The Impact of Immunotherapy on Sleep and Circadian Rhythms in Patients with Cancer.

Immunotherapy has revolutionized treatments for both early and advanced cancers, and as their role evolves, their impact on sleep and circadian rhythms continues to unfold. The recognition, evaluation, and treatment of sleep and circadian rhythm disturbance leads to improved symptom management, quality of life and treatment outcomes. An intricate complex relationship exists in the microenvironment with immunity, sleep and the tumor, and these may further vary based on the cancer, addition of standard chemotherapy, and pre-existing patient factors. Sleep and circadian rhythms may offer tools to better utilize immunotherapy in the care of cancer patients, leading to better treatment outcome, reduced symptom burden, and increased quality of life.

Utility of Bronchoalveolar Lavage for the Diagnosis and Management of COVID-19 in Patients With Cancer.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) on nasopharyngeal swab (NPS), remains the most reliable and practical test to diagnose coronavirus disease 2019 (COVID-19). Current literature is sparse regarding the rates of discordance between NPS and bronchoalveolar lavage (BAL) in patients with cancer. METHODS: We conducted a retrospective cohort study of adult patients with cancer who had BAL samples tested for SARS-CoV-2 at a comprehensive cancer center. Patients without NPS PCR for SARS-CoV-2 before BAL were excluded. RESULTS: In a cohort of 345 patients, 12% and 17% tested positive for SARS-CoV-2 on NPS and BAL, respectively. There was a 6.3% NPS-/BAL+ discordance rate and a 9.5% NPS+/BAL- discordance rate. Patients with lymphoma (adjusted odds ratio [aOR] = 4.06; P = .007) and Hispanic patients (aOR = 3.76; P = .009) were more likely to have NPS-/BAL+ discordance on multivariate analysis. Among patients with NPS- /BAL- for SARS-CoV-2, an alternate infectious (23%) and a noninfectious etiology (16%) were identified in BAL. CONCLUSIONS: Our discordance rates between NPS and BAL were sufficient to recommend BAL in certain patients with cancer with a high clinical suspicion of COVID-19. BAL has value in identifying alternative etiologies of illness in patients with suspected or confirmed COVID-19.

Interstitial lung abnormalities after hospitalization for COVID-19 in patients with cancer: A prospective cohort study.

INTRODUCTION: Survivors of SARS-CoV-2 pneumonia often develop persistent respiratory symptom and interstitial lung abnormalities (ILAs) after infection. Risk factors for ILA development and duration of ILA persistence after SARS-CoV-2 infection are not well described in immunocompromised hosts, such as cancer patients. METHODS: We conducted a prospective cohort study of 95 patients at a major cancer center and 45 patients at a tertiary referral center. We collected clinical and radiographic data during the index hospitalization for COVID-19 pneumonia and measured pneumonia severity using a semi-quantitative radiographic score, the Radiologic Severity Index (RSI). Patients were evaluated in post-COVID-19 clinics at 3 and 6 months after discharge and underwent comprehensive pulmonary evaluations (symptom assessment, chest computed tomography, pulmonary function tests, 6-min walk test). The association of clinical and radiological factors with ILAs at 3 and 6 months post-discharge was measured using univariable and multivariable logistic regression. RESULTS: Sixty-six (70%) patients of cancer cohort had ILAs at 3 months, of whom 39 had persistent respiratory symptoms. Twenty-four (26%) patients had persistent ILA at 6 months after hospital discharge. In adjusted models, higher peak RSI at admission was associated with ILAs at 3 (OR 1.5 per 5-point increase, 95% CI 1.1-1.9) and 6 months (OR 1.3 per 5-point increase, 95% CI 1.1-1.6) post-discharge. Fibrotic ILAs (reticulation, traction bronchiectasis, and architectural distortion) were more common at 6 months post-discharge. CONCLUSIONS: Post-COVID-19 ILAs are common in cancer patients 3 months after hospital discharge, and peak RSI and older age are strong predictors of persistent ILAs.

Exploring the Effects of Perceived Stress on the Within-Person Relationships Between Daily Activity Levels and Sleep in Women: An Ecological Momentary Assessment Study.

BACKGROUND: Many studies show positive bidirectional associations between physical activity (PA) and sleep at the between-person level. There is an increased interest in investigating these associations at the within-person level. Few studies examined the effects of time-varying moderators on the within-person bidirectional associations between PA and sleep. This study aimed to examine the bidirectional within-person day-level associations between activity levels and self-reported sleep duration and explore the moderating effects of perceived stress on these day-level associations. METHOD: Data from 158 women that included 7-day free-living monitoring over 4 measurement periods was analyzed using multilevel modeling to explore the moderating effects of daily stress on the bidirectional, within-person associations between activity levels and self-reported sleep duration. Moderate-to-vigorous PA (MVPA) and sedentary behavior (SB) were estimated from a waist-worn accelerometer. Self-reported sleep duration and perceived stress were collected by ecological momentary assessment. RESULTS: No significant within-person associations between MVPA minutes and self-reported sleep duration were found in either direction. However, engaging in more MVPA than one's usual level was associated with longer sleep later that night when perceived stress was higher than usual (p = .04). Bidirectional negative within-person association between SB minutes and self-reported sleep duration was found (ps < .01). The negative association between SB and sleep duration later that night was stronger when perceived stress was lower than usual (p = .01). CONCLUSION: Daily stress played an important role in the day-to-day associations between activity levels and sleep.

Characteristics of Cancer-Related Fatigue and Concomitant Sleep Disturbance in Cancer Patients.

CONTEXT: Cancer patients often experience cancer-related fatigue (CRF) and sleep disturbances due to cancer and cancer treatment, and symptoms can persist long after treatment. Despite these common occurrences, few studies simultaneously characterize CRF and sleep architecture among cancer patients. OBJECTIVES: The objective was to characterize CRF and the sleep architecture of patients seen in a CRF clinic and sleep clinic at the University of Texas MD Anderson Cancer Center. METHODS: CRF Clinic medical records were retrospectively reviewed from September 1, 2006, to September 30, 2010, for self-reported performance status, fatigue, pain, sleep disturbance, depression, anxiety, and sleepiness (n = 219). Polysomnography results were recorded for those referred for additional sleep consultation (n = 39). RESULTS: Notably, patients often reported fatigue, sleep disturbance, excessive daytime sleepiness, and a majority of patients referred for a sleep consultation were diagnosed with obstructive sleep apnea (n = 33). CONCLUSION: The results highlight the promise of an interdisciplinary collaboration between dedicated a CRF clinic and sleep clinic to conduct effective assessments to identify treatable CRF and sleep disorders.

Feasibility and Efficacy of Inspiratory Muscle Training in Patients with Head and Neck Cancer receiving Concurrent Chemoradiotherapy.

OBJECTIVES: Patients with head and neck cancer (HNC) undergoing concurrent chemoradiotherapy (CCRT) often experience pulmonary symptoms. This study evaluated if a 7-week inspiratory muscle training (IMT) program during CCRT is feasible, adherent, and safe in patients with HNC. This study also evaluated the effect of IMT on diaphragm thickness, mobility, and cardiorespiratory parameters in patients with HNC receiving CCRT. METHODS: Ten participants with advanced stage HNC receiving CCRT were recruited for the study. Feasibility, adherence, and safety of the intervention were the primary outcomes. Changes in diaphragm thickness and mobility, maximal inspiratory pressure, maximal expiratory pressure, forced vital capacity, forced expiratory volume in first second and functional capacity using 6-MWT were measured at baseline and post 7 weeks of CCRT. IMT was performed at one session per day for 5 days a week for 7 weeks. Eight sets of two minutes of inspiratory manoeuvres with one minute rest period between them with intensity of 40% MIP were given. RESULTS: Ten participants  were included in this study out of the 13 patients screened, indicating the feasibility to be 76.9%. Participants completed a total of 260 training sessions out of the 350 planned sessions denoting the adherence level as 74%. Diaphragm thickness and MEP remained significantly unchanged while significant decline was seen in diaphragm mobility, MIP,FVC, FEV1 and 6-MWD at the end of 7 weeks. No adverse events were reported following the intervention. CONCLUSION: Inspiratory muscle training did not show significant effect on the diaphragm thickness, mobility, and cardiorespiratory parameters; however, it was feasible, adherent, and safe in patients with HNC receiving CCRT.

Evaluation and Management of Sleep and Circadian Rhythm Disturbance in Cancer.

OPINION STATEMENT: Sleep and circadian rhythm disturbance are among the most commonly experienced symptoms in patients with cancer. These disturbances occur throughout the spectrum of cancer care from diagnosis, treatment, and long into survivorship. The pathogenesis of these symptoms and disturbances is based on common inflammatory pathways related to cancer and its' treatments. The evaluation of sleep and circadian disorders requires an understanding of how these symptoms cluster with other cancer-related symptoms and potentiate each other. A thorough evaluation of these symptoms and disorders utilizing validated diagnostic tools, directed review of clinical information, and diagnostic testing is recommended. Treatment of sleep and circadian disturbance in cancer patients should be based on the findings of a detailed evaluation, including specific treatment of primary sleep and circadian disorders, and utilize integrative and personalised management of cancer-related symptoms through multiple pharmacologic and non-pharmacologic modalities. Recognition, evaluation, and treatment of sleep and circadian rhythm disturbance in cancer may lead to improved symptom management, quality of life, and outcomes.

Pulmonary Function Testing in Patients with Tracheostomies: Feasibility and Technical Considerations.

PURPOSE: Pulmonary function testing (PFT) in patients with tracheostomies has been perceived as difficult to perform and clinically unreliable. We studied the feasibility, quality, repeatability and clinical significance of PFT. METHODS: Patients with tracheostomies that underwent PFT from January 1, 2010 to February 29, 2012 were identified. Clinical history and PFT data were reviewed retrospectively. RESULTS: Fifty patients (88% men) were identified. Forty-seven (94%) patients were able to perform PFT. Acceptable repeatability was obtained for FVC in 39 (83%) and for FEV1 in 41 (87%). Patients with tracheostomies showed difficulty in meeting ATS end-of-test criteria; only 9 (19%) met plateau criteria and 25 (53%) had exhalation times of greater than 6 s. Obstructive pattern was observed in 30 (64%) and restrictive pattern in 9 (19%). DLCO measurements were attempted in 43 patients and satisfactorily obtained in 34 (79%). CONCLUSIONS: PFT can be performed with reliability in patients with tracheostomies, and they are useful for detecting and classifying types of lung dysfunction.

Sleep duration and type 2 diabetes risk: A prospective study in a population-based Mexican American cohort.

STUDY OBJECTIVES: The primary aim of the study was to estimate the effect of sleep duration on prospective type 2 diabetes (T2D) risk across demographic characteristics and follow-up periods, and test body mass index (BMI) as a mediator and moderator. METHODS: Data included adults (Mage = 39.0 ± 12.7 years) born in the United States or Mexico recruited from 2001 to 2012 in a Mexican American cohort study conducted in Houston, TX (n = 15,779). Participants completed self-reported questionnaires at baseline related to health, health behaviors (sleep duration, physical activity, smoking, drinking), and sociocultural factors and were followed up annually. RESULTS: Cox proportional hazard models estimated hazard ratios (HR) for the effect of sleep duration on T2D diagnosis at follow-up. Of the participants, 10.3% were diagnosed with T2D. Self-reported ≤5 hours of sleep, compared to 7-8 hours, at baseline predicted greater risk for T2D (HR = 1.32, P = .001), yet was no longer significant after adjusting for sociodemographic characteristics and BMI. Notably, those with BMI <25 kg/m2 reporting ≤5 hours of sleep were at significant risk for T2D at 3 (HR = 4.13, P = .024) and 5-year follow-up (HR = 3.73, P = .008) compared to 7-8 hours. Obesity status accounted for 31.6% and 27.3% of the variance in the association between ≤5 and 6 hours of sleep and increased T2D risk, respectively. CONCLUSIONS: Results highlighted the mediating and moderating role of BMI, and its effect on T2D risk at earlier follow-up among those without obesity. T2D prevention and control for Mexican American adults should consider the role of chronic sleep loss.

Excessive daytime sleepiness in cancer patients.

PURPOSE: Excessive daytime sleepiness (EDS) is commonly reported in patients with cancer, and it is also a cardinal feature of central disorders of hypersomnolence. Multiple sleep latency testing (MSLT) is used for objective assessment. METHODS: A retrospective review of patients with cancer history who underwent formal sleep evaluation and MSLT from 2006 to 2019 was performed. Clinical characteristics, sleep-related history, and polysomnographic data were reviewed. RESULTS: Of 16 patients with cancer history, 9 were women (56%) and median age was 49. Cancer diagnoses included 4 central nervous system, 3 breast, 1 lymphoma, and 9 other solid malignancies, and 31% were undergoing active treatment. Comorbid conditions included depression, obstructive sleep apnea, and cancer-related fatigue. Daytime fatigue (94%), daily naps (81%), and EDS (69%) were the most common symptoms. Hypnopompic and hypnogogic hallucinations, sleep paralysis, sleep attacks, and cataplexy were present in a few. Epworth Sleepiness Scale scores were consistent with EDS in 88%, and mean sleep latency was less than 8 min in 69%. Only 31% had more than 2 sleep-onset REM periods. MSLT supported diagnoses of central disorders of hypersomnolence in 5 patients (4 narcolepsy, 1 idiopathic hypersomnia); 5 hypersomnia due to a medical disorder, psychiatric condition, or medication; and 6 with normal results. Pharmacotherapy was prescribed in 5 patients. CONCLUSIONS: EDS in patients with cancer may be multifactorial, but persistent symptoms may indicate an underlying disorder of hypersomnolence. Sleep referral and polysomnography to exclude other sleep disorders may be indicated. MSLT can help confirm the diagnosis. In those with normal MSLT, further evaluation for mood disorder should be considered.

Investigating the within-person relationships between activity levels and sleep duration using Fitbit data.

The advancement of wearable technologies provides opportunities to continuously track individuals' daily activity levels and sleep patterns over extended periods of time. These data are useful in examining the reciprocal relationships between physical activity and sleep at the intrapersonal level. The purpose of this study is to test the bidirectional relationships between daily activity levels and sleep duration. The current study analyzed activity and sleep data collected from a Fitbit device as part of a 6 month employer-sponsored weight loss program. A total of 105 overweight/obese adults were included (92% female, 70% obese, and 44% Hispanic). Multilevel models were used to examine (a) whether daily active and sedentary minutes predicted that night's sleep duration and (b) whether sleep duration predicted active and sedentary minutes the following day. Potential extended effects were explored by using a 2 day average of the activity minutes/sleep duration as the predictor. No significant relationships between active minutes and sleep duration were found on a daily basis. However, having less sleep over two nights than one's usual level was associated with an increased likelihood of engaging in some physical activity the following day. There was a significant bidirectional negative association between sedentary minutes and sleep duration for both the daily and 2 day models. Data from wearable trackers, such as Fitbit, can be used to investigate the daily within-person relationship between activity levels and sleep duration. Future studies should investigate other sleep metrics that may be obtained from wearable trackers, as well as potential moderators and mediators of daily activity levels and sleep.

Complications following symptom-limited thoracentesis using suction.

BACKGROUND: Thoracentesis using suction is perceived to have increased risk of complications, including pneumothorax and re-expansion pulmonary oedema (REPO). Current guidelines recommend limiting drainage to 1.5 L to avoid REPO. Our purpose was to examine the incidence of complications with symptom-limited drainage of pleural fluid using suction and identify risk factors for REPO. METHODS: A retrospective cohort study of all adult patients who underwent symptom-limited thoracentesis using suction at our institution between January 1, 2004 and August 31, 2018 was performed, and a total of 10 344 thoracenteses were included. RESULTS: Pleural fluid ≥1.5 L was removed in 19% of the procedures. Thoracentesis was stopped due to chest discomfort (39%), complete drainage of fluid (37%) and persistent cough (13%). Pneumothorax based on chest radiography was detected in 3.98%, but only 0.28% required intervention. The incidence of REPO was 0.08%. The incidence of REPO increased with Eastern Cooperative Oncology Group performance status (ECOG PS) ≥3 compounded with ≥1.5 L (0.04-0.54%; 95% CI 0.13-2.06 L). Thoracentesis in those with ipsilateral mediastinal shift did not increase complications, but less fluid was removed (p<0.01). CONCLUSIONS: Symptom-limited thoracentesis using suction is safe even with large volumes. Pneumothorax requiring intervention and REPO are both rare. There were no increased procedural complications in those with ipsilateral mediastinal shift. REPO increased with poor ECOG PS and drainage ≥1.5 L. Symptom-limited drainage using suction without pleural manometry is safe.

Distinct Immunophenotypes of T Cells in Bronchoalveolar Lavage Fluid From Leukemia Patients With Immune Checkpoint Inhibitors-Related Pulmonary Complications.

Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) treated with immune checkpoint inhibitors (ICIs) are at risk of pneumonitis as well as pneumonia (combined henceforth as ICI-related pulmonary complications). Little is known about the cellular and molecular mechanisms underlying ICI-related pulmonary complications. We characterized lymphocytes from bronchoalveolar lavage (BAL) fluid and peripheral blood from seven AML/MDS patients with pulmonary symptoms after ICI-based therapy (ICI group) and four ICI-naïve AML/MDS patients with extracellular bacterial or fungal pneumonias (controls). BAL T cells in the ICI group were clonally expanded, and BAL IFNγ+ IL-17- CD8+ T and CXCR3+ CCR6+ Th17/Th1 cells were enriched in the ICI group. Our data suggest that these cells may play a critical role in the pathophysiology of ICI-related pulmonary complications. Understanding of these cell populations may also provide predictive and diagnostic biomarkers of ICI-related pulmonary complications, eventually enabling differentiation of pneumonitis from pneumonia in AML/MDS patients receiving ICI-based therapies.

Role of Infliximab in Immune Checkpoint Inhibitor-Induced Pneumonitis.

Introduction: Since immune checkpoint inhibitor (ICI) blockade has become standard therapy for many cancers, immune-related adverse events (irAEs) have increased. ICI-pneumonitis is infrequent but potentially fatal. In cases not responsive to corticosteroids, additional immunosuppression is recommended. Data for use of infliximab in ≥ grade 3 pneumonitis is sparse. Materials and Methods: A retrospective review of patients who received infliximab for ICI-pneumonitis from March 2016 to October 2018 was performed. Clinical characteristics were reviewed. Results: Nine patients (44% women) with ≥ grade 3 pneumonitis were included. Concurrent/prior irAEs were present in 55%. Bronchoscopy was performed in 67%. Median corticosteroid dose was 1.2 mg/kg prior to infliximab, and time from administration of corticosteroids to infliximab ranged from 2 to 34 days. Four patients improved, but the remainder died. Conclusion: We report improvement of ICI-pneumonitis with infliximab in 4 out of 9 patients in a small, retrospective cohort. Further prospective randomized controlled trials are needed.

Routine Microbiologic Studies of Pleural Fluid Specimens in Cancer Patients.

BACKGROUND: Patients who have pleural effusions typically undergo thoracentesis with examination of pleural fluid in their initial assessment. However, limited data are available on the diagnostic yield of pleural fluid bacterial cultures and fungal and acid-fast bacilli (AFB) smear and cultures in patients with cancer. METHODS: We performed a retrospective cohort study of consecutive patients who had new onset pleural effusions and underwent an initial thoracentesis. The primary outcome was diagnostic yield of pleural fluid bacterial cultures and fungal and AFB smear and cultures. RESULTS: Of 1637 patients, 1547 (94%) had evidence of active malignancy and 1359 (83%) had evidence of metastatic disease. Of the 1637 patients, 542 (33%) had high clinical suspicion of pneumonia within 14 days prior to thoracentesis. Only 14 patients (1.1%) had positive pleural fluid bacterial cultures, and only 6 of these positive cultures met the criteria for true pleural space infection. CONCLUSIONS: The incidence of positive results from pleural fluid bacterial, fungal, and AFB in cancer populations is very low. Unless there is a suspicion for infection, microbiological analysis should be ordered selectively.

Sleep and obesity: the mediating role of health behaviors among African Americans.

OBJECTIVES: To examine the role of health behaviors (eg, physical activity, sedentary behaviors, and diet) in the relationship between sleep (ie, duration and quality) and BMI among African American adults. DESIGN: A cross-sectional self-report questionnaire included questions related to health and health-related behaviors. SETTING: This study was based on data from the CHURCH study, which aimed to address cancer health disparities among church-going African Americans in Houston, TX. PARTICIPANTS: African American adults were recruited from three large community churches. The sample included a total of 1837 participants (75.2% female; mean age 48.2 ±â€¯13.7y; mean BMI 32.0 ±â€¯7.5 kg/m2). MEASUREMENTS: Linear regression models and path analyses controlling for demographic characteristics and depression estimated the associations between sleep and BMI as well as the mediating roles of health behaviors. RESULTS: The average self-reported sleep duration was 6.2 ±â€¯1.5 h/night with 61%, 35.8%, and 1.6% reporting short (≤6 h/night), normal (7-9 h/night), and long sleep (≥10 h/night), respectively. Short sleep was related to greater BMI (b = 1.37, SE = 0.38, P = .01), and the relationship was mediated by sedentary behaviors (est. = 0.08, SE = 0.04, 95% CI: 0.02, 0.17). CONCLUSIONS: Short sleep and poor quality sleep was related to poor diet and physical activity-related health behaviors, and BMI. The link between sleep and obesity is, in part, due to energy imbalance from increased sedentary behavior.

Incidence of Bleeding Complications With Flexible Bronchoscopy in Cancer Patients With Thrombocytopenia.

BACKGROUND: Bronchoscopy is a safe procedure, but current guidelines recommend transfusion for platelets <20 K/µL. Studies of bronchoscopy in thrombocytopenia are limited. OBJECTIVES: Our objective was to evaluate the incidence of bleeding with flexible bronchoscopy in those with thrombocytopenia especially those <20 K/µL. METHOD: We performed a retrospective review of all flexible bronchoscopies between June 1, 2008 and December 31, 2010. Biopsies and therapeutic procedures were excluded. The χ, Fisher exact, and Rank-sum test were conducted to evaluate associations of clinically significant bleeding. RESULTS: There were 1711 patients who underwent 2053 flexible bronchoscopies. Cancer diagnosis included hematologic (61.3%) and solid organ malignancy (34.9%). Half of the bronchoscopies had moderate to severe thrombocytopenia (<100 K/µL) with the following ranges: 14.7% with 50 to <100 K/µL, 20.6% with 20 to <50 K/µL, 10.6% with 10 to <20 K/µL, 4.1% with <10 K/µL. Platelet transfusion was given in 90.6% of those with platelets <10 K/µL and 55.5% of those with platelets 10 to <20 K/µL. The nasal route for bronchoscopy was used in 92.4%. Bleeding complication rate however was 1.1% (0.2% major) and not affected by platelets. CONCLUSION: Bronchoscopy with lavage can be safely performed without platelet transfusion in those with platelets of ≥10 K/µL. In the absence of nasal bleeding, trauma, or deformity, the nasal route can be used for bronchoscopy.

Effect of Prophylactic Fentanyl Buccal Tablet on Episodic Exertional Dyspnea: A Pilot Double-Blind Randomized Controlled Trial.

CONTEXT: Episodic dyspnea is one of the most common, debilitating, and difficult-to-treat symptoms. OBJECTIVE: We conducted a pilot study to examine the effect of prophylactic fentanyl buccal tablet (FBT) on exercise-induced dyspnea. METHODS: In this parallel, double-blind randomized placebo-controlled trial, opioid-tolerant patients were asked to complete a six-minute walk test (6MWT) at baseline and then a second 6MWT 30 minutes after a single dose of FBT (equivalent to 20-50% of their total opioid dose) or matching placebo. We compared dyspnea Numeric Rating Scale (NRS, 0-10, primary outcome), walk distance, vital signs, neurocognitive function, and adverse events between the two 6MWTs. RESULTS: Among 22 patients enrolled, 20 (91%) completed the study. FBT was associated with a significant within-arm reduction in dyspnea NRS between 0 and six minutes (mean change -2.4, 95% CI -3.5, -1.3) and respiratory rate (mean change -2.6, 95% CI -4.7, -0.4). Placebo was also associated with a nonstatistically significant decrease in dyspnea (mean change -1.1). Between-arm comparison of dyspnea scores in the second 6MWT favored FBT, albeit not statistically significant (estimate -0.25, P = 0.068). Global impression revealed more patients in the FBT group than placebo group reporting their dyspnea was at least "somewhat better" in the second 6MWT (4 of 9 vs. 0 of 11, P = 0.03). The other secondary outcomes did not differ significantly between arms. CONCLUSIONS: This study supports that prophylactic FBT was associated with a reduction of exertional dyspnea and was well tolerated. Our findings support the need for larger trials to confirm the therapeutic potential of rapid-onset opioids.