Indeterminate randomized controlled trials (RCTs) in ARDS may arise from sample size misspecification, leading to abandonment of efficacious therapies.

Restless legs syndrome (RLS) is a sensory-motor neurologic disorder present to a clinically significant degree in 2% to 3% of the adult population, more commonly with advancing age and in women, that dramatically affects sleep and quality of life. Addressing factors that worsen RLS (eg, iron deficiency, antidepressant or antihistamine administration, OSA) is an important first step in treatment. RLS can generally be well treated with medications such as the alpha2-delta calcium channel ligands (A2Ds) gabapentin, pregabalin, and gabapentin enacarbil or, if these are poorly tolerated or lack efficacy, the dopamine agonists (DAs) pramipexole, ropinirole, or rotigotine. Oral or IV iron supplementation is often efficacious as initial treatment in patients with low normal serum indexes. However, at least one-third of patients do not achieve acceptable symptom relief from initial treatments. Furthermore, DAs, the most commonly used medications for RLS, commonly produce augmentation, a progressive, long-term, iatrogenic worsening of RLS symptoms characterized by increasing severity as well as temporal and anatomic extension of symptoms. If dopaminergic augmentation of RLS is present, substitution of an A2D or opioid for the DA is the primary goal. However, given the profound rebound RLS and insomnia that occurs with even small dose reductions of DAs, the initial change should be the addition of one of these alternate treatments. Once adequate doses, or symptom relief, are achieved with the second agent, subsequent very slow down-titration and discontinuation of the DA is often possible and can lead to dramatic long-term relief of RLS symptoms and improvement in sleep.

Sleep disturbances are often cited as a primary reason for medicinal cannabis use, and there is increasing clinical interest in the therapeutic potential of cannabinoids in treating sleep disorders. Burgeoning evidence suggests a role of the endocannabinoid system in regulating the circadian sleep-wake cycle, highlighting a potential avenue for developing novel therapeutics. Despite widespread use of cannabis products as sleep aids globally, robustly designed studies verifying efficacy in sleep-disordered populations are limited. Although some study outcomes have suggested cannabinoid utility in insomnia disorder and sleep apnea, most studies to date are limited by small sample sizes, lack of rigorously controlled study designs, and high risk of bias. This critical review summarizes the current evidence for the use of cannabinoids as a treatment for sleep disorders and provides an overview of endocannabinoid modulation of sleep-wake cycles, as well as the sleep-modulating effects of plant-derived cannabinoids such as delta-9-tetrahydrocannbinol, cannabidiol, and cannabinol. The review also discusses practical considerations for clinicians regarding cannabinoid formulations, routes of administration, respiratory concerns, dosing, potential side effects, drug interactions, and effects relevant to driving, tolerance, and withdrawal. Although current interest in, and uptake of, medicinal cannabis use for sleep disorders may have surpassed the evidence base, there is a strong rationale for continued investigation into the therapeutic potential of cannabinoids.

Mortality historically has been the primary outcome of choice for acute and critical care clinical trials. However, undue reliance on mortality can limit the scope of trials that can be performed. Large sample sizes are usually needed for trials powered for a mortality outcome, and focusing solely on mortality fails to recognize the importance that reducing morbidity can have on patients' lives. The COVID-19 pandemic has highlighted the need for rapid, efficient trials to rigorously evaluate new therapies for hospitalized patients with acute lung injury. Oxygen-free days (OFDs) is a novel outcome for clinical trials that is a composite of mortality and duration of new supplemental oxygen use. It is designed to characterize recovery from acute lung injury in populations with a high prevalence of new hypoxemia and supplemental oxygen use. In these populations, OFDs captures two patient-centered consequences of acute lung injury: mortality and hypoxemic lung dysfunction. Power to detect differences in OFDs typically is greater than that for other clinical trial outcomes, such as mortality and ventilator-free days. OFDs is the primary outcome for the Fourth Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4) Host Tissue platform, which evaluates novel therapies targeting the host response to COVID-19 among adults hospitalized with COVID-19 and new hypoxemia. This article outlines the rationale for use of OFDs as an outcome for clinical trials, proposes a standardized method for defining and analyzing OFDs, and provides a framework for sample size calculations using the OFD outcome.

Accurate assessment of maximum respiratory pressure is vital when tracking disease progression and devising treatment strategies. Previous studies indicate a learning effect when undertaking maximum respiratory pressure measurements. The extent of this learning effect and methodologies undertaken to mitigate this learning effect have not been investigated systematically.

The current approach to interpretation of lung function measurements assumes that differences in lung function between racial and ethnic groups represent inherent and biological differences. Observed differences in lung function between White and Black populations are often attributed to physiological differences in body proportions (eg, chest size, leg length); however, most studies investigating the observed differences have not considered the impact of socioeconomic status (SES).

In people with COPD, pulmonary gas-exchange efficiency may be impaired because of abnormal alveolar ventilation (V˙A), capillary perfusion (Q˙c), or both. Both have been reported in early and mild stages of the disease. Such derangements often accompany significant clinical consequences such as activity-related dyspnea and exercise intolerance. Although much attention has been paid to pharmacologic treatment of mechanical abnormalities in COPD (eg, bronchodilators to deflate the lungs), increasing neurochemical afferent activity, secondary to gas-exchange inefficiency, has remained elusive as a therapeutic target. Hence, in this invited review, we first summarize how dyspnea, leading to poor exercise tolerance in COPD, may be explained by an increased venous admixture resulting from low V˙A/Q˙c, or wasted ventilation related to high V˙A/Q˙c, or both. We review the conflicting evidence supporting current treatments for gas-exchange inefficiency and exercise tolerance that act primarily on V˙A (bronchodilators, antiinflammatory medications) or Q˙c (oral and inhaled vasodilators, almitrine, and supplemental oxygen). Finally, to address the current knowledge and health care gaps, we propose two independent clinical research foci that may lead to a better understanding of the role of pulmonary gas-exchange inefficiency and activity-related dyspnea in COPD: (1) enhanced and deeper phenotyping of patients with COPD with V˙A/Q˙c abnormalities and (2) evaluation of existing and novel pharmacologic treatments to improve gas-exchange inefficiency, exertional dyspnea, and exercise tolerance across the spectrum of COPD severity.

The outbreak of COVID-19 has brought renewed attention to past narratives of disease outbreaks. What do the Black Death and COVID-19 have in common? How we tell outbreak stories is shaped by political, cultural, social, and historical contexts. It is deeply rhetorical. The general public relies on experts (scientists, historians, and government officials) to provide credible information, but uncertainties during an outbreak can make it difficult to provide definitive answers quickly. Experts need to be conscious about the contexts in which their statements would be received. Regarding the Black Death, historians of medicine have relied heavily on a single medieval account of the outbreak, which confirmed their preconceptions about Mongol violence, allowing them to present the Black Death as an instance of biological warfare. Looking at other medieval accounts, however, makes clear that this narrative of Mongol biological warfare is false. Similarly, modern outbreak narratives also tend to use militarized language, which results in othering peoples and cultures where a disease might have originated. Given the contemporary political tensions between China and the United States, narratives about the origin of the SARS-CoV-2 virus and its transmission have led to a transnational infodemic of misinformation as well as discrimination and violence against people of Asian descent. In light of this long-running pattern, we argue for more interdisciplinary collaborations between the experts whose work is used to build outbreak narratives to adopt more critical rhetorical approaches in communicating with the public.

The terms sex and gender often are used interchangeably, but have specific meaning when it comes to their effects on lung disease. Ample evidence is now available that sex and gender affect the incidence, susceptibility, presentation, diagnosis, and severity of many lung diseases. Some conditions are more prevalent in women, such as asthma. Other conditions are seen almost exclusively in women, like lymphangioleiomyomatosis. Some life stages-such as pregnancy-are unique to women and can affect the onset and course of lung disease. Clinical presentation may differ as well, such as higher number of exacerbations experienced by women with COPD and greater cardiovascular morbidity in women with sleep-disordered breathing. In addition, response to therapy and medication safety may also differ by sex, and yet, pharmacogenomic factors often are not addressed adequately in clinical trials. Various aspects of lung and sleep biology and pathobiology are impacted by female sex and female reproductive transitions. Differential gene expression or organ development can be impacted by these biological differences. Understanding these differences is the first step in moving toward precision medicine for women. This article is a state-of-the-art review of specific effects of sex and gender focused on epidemiology, disease presentation, risk factors, and management of lung diseases. Pathobiological mechanisms explaining sex differences in these diseases are beyond the scope of this article. We review the literature and focus on recent guidelines about using sex and gender in research. We also review sex and gender differences in lung diseases.

In 2019, the United States experienced a nationwide outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI). More than one-half of these patients required admission to an ICU.

Asthma exacerbations can be life-threatening, with 25,000 to 50,000 such patients per year requiring admission to an ICU in the United States. Appropriate triage of life-threatening asthma is dependent on both static assessment of airway function and dynamic assessment of response to therapy. Treatment strategies focus on achieving effective bronchodilation with inhaled β2-agonists, muscarinic antagonists, and magnesium sulphate while reducing inflammation with systemic corticosteroids. Correction of hypoxemia and hypercapnia, a key in managing life-threatening asthma, occasionally requires the incorporation of noninvasive mechanical ventilation to decrease the work of breathing. Endotracheal intubation and mechanical ventilation should not be delayed if clinical improvement is not achieved with conservative therapies. However, mechanical ventilation in these patients often requires controlled hypoventilation, adequate sedation, and occasional use of muscle relaxation to avoid dynamic hyperinflation, which can result in barotrauma or volutrauma. Sedation with ketamine or propofol is preferred because of their potential bronchodilation properties. In this review, we outline strategies for the assessment and management of patients with acute life-threatening asthma focusing on those requiring admission to the ICU.

Previous studies regarding the prevalence of frailty in patients with lung cancer and mortality in frail patients with lung cancer are inconsistent and require clarification.

Sedation is an essential component of treatment for some patients admitted to the ICU, but it carries a risk of sedation-related delirium. Sedation-related delirium is associated with higher mortality and increased length of stay, but pharmacologic treatments for delirium can lead to oversedation or other adverse effects. Therefore, nonpharmacologic treatments are recommended in the literature; however, these recommendations are quite general and do not provide structured interventions. To establish a structured nonpharmacologic intervention that could improve indications of delirium after sedation, we combined evidence-based interventions including recordings of sensory-rich stories told by the patient's family and patient-specific music into our novel positive stimulation for medically sedated patients (PSMSP) protocol. The positive listening stimulation playlist organized by a board-certified music therapist (MT-BC) within the PSMSP protocol can be used in carefully monitored sessions with the MT-BC potentially to decrease agitation and stabilize arousal, as well as being played by nursing staff throughout the patient's recovery from sedation. Further controlled studies will be necessary, but the PSMSP protocol has the potential to reduce agitation and increase arousal during listening, as highlighted by the case of a patient recovering from sedation during treatment for COVID-19 pneumonia. It is important for the entire critical care team to be aware of nonpharmacologic treatments like PSMSP that are available for delirium mitigation so that, where applicable, these therapies can be incorporated into the patient's treatment regimen.

As outcomes have improved across the hematologic malignancy population, candidacy for ICU admission has increased. This complex population may develop a variety of complications related to their treatment or underlying disease that can result in critical illness necessitating ICU support. This review highlights common causes of critical illness associated with hematologic malignancies, including the following: (1) neutropenic sepsis; (2) hyperleukocytosis and leukostasis across patients with acute myeloid leukemia; (3) complications of acute promyelocytic leukemia; (4) tumor lysis syndrome; and (5) critical care complications that can arise following hematopoietic stem cell transplantation.

Cystic fibrosis (CF) is characterized by chronic airway infection and progressive respiratory decline. Historically, a narrow spectrum of bacterial pathogens was believed to comprise the bulk of respiratory infections in CF, with Haemophilus influenzae and Staphylococcus aureus dominating childhood infections, and Pseudomonas aeruginosa or, less commonly, a member of the Burkholderia cepacia complex becoming the dominant infecting organism in adulthood. Today, the landscape is changing for airway infection in CF. The prevalence of "less typical" gram-negative bacterial infections are rising due to a number of factors: the CF population is aging; new therapies are being introduced; antibiotic usage is increasing; diagnostic tests are evolving; and taxonomic changes are being made as new bacterial species are being discovered. Less is known about the clinical relevance and evidence for treatment strategies for many of the other lower prevalence organisms that are encountered in CF. The aim of this article was to discuss the current evidence and recommended strategies for treating airway infection in CF, focusing on bacterial infections.

The effect of nonobstructive chronic bronchitis (CB) on mortality is unclear.

Predictive analytic models leveraging machine learning methods increasingly have become vital to health care organizations hoping to improve clinical outcomes and the efficiency of care delivery for all patients. Unfortunately, predictive models could harm populations that have experienced interpersonal, institutional, and structural biases. Models learn from historically collected data that could be biased. In addition, bias impacts a model's development, application, and interpretation. We present a strategy to evaluate for and mitigate biases in machine learning models that potentially could create harm. We recommend analyzing for disparities between less and more socially advantaged populations across model performance metrics (eg, accuracy, positive predictive value), patient outcomes, and resource allocation and then identify root causes of the disparities (eg, biased data, interpretation) and brainstorm solutions to address the disparities. This strategy follows the lifecycle of machine learning models in health care, namely, identifying the clinical problem, model design, data collection, model training, model validation, model deployment, and monitoring after deployment. To illustrate this approach, we use a hypothetical case of a health system developing and deploying a machine learning model to predict the risk of mortality in 6 months for patients admitted to the hospital to target a hospital's delivery of palliative care services to those with the highest mortality risk. The core ethical concepts of equity and transparency guide our proposed framework to help ensure the safe and effective use of predictive algorithms in health care to help everyone achieve their best possible health.

Although maintaining some amount of positive end-expiratory pressure (PEEP) seems essential, selecting and titrating a specific level for patients with ARDS remains challenging despite extensive research on the subject. Although an "open lung" approach to ventilation is popular and has some degree of biological plausibility, it is not without risk. Furthermore, there is no clear evidence-based guidance regarding initial PEEP settings or how to titrate them early in the course of the illness. Many busy clinicians use a "one-size-fits-all" approach based on local medical culture, but an individualized approach has the potential to offer significant benefit. Here we present a pragmatic approach based on simple measurements available on all ventilators, focused on achieving balance between the potential risks and benefits of PEEP. Acknowledging "best PEEP" as an impossible goal, we aim for a straightforward method to achieve "better PEEP."

Direct oral anticoagulants (DOACs) are increasingly used in clinical practice and have become essential in the management of atrial fibrillation and VTE. The enthusiasm for DOACs has fueled the off-label application of these agents in cardiopulmonary disease, and their use has often outpaced the evidence supporting their application. This article reviews the evidence and current off-label use of DOACs in various cardiopulmonary disease states.

Basic critical care echocardiography emphasizes two-dimensional (2D) findings, such as ventricular function, inferior vena cava size, and pericardial assessment, while generally excluding quantitative findings and Doppler-based techniques. Although this approach offers advantages, including efficiency and expedited training, it complicates attempts to understand the hemodynamic importance of any 2D abnormalities detected. Stroke volume (SV), as the summative event of the cardiac cycle, is the most pragmatic available indicator through which a clinician can rapidly determine, no matter the 2D findings, whether aberrant cardiac physiology is contributing to the state of shock. An estimate of SV allows 2D findings to be placed into better context in terms of both hemodynamic significance and acuity. This article describes the technique of SV determination, reviews common confounding factors and pitfalls, and suggests a systematic approach for using SV measurements to help integrate important 2D findings into the clinical context.