with non-NIV subjects (HR, 0.63; 95% CI, 0.45-0.87; P = 0.006). Among NIV subjects, we found that NIV use for an average of ≥4 h/d was associated with improved survival.Conclusions: NIV use was associated with significantly better survival in ALS after matching and adjusting for confounders. Increasing duration of daily NIV use was associated with longer survival. Randomized clinical trials should be performed to identify ideal thresholds for improving survival and optimizing adherence in ALS.

Transition of patients with neuromuscular disease and chronic ventilator-dependent respiratory failure from pediatric to adult pulmonary care.

Improvements in medical care have allowed many children with neuromuscular disease and chronic respiratory failure to survive into adulthood. There are currently no published guidelines to facilitate transition from pediatric to adult respiratory care in this population. The transition process in neuromuscular disease and chronic respiratory failure is uniquely challenging in that the patients are often declining in health and losing independence as they approach adulthood. Barriers to transition include lack of access to adult providers, incompatible health insurance, loss of resources within patients' medical structures, absence of transition preparation, and patient and family insecurity with a new healthcare system. The six core elements and optimal time frame of transition should be applied, with special consideration of the psychosocial aspects associated with neuromuscular disease. Successful transition revolves around information, open communication between young adults and their medical care team, and individualized planning to ensure optimal health and quality of life.

Classifying Patients with Amyotrophic Lateral Sclerosis by Changes in FVC. A Group-based Trajectory Analysis.

Rationale: A model for stratifying progression of respiratory muscle weakness in amyotrophic lateral sclerosis (ALS) would identify disease mechanisms and phenotypes suitable for future investigations. This study sought to categorize progression of FVC after presentation to an outpatient ALS clinic.Objectives: To identify clinical phenotypes of ALS respiratory progression based on FVC trajectories over time.Methods: We derived a group-based trajectory model from a single-center cohort of 837 patients with ALS who presented between 2006 and 2015. We applied our model to the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database with 7,461 patients with ALS. Baseline characteristics at first visit were used as predictors of trajectory group membership. The primary outcome was trajectory of FVC over time in months.Measurements and Main Results: We found three trajectories of FVC over time, termed "stable low," "rapid progressor," and "slow progressor." Compared with the slow progressors, the rapid progressors had shorter diagnosis delay, more bulbar-onset disease, and a lower ALS Functional Rating Scale-Revised (ALSFRS-R) total score at baseline. The stable low group had a shorter diagnosis delay, lower body mass index, more bulbar-onset disease, lower ALSFRS-R total score, and were more likely to have an ALSFRS-R orthopnea score lower than 4 compared with the slow progressors. We found that projected group membership predicted respiratory insufficiency in the PRO-ACT cohort (concordance statistic = 0.78, 95% CI, 0.76-0.79).Conclusions: We derived a group-based trajectory model for FVC progression in ALS, which validated against the outcome of respiratory insufficiency in an external cohort. Future studies may focus on patients predicted to be rapid progressors.

Sleep and Work in ICU Physicians During a Randomized Trial of Nighttime Intensivist Staffing.

OBJECTIVES: To compare sleep, work hours, and behavioral alertness in faculty and fellows during a randomized trial of nighttime in-hospital intensivist staffing compared with a standard daytime intensivist model. DESIGN: Prospective observational study. SETTING: Medical ICU of a tertiary care academic medical center during a randomized controlled trial of in-hospital nighttime intensivist staffing. PATIENTS: Twenty faculty and 13 fellows assigned to rotations in the medical ICU during 2012. INTERVENTIONS: As part of the parent study, there was weekly randomization of staffing model, stratified by 2-week faculty rotation. During the standard staffing model, there were in-hospital residents, with a fellow and faculty member available at nighttime by phone. In the intervention, there were in-hospital residents with an in-hospital nighttime intensivist. Fellows and faculty completed diaries detailing their sleep, work, and well-being; wore actigraphs; and performed psychomotor vigilance testing daily. MEASUREMENTS AND MAIN RESULTS: Daily sleep time (mean hours [SD]) was increased for fellows and faculty in the intervention versus control (6.7 [0.3] vs 6.0 [0.2]; p < 0.001 and 6.7 [0.1] vs 6.4 [0.2]; p < 0.001, respectively). In-hospital work duration did not differ between the models for fellows or faculty. Total hours of work done at home was different for both fellows and faculty (0.1 [< 0.1] intervention vs 1.0 [0.1] control; p < 0.001 and 0.2 [< 0.1] intervention vs 0.6 [0.1] control; p < 0.001, respectively). Psychomotor vigilance testing did not demonstrate any differences. Measures of well-being including physical exhaustion and alertness were improved in faculty and fellows in the intervention staffing model. CONCLUSIONS: Although no differences were measured in patient outcomes between the two staffing models, in-hospital nighttime intensivist staffing was associated with small increases in total sleep duration for faculty and fellows, reductions in total work hours for fellows only, and improvements in subjective well-being for both groups. Staffing models should consider how work duration, sleep, and well-being may impact burnout and sustainability.

Development of a prognostic model of respiratory insufficiency or death in amyotrophic lateral sclerosis.

A clinically useful model to prognose onset of respiratory insufficiency in amyotrophic lateral sclerosis (ALS) would inform disease interventions, communication and clinical trial design. We aimed to derive and validate a clinical prognostic model for respiratory insufficiency within 6 months of presentation to an outpatient ALS clinic.We used multivariable logistic regression and internal cross-validation to derive a clinical prognostic model using a single-centre cohort of 765 ALS patients who presented between 2006 and 2015. External validation was performed using the multicentre Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database with 7083 ALS patients. Predictors included baseline characteristics at first outpatient visit. The primary outcome was respiratory insufficiency within 6 months, defined by initiation of noninvasive ventilation, forced vital capacity (FVC) <50% predicted, tracheostomy, or death.Of 765 patients in our centre, 300 (39%) had respiratory insufficiency or death within 6 months. Six baseline characteristics (diagnosis age, delay between symptom onset and diagnosis, FVC, symptom onset site, amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) total score and ALSFRS-R dyspnoea score) were used to prognose the risk of the primary outcome. The derivation cohort c-statistic was 0.86 (95% CI 0.84-0.89) and internal cross-validation produced a c-statistic of 0.86 (95% CI 0.85-0.87). External validation of the model using the PRO-ACT cohort produced a c-statistic of 0.74 (95% CI 0.72-0.75).We derived and externally validated a clinical prognostic rule for respiratory insufficiency in ALS. Future studies should investigate interventions on equivalent high-risk patients.

Assessing Response to Therapy for Nontuberculous Mycobacterial Lung Disease: Quo Vadis?

Assessing progression of disease or response to treatment remains a major challenge in the clinical management of nontuberculous mycobacterial (NTM) infections of the lungs. Serial assessments of validated measures of treatment response address whether the current therapeutic approach is on track toward clinical cure, which remains a fundamental question for clinicians and patients during the course of NTM disease treatment. The 2015 NTM Research Consortium Workshop, which included a patient advisory panel, identified treatment response biomarkers as a priority area for investigation. Limited progress in addressing this challenge also hampers drug development efforts. The Biomarker Qualification Program at the FDA supports the use of a validated treatment response biomarker across multiple drug development programs. Current approaches in clinical practice include microbiologic and radiographic monitoring, along with symptomatic and quality-of-life assessments. Blood-based monitoring, including assessments of humoral and cell-mediated NTM-driven immune responses, remain under investigation. Alignment of data collection schemes in prospective multicenter studies, including the support of biosample repositories, will support identification of treatment response biomarkers under standard-of-care and investigational therapeutic strategies. In this review, we outline the role of treatment monitoring biomarkers in both clinical practice and drug development frameworks.

Towards an expert consensus to delineate a clinical syndrome of chronic breathlessness.

Breathlessness that persists despite treatment for the underlying conditions is debilitating. Identifying this discrete entity as a clinical syndrome should raise awareness amongst patients, clinicians, service providers, researchers and research funders.Using the Delphi method, questions and statements were generated via expert group consultations and one-to-one interviews (n=17). These were subsequently circulated in three survey rounds (n=34, n=25, n=31) to an extended international group from various settings (clinical and laboratory; hospital, hospice and community) and working within the basic sciences and clinical specialties. The a priori target agreement for each question was 70%. Findings were discussed at a multinational workshop.The agreed term, chronic breathlessness syndrome, was defined as breathlessness that persists despite optimal treatment of the underlying pathophysiology and that results in disability. A stated duration was not needed for "chronic". Key terms for French and German translation were also discussed and the need for further consensus recognised, especially with regard to cultural and linguistic interpretation.We propose criteria for chronic breathlessness syndrome. Recognition is an important first step to address the therapeutic nihilism that has pervaded this neglected symptom and could empower patients and caregivers, improve clinical care, focus research, and encourage wider uptake of available and emerging evidence-based interventions.